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{\f236\fdecor\fcharset0\fprq2{\*\panose 04040505050a02020702}Harrington;}{\f237\fnil\fcharset2\fprq2{\*\panose 05010101010101010101}Holidays MT;}{\f238\fdecor\fcharset0\fprq2{\*\panose 04020605060303030202}Imprint MT Shadow;}
{\f239\fdecor\fcharset0\fprq2{\*\panose 04040403040a02020202}Juice ITC;}{\f240\fnil\fcharset2\fprq2{\*\panose 05010101010101010101}Keystrokes MT;}{\f241\fdecor\fcharset0\fprq2{\*\panose 040307050d0c02020703}Kino MT;}
{\f242\froman\fcharset0\fprq2{\*\panose 020a0a07050505020404}Wide Latin;}{\f243\fnil\fcharset0\fprq2{\*\panose 00000000000000000000}Lucida Blackletter;}{\f244\froman\fcharset0\fprq2{\*\panose 02040602050505020304}Lucida Bright;}
{\f245\fscript\fcharset0\fprq2{\*\panose 03010101010101010101}Lucida Calligraphy;}{\f246\froman\fcharset0\fprq2{\*\panose 02060602050505020204}Lucida Fax;}{\f247\fscript\fcharset0\fprq2{\*\panose 03010101010101010101}Lucida Handwriting;}
{\f248\fmodern\fcharset0\fprq1{\*\panose 020b0509030504030204}Lucida Sans Typewriter;}{\f249\fswiss\fcharset0\fprq2{\*\panose 020e0502030308020204}Maiandra GD;}{\f250\froman\fcharset0\fprq2{\*\panose 00050102010706020507}Map Symbols;}
{\f251\fscript\fcharset238\fprq2{\*\panose 03020702040402020504}Marigold;}{\f252\fnil\fcharset0\fprq2{\*\panose 00000000000000000000}Marquee Engraved;}{\f253\fdecor\fcharset0\fprq2{\*\panose 04040403030d02020704}Matisse ITC;}
{\f254\fscript\fcharset0\fprq2{\*\panose 03020802060602070202}Matura MT Script Capitals;}{\f255\fnil\fcharset0\fprq2{\*\panose 00000000000000000000}Mead Bold;}{\f256\fnil\fcharset0\fprq2{\*\panose 01010101010101010101}Mercurius Script MT Bold;}
{\f257\fscript\fcharset0\fprq2{\*\panose 03090702030407020403}Mistral;}{\f258\froman\fcharset0\fprq2{\*\panose 02070704070505020303}Modern No. 20;}{\f259\fnil\fcharset2\fprq2{\*\panose 01010601010101010101}Monotype Sorts;}
{\f260\fswiss\fcharset0\fprq2{\*\panose 020b0504020203020204}News Gothic MT;}{\f261\fmodern\fcharset0\fprq2{\*\panose 02010509020102010303}OCR A Extended;}{\f262\fdecor\fcharset0\fprq2{\*\panose 04050602080702020203}Onyx;}
{\f263\fnil\fcharset2\fprq2{\*\panose 05000000000000000000}MS Outlook;}{\f264\fnil\fcharset2\fprq2{\*\panose 05010101010101010101}Parties MT;}{\f265\froman\fcharset0\fprq2{\*\panose 02020502060401020303}Perpetua;}
{\f266\froman\fcharset0\fprq2{\*\panose 02020502060505020804}Perpetua Titling MT;}{\f267\fswiss\fcharset0\fprq2{\*\panose 020b0606030402050204}Placard Condensed;}{\f268\fdecor\fcharset0\fprq2{\*\panose 040506030a0602020202}Playbill;}
{\f269\fdecor\fcharset0\fprq2{\*\panose 040c0101020201010102}Ransom;}{\f270\froman\fcharset0\fprq2{\*\panose 02060603050405020104}Rockwell Condensed;}{\f271\froman\fcharset0\fprq2{\*\panose 02060603020205020403}Rockwell;}
{\f272\froman\fcharset0\fprq2{\*\panose 02060903040505020403}Rockwell Extra Bold;}{\f273\fnil\fcharset2\fprq2{\*\panose 05010101010101010101}Signs MT;}{\f274\fdecor\fcharset0\fprq2{\*\panose 04040a07060a02020202}Snap ITC;}
{\f275\fnil\fcharset2\fprq2{\*\panose 05010101010101010101}Sports Two MT;}{\f276\fnil\fcharset2\fprq2{\*\panose 05010101010101010101}Sports Three MT;}{\f277\fdecor\fcharset0\fprq2{\*\panose 040409050d0802020404}Stencil;}
{\f278\fdecor\fcharset0\fprq2{\*\panose 04020404030d07020202}Tempus Sans ITC;}{\f279\fnil\fcharset2\fprq2{\*\panose 05010101010101010101}Transport MT;}{\f280\fmodern\fcharset0\fprq1{\*\panose 020b0609020202020204}Monospac821 DL;}
{\f281\fmodern\fcharset0\fprq1{\*\panose 020b0609020202090204}Monospac821 BT;}{\f282\fnil\fcharset0\fprq2{\*\panose 00000000000000000000}Ultra Shadow;}{\f283\fnil\fcharset2\fprq2{\*\panose 05010101010101010101}Vacation MT;}
{\f284\fscript\fcharset0\fprq2{\*\panose 03070502030502020203}Viner Hand ITC;}{\f285\froman\fcharset0\fprq0{\*\panose 00000000000000000000}TimesNewRomanPSMT;}{\f286\froman\fcharset0\fprq0{\*\panose 00000000000000000000}Goudy;}
{\f287\froman\fcharset0\fprq0{\*\panose 00000000000000000000}Minion-Italic;}{\f288\froman\fcharset238\fprq2 Times New Roman CE;}{\f289\froman\fcharset204\fprq2 Times New Roman Cyr;}{\f291\froman\fcharset161\fprq2 Times New Roman Greek;}
{\f292\froman\fcharset162\fprq2 Times New Roman Tur;}{\f293\froman\fcharset177\fprq2 Times New Roman (Hebrew);}{\f294\froman\fcharset178\fprq2 Times New Roman (Arabic);}{\f295\froman\fcharset186\fprq2 Times New Roman Baltic;}
{\f296\froman\fcharset163\fprq2 Times New Roman (Vietnamese);}{\f298\fswiss\fcharset238\fprq2 Arial CE;}{\f299\fswiss\fcharset204\fprq2 Arial Cyr;}{\f301\fswiss\fcharset161\fprq2 Arial Greek;}{\f302\fswiss\fcharset162\fprq2 Arial Tur;}
{\f303\fswiss\fcharset177\fprq2 Arial (Hebrew);}{\f304\fswiss\fcharset178\fprq2 Arial (Arabic);}{\f305\fswiss\fcharset186\fprq2 Arial Baltic;}{\f306\fswiss\fcharset163\fprq2 Arial (Vietnamese);}{\f308\fmodern\fcharset238\fprq1 Courier New CE;}
{\f309\fmodern\fcharset204\fprq1 Courier New Cyr;}{\f311\fmodern\fcharset161\fprq1 Courier New Greek;}{\f312\fmodern\fcharset162\fprq1 Courier New Tur;}{\f313\fmodern\fcharset177\fprq1 Courier New (Hebrew);}
{\f314\fmodern\fcharset178\fprq1 Courier New (Arabic);}{\f315\fmodern\fcharset186\fprq1 Courier New Baltic;}{\f316\fmodern\fcharset163\fprq1 Courier New (Vietnamese);}
{\f400\fmodern\fcharset0\fprq1 MS Mincho Western{\*\falt \'82\'6c\'82\'72 \'96\'be\'92\'a9};}{\f398\fmodern\fcharset238\fprq1 MS Mincho CE{\*\falt \'82\'6c\'82\'72 \'96\'be\'92\'a9};}
{\f399\fmodern\fcharset204\fprq1 MS Mincho Cyr{\*\falt \'82\'6c\'82\'72 \'96\'be\'92\'a9};}{\f401\fmodern\fcharset161\fprq1 MS Mincho Greek{\*\falt \'82\'6c\'82\'72 \'96\'be\'92\'a9};}
{\f402\fmodern\fcharset162\fprq1 MS Mincho Tur{\*\falt \'82\'6c\'82\'72 \'96\'be\'92\'a9};}{\f405\fmodern\fcharset186\fprq1 MS Mincho Baltic{\*\falt \'82\'6c\'82\'72 \'96\'be\'92\'a9};}
{\f410\froman\fcharset0\fprq2 Batang Western{\*\falt \'b9\'d9\'c5\'c1};}{\f408\froman\fcharset238\fprq2 Batang CE{\*\falt \'b9\'d9\'c5\'c1};}{\f409\froman\fcharset204\fprq2 Batang Cyr{\*\falt \'b9\'d9\'c5\'c1};}
{\f411\froman\fcharset161\fprq2 Batang Greek{\*\falt \'b9\'d9\'c5\'c1};}{\f412\froman\fcharset162\fprq2 Batang Tur{\*\falt \'b9\'d9\'c5\'c1};}{\f415\froman\fcharset186\fprq2 Batang Baltic{\*\falt \'b9\'d9\'c5\'c1};}
{\f420\fnil\fcharset0\fprq2 SimSun Western{\*\falt \'cb\'ce\'cc\'e5};}{\f430\froman\fcharset0\fprq2 PMingLiU Western{\*\falt \'b7\'73\'b2\'d3\'a9\'fa\'c5\'e9};}
{\f440\fmodern\fcharset0\fprq1 MS Gothic Western{\*\falt \'82\'6c\'82\'72 \'83\'53\'83\'56\'83\'62\'83\'4e};}{\f438\fmodern\fcharset238\fprq1 MS Gothic CE{\*\falt \'82\'6c\'82\'72 \'83\'53\'83\'56\'83\'62\'83\'4e};}
{\f439\fmodern\fcharset204\fprq1 MS Gothic Cyr{\*\falt \'82\'6c\'82\'72 \'83\'53\'83\'56\'83\'62\'83\'4e};}{\f441\fmodern\fcharset161\fprq1 MS Gothic Greek{\*\falt \'82\'6c\'82\'72 \'83\'53\'83\'56\'83\'62\'83\'4e};}
{\f442\fmodern\fcharset162\fprq1 MS Gothic Tur{\*\falt \'82\'6c\'82\'72 \'83\'53\'83\'56\'83\'62\'83\'4e};}{\f445\fmodern\fcharset186\fprq1 MS Gothic Baltic{\*\falt \'82\'6c\'82\'72 \'83\'53\'83\'56\'83\'62\'83\'4e};}
{\f450\fswiss\fcharset0\fprq2 Dotum Western{\*\falt \'b5\'b8\'bf\'f2};}{\f448\fswiss\fcharset238\fprq2 Dotum CE{\*\falt \'b5\'b8\'bf\'f2};}{\f449\fswiss\fcharset204\fprq2 Dotum Cyr{\*\falt \'b5\'b8\'bf\'f2};}
{\f451\fswiss\fcharset161\fprq2 Dotum Greek{\*\falt \'b5\'b8\'bf\'f2};}{\f452\fswiss\fcharset162\fprq2 Dotum Tur{\*\falt \'b5\'b8\'bf\'f2};}{\f455\fswiss\fcharset186\fprq2 Dotum Baltic{\*\falt \'b5\'b8\'bf\'f2};}
{\f470\fmodern\fcharset0\fprq1 MingLiU Western{\*\falt \'b2\'d3\'a9\'fa\'c5\'e9};}{\f490\fswiss\fcharset0\fprq2 Gulim Western{\*\falt \'b1\'bc\'b8\'b2};}{\f488\fswiss\fcharset238\fprq2 Gulim CE{\*\falt \'b1\'bc\'b8\'b2};}
{\f489\fswiss\fcharset204\fprq2 Gulim Cyr{\*\falt \'b1\'bc\'b8\'b2};}{\f491\fswiss\fcharset161\fprq2 Gulim Greek{\*\falt \'b1\'bc\'b8\'b2};}{\f492\fswiss\fcharset162\fprq2 Gulim Tur{\*\falt \'b1\'bc\'b8\'b2};}
{\f495\fswiss\fcharset186\fprq2 Gulim Baltic{\*\falt \'b1\'bc\'b8\'b2};}{\f517\froman\fcharset222\fprq2 Angsana New (Thai);}{\f527\fswiss\fcharset222\fprq2 Cordia New (Thai);}{\f548\froman\fcharset238\fprq2 Sylfaen CE;}
{\f549\froman\fcharset204\fprq2 Sylfaen Cyr;}{\f551\froman\fcharset161\fprq2 Sylfaen Greek;}{\f552\froman\fcharset162\fprq2 Sylfaen Tur;}{\f555\froman\fcharset186\fprq2 Sylfaen Baltic;}{\f638\fswiss\fcharset238\fprq2 Tahoma CE;}
{\f639\fswiss\fcharset204\fprq2 Tahoma Cyr;}{\f641\fswiss\fcharset161\fprq2 Tahoma Greek;}{\f642\fswiss\fcharset162\fprq2 Tahoma Tur;}{\f643\fswiss\fcharset177\fprq2 Tahoma (Hebrew);}{\f644\fswiss\fcharset178\fprq2 Tahoma (Arabic);}
{\f645\fswiss\fcharset186\fprq2 Tahoma Baltic;}{\f646\fswiss\fcharset163\fprq2 Tahoma (Vietnamese);}{\f647\fswiss\fcharset222\fprq2 Tahoma (Thai);}{\f648\fswiss\fcharset238\fprq2 Verdana CE;}{\f649\fswiss\fcharset204\fprq2 Verdana Cyr;}
{\f651\fswiss\fcharset161\fprq2 Verdana Greek;}{\f652\fswiss\fcharset162\fprq2 Verdana Tur;}{\f655\fswiss\fcharset186\fprq2 Verdana Baltic;}{\f656\fswiss\fcharset163\fprq2 Verdana (Vietnamese);}{\f730\fscript\fcharset0\fprq2 Coronet;}
{\f758\fmodern\fcharset238\fprq1 Lucida Console CE;}{\f759\fmodern\fcharset204\fprq1 Lucida Console Cyr;}{\f761\fmodern\fcharset161\fprq1 Lucida Console Greek;}{\f762\fmodern\fcharset162\fprq1 Lucida Console Tur;}
{\f768\fswiss\fcharset238\fprq2 Lucida Sans Unicode CE;}{\f769\fswiss\fcharset204\fprq2 Lucida Sans Unicode Cyr;}{\f771\fswiss\fcharset161\fprq2 Lucida Sans Unicode Greek;}{\f772\fswiss\fcharset162\fprq2 Lucida Sans Unicode Tur;}
{\f773\fswiss\fcharset177\fprq2 Lucida Sans Unicode (Hebrew);}{\f778\fswiss\fcharset238\fprq2 Arial Black CE;}{\f779\fswiss\fcharset204\fprq2 Arial Black Cyr;}{\f781\fswiss\fcharset161\fprq2 Arial Black Greek;}
{\f782\fswiss\fcharset162\fprq2 Arial Black Tur;}{\f785\fswiss\fcharset186\fprq2 Arial Black Baltic;}{\f788\fscript\fcharset238\fprq2 Comic Sans MS CE;}{\f789\fscript\fcharset204\fprq2 Comic Sans MS Cyr;}
{\f791\fscript\fcharset161\fprq2 Comic Sans MS Greek;}{\f792\fscript\fcharset162\fprq2 Comic Sans MS Tur;}{\f795\fscript\fcharset186\fprq2 Comic Sans MS Baltic;}{\f798\fswiss\fcharset238\fprq2 Impact CE;}{\f799\fswiss\fcharset204\fprq2 Impact Cyr;}
{\f801\fswiss\fcharset161\fprq2 Impact Greek;}{\f802\fswiss\fcharset162\fprq2 Impact Tur;}{\f805\fswiss\fcharset186\fprq2 Impact Baltic;}{\f808\froman\fcharset238\fprq2 Georgia CE;}{\f809\froman\fcharset204\fprq2 Georgia Cyr;}
{\f811\froman\fcharset161\fprq2 Georgia Greek;}{\f812\froman\fcharset162\fprq2 Georgia Tur;}{\f815\froman\fcharset186\fprq2 Georgia Baltic;}{\f818\fswiss\fcharset238\fprq2 Franklin Gothic Medium CE;}
{\f819\fswiss\fcharset204\fprq2 Franklin Gothic Medium Cyr;}{\f821\fswiss\fcharset161\fprq2 Franklin Gothic Medium Greek;}{\f822\fswiss\fcharset162\fprq2 Franklin Gothic Medium Tur;}{\f825\fswiss\fcharset186\fprq2 Franklin Gothic Medium Baltic;}
{\f828\froman\fcharset238\fprq2 Palatino Linotype CE;}{\f829\froman\fcharset204\fprq2 Palatino Linotype Cyr;}{\f831\froman\fcharset161\fprq2 Palatino Linotype Greek;}{\f832\froman\fcharset162\fprq2 Palatino Linotype Tur;}
{\f835\froman\fcharset186\fprq2 Palatino Linotype Baltic;}{\f836\froman\fcharset163\fprq2 Palatino Linotype (Vietnamese);}{\f838\fswiss\fcharset238\fprq2 Trebuchet MS CE;}{\f839\fswiss\fcharset204\fprq2 Trebuchet MS Cyr;}
{\f841\fswiss\fcharset161\fprq2 Trebuchet MS Greek;}{\f842\fswiss\fcharset162\fprq2 Trebuchet MS Tur;}{\f845\fswiss\fcharset186\fprq2 Trebuchet MS Baltic;}{\f878\fswiss\fcharset238\fprq2 Microsoft Sans Serif CE;}
{\f879\fswiss\fcharset204\fprq2 Microsoft Sans Serif Cyr;}{\f881\fswiss\fcharset161\fprq2 Microsoft Sans Serif Greek;}{\f882\fswiss\fcharset162\fprq2 Microsoft Sans Serif Tur;}{\f883\fswiss\fcharset177\fprq2 Microsoft Sans Serif (Hebrew);}
{\f884\fswiss\fcharset178\fprq2 Microsoft Sans Serif (Arabic);}{\f885\fswiss\fcharset186\fprq2 Microsoft Sans Serif Baltic;}{\f886\fswiss\fcharset163\fprq2 Microsoft Sans Serif (Vietnamese);}{\f887\fswiss\fcharset222\fprq2 Microsoft Sans Serif (Thai);}
{\f892\fdecor\fcharset162\fprq2 Allegro BT Tur;}{\f898\fswiss\fcharset238\fprq2 AvantGarde Md BT CE;}{\f901\fswiss\fcharset161\fprq2 AvantGarde Md BT Greek;}{\f902\fswiss\fcharset162\fprq2 AvantGarde Md BT Tur;}
{\f908\fswiss\fcharset238\fprq2 AvantGarde Bk BT CE;}{\f911\fswiss\fcharset161\fprq2 AvantGarde Bk BT Greek;}{\f912\fswiss\fcharset162\fprq2 AvantGarde Bk BT Tur;}{\f918\fswiss\fcharset238\fprq2 BankGothic Md BT CE;}
{\f921\fswiss\fcharset161\fprq2 BankGothic Md BT Greek;}{\f922\fswiss\fcharset162\fprq2 BankGothic Md BT Tur;}{\f928\froman\fcharset238\fprq2 Benguiat Bk BT CE;}{\f931\froman\fcharset161\fprq2 Benguiat Bk BT Greek;}
{\f932\froman\fcharset162\fprq2 Benguiat Bk BT Tur;}{\f942\fdecor\fcharset162\fprq2 BernhardFashion BT Tur;}{\f952\froman\fcharset162\fprq2 BernhardMod BT Tur;}{\f962\fdecor\fcharset162\fprq2 Bremen Bd BT Tur;}
{\f988\fswiss\fcharset238\fprq2 CopprplGoth Bd BT CE;}{\f991\fswiss\fcharset161\fprq2 CopprplGoth Bd BT Greek;}{\f992\fswiss\fcharset162\fprq2 CopprplGoth Bd BT Tur;}{\f1012\fscript\fcharset162\fprq2 English111 Vivace BT Tur;}
{\f1022\fdecor\fcharset162\fprq2 FuturaBlack BT Tur;}{\f1032\fswiss\fcharset162\fprq2 Futura Md BT Tur;}{\f1042\fswiss\fcharset162\fprq2 Futura XBlk BT Tur;}{\f1052\fswiss\fcharset162\fprq2 Futura Lt BT Tur;}
{\f1062\fdecor\fcharset162\fprq2 GoudyHandtooled BT Tur;}{\f1072\froman\fcharset162\fprq2 GoudyOlSt BT Tur;}{\f1082\fswiss\fcharset162\fprq2 Humanst521 BT Tur;}{\f1088\fswiss\fcharset238\fprq2 Kabel Bk BT CE;}
{\f1091\fswiss\fcharset161\fprq2 Kabel Bk BT Greek;}{\f1092\fswiss\fcharset162\fprq2 Kabel Bk BT Tur;}{\f1098\fswiss\fcharset238\fprq2 Kabel Ult BT CE;}{\f1101\fswiss\fcharset161\fprq2 Kabel Ult BT Greek;}
{\f1102\fswiss\fcharset162\fprq2 Kabel Ult BT Tur;}{\f1142\fscript\fcharset162\fprq2 OzHandicraft BT Tur;}{\f1148\froman\fcharset238\fprq2 PosterBodoni BT CE;}{\f1151\froman\fcharset161\fprq2 PosterBodoni BT Greek;}
{\f1152\froman\fcharset162\fprq2 PosterBodoni BT Tur;}{\f1162\froman\fcharset162\fprq2 Serifa BT Tur;}{\f1172\froman\fcharset162\fprq2 Serifa Th BT Tur;}{\f1178\froman\fcharset238\fprq2 Souvenir Lt BT CE;}
{\f1181\froman\fcharset161\fprq2 Souvenir Lt BT Greek;}{\f1182\froman\fcharset162\fprq2 Souvenir Lt BT Tur;}{\f1192\fscript\fcharset162\fprq2 Staccato222 BT Tur;}{\f1202\fswiss\fcharset162\fprq2 Swiss911 XCm BT Tur;}
{\f1212\fscript\fcharset162\fprq2 TypoUpright BT Tur;}{\f1462\froman\fcharset162\fprq2 ZapfEllipt BT Tur;}{\f1472\fswiss\fcharset162\fprq2 Zurich Ex BT Tur;}{\f1478\fswiss\fcharset238\fprq2 Arial Narrow CE;}
{\f1479\fswiss\fcharset204\fprq2 Arial Narrow Cyr;}{\f1481\fswiss\fcharset161\fprq2 Arial Narrow Greek;}{\f1482\fswiss\fcharset162\fprq2 Arial Narrow Tur;}{\f1485\fswiss\fcharset186\fprq2 Arial Narrow Baltic;}
{\f1488\froman\fcharset238\fprq2 Book Antiqua CE;}{\f1489\froman\fcharset204\fprq2 Book Antiqua Cyr;}{\f1491\froman\fcharset161\fprq2 Book Antiqua Greek;}{\f1492\froman\fcharset162\fprq2 Book Antiqua Tur;}
{\f1495\froman\fcharset186\fprq2 Book Antiqua Baltic;}{\f1498\froman\fcharset238\fprq2 Bookman Old Style CE;}{\f1499\froman\fcharset204\fprq2 Bookman Old Style Cyr;}{\f1501\froman\fcharset161\fprq2 Bookman Old Style Greek;}
{\f1502\froman\fcharset162\fprq2 Bookman Old Style Tur;}{\f1505\froman\fcharset186\fprq2 Bookman Old Style Baltic;}{\f1508\fswiss\fcharset238\fprq2 Century Gothic CE;}{\f1509\fswiss\fcharset204\fprq2 Century Gothic Cyr;}
{\f1511\fswiss\fcharset161\fprq2 Century Gothic Greek;}{\f1512\fswiss\fcharset162\fprq2 Century Gothic Tur;}{\f1515\fswiss\fcharset186\fprq2 Century Gothic Baltic;}{\f1518\froman\fcharset238\fprq2 Garamond CE;}
{\f1519\froman\fcharset204\fprq2 Garamond Cyr;}{\f1521\froman\fcharset161\fprq2 Garamond Greek;}{\f1522\froman\fcharset162\fprq2 Garamond Tur;}{\f1525\froman\fcharset186\fprq2 Garamond Baltic;}{\f1528\fswiss\fcharset238\fprq2 Haettenschweiler CE;}
{\f1529\fswiss\fcharset204\fprq2 Haettenschweiler Cyr;}{\f1531\fswiss\fcharset161\fprq2 Haettenschweiler Greek;}{\f1532\fswiss\fcharset162\fprq2 Haettenschweiler Tur;}{\f1535\fswiss\fcharset186\fprq2 Haettenschweiler Baltic;}
{\f1538\fscript\fcharset238\fprq2 Monotype Corsiva CE;}{\f1539\fscript\fcharset204\fprq2 Monotype Corsiva Cyr;}{\f1541\fscript\fcharset161\fprq2 Monotype Corsiva Greek;}{\f1542\fscript\fcharset162\fprq2 Monotype Corsiva Tur;}
{\f1545\fscript\fcharset186\fprq2 Monotype Corsiva Baltic;}{\f1607\fswiss\fcharset222\fprq2 Browallia New (Thai);}{\f1860\fmodern\fcharset0\fprq1 @MS Mincho Western;}{\f1858\fmodern\fcharset238\fprq1 @MS Mincho CE;}
{\f1859\fmodern\fcharset204\fprq1 @MS Mincho Cyr;}{\f1861\fmodern\fcharset161\fprq1 @MS Mincho Greek;}{\f1862\fmodern\fcharset162\fprq1 @MS Mincho Tur;}{\f1865\fmodern\fcharset186\fprq1 @MS Mincho Baltic;}
{\f1870\froman\fcharset0\fprq2 MS PMincho Western;}{\f1868\froman\fcharset238\fprq2 MS PMincho CE;}{\f1869\froman\fcharset204\fprq2 MS PMincho Cyr;}{\f1871\froman\fcharset161\fprq2 MS PMincho Greek;}{\f1872\froman\fcharset162\fprq2 MS PMincho Tur;}
{\f1875\froman\fcharset186\fprq2 MS PMincho Baltic;}{\f1880\froman\fcharset0\fprq2 @MS PMincho Western;}{\f1878\froman\fcharset238\fprq2 @MS PMincho CE;}{\f1879\froman\fcharset204\fprq2 @MS PMincho Cyr;}{\f1881\froman\fcharset161\fprq2 @MS PMincho Greek;}
{\f1882\froman\fcharset162\fprq2 @MS PMincho Tur;}{\f1885\froman\fcharset186\fprq2 @MS PMincho Baltic;}{\f1890\fmodern\fcharset0\fprq1 @MS Gothic Western;}{\f1888\fmodern\fcharset238\fprq1 @MS Gothic CE;}{\f1889\fmodern\fcharset204\fprq1 @MS Gothic Cyr;}
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{\title BACKGROUND}{\author Valerie Gutmann}{\operator Computing Services}{\creatim\yr2005\mo5\dy5\hr12\min36}{\revtim\yr2005\mo5\dy5\hr12\min36}{\printim\yr2005\mo4\dy5\hr19\min8}{\version2}{\edmins1}{\nofpages98}{\nofwords21895}{\nofchars124803}
{\nofcharsws146406}{\vern16389}}\widowctrl\ftnbj\aenddoc\noxlattoyen\expshrtn\noultrlspc\dntblnsbdb\nospaceforul\formshade\horzdoc\dgmargin\dghspace120\dgvspace180\dghorigin1800\dgvorigin1440\dghshow2\dgvshow1
\jexpand\viewkind1\viewscale100\pgbrdrhead\pgbrdrfoot\splytwnine\ftnlytwnine\htmautsp\nolnhtadjtbl\useltbaln\alntblind\lytcalctblwd\lyttblrtgr\lnbrkrule\nobrkwrptbl\snaptogridincell\allowfieldendsel\wrppunct\asianbrkrule\rsidroot5990923 \fet0\sectd 
\pgnrestart\linex0\endnhere\titlepg\sectlinegrid360\sectdefaultcl\sectrsid4666048\sftnbj {\footer \pard\plain \s24\ql \li0\ri0\widctlpar\tqc\tx4320\tqr\tx8640\pvpara\phmrg\posxc\posy0\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3892126 
\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs25\insrsid4156601 
\par }\pard \s24\ql \li0\ri0\widctlpar\tqc\tx4320\tqr\tx8640\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\insrsid4156601 
\par }}{\*\pnseclvl1\pnucrm\pnstart1\pnindent720\pnhang {\pntxta .}}{\*\pnseclvl2\pnucltr\pnstart1\pnindent720\pnhang {\pntxta .}}{\*\pnseclvl3\pndec\pnstart1\pnindent720\pnhang {\pntxta .}}{\*\pnseclvl4\pnlcltr\pnstart1\pnindent720\pnhang {\pntxta )}}
{\*\pnseclvl5\pndec\pnstart1\pnindent720\pnhang {\pntxtb (}{\pntxta )}}{\*\pnseclvl6\pnlcltr\pnstart1\pnindent720\pnhang {\pntxtb (}{\pntxta )}}{\*\pnseclvl7\pnlcrm\pnstart1\pnindent720\pnhang {\pntxtb (}{\pntxta )}}{\*\pnseclvl8
\pnlcltr\pnstart1\pnindent720\pnhang {\pntxtb (}{\pntxta )}}{\*\pnseclvl9\pnlcrm\pnstart1\pnindent720\pnhang {\pntxtb (}{\pntxta )}}\pard\plain \qc \li0\ri0\sl480\slmult1
\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid4666048 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\b\fs32\insrsid4666048 
\par 
\par 
\par }\pard \qc \li0\ri0\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid4666048 {\b\fs32\insrsid4666048 A New Era in }{\b\fs32\insrsid4666048\charrsid15299609 Drug Development: }{\b\fs32\insrsid4666048 
Legal and Ethical Implications of Pharmacogenomics }{\b\fs32\insrsid4666048\charrsid15299609 
\par }\pard \qc \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid4666048 {\b\fs32\insrsid4666048\charrsid15299609 
\par }{\b\fs32\insrsid4666048 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\tqc\tx4320\tx6285\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid4666048 {\b\fs32\insrsid4666048 \tab }{\b\fs32\insrsid4666048\charrsid15299609 Valerie Gutmann}{\b\fs32\insrsid4666048 
\tab 
\par }\pard \qc \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid4666048 {\b\fs32\insrsid4666048\charrsid15299609 J.D. Candidate, 2005
\par }{\b\fs32\insrsid4666048 
\par 
\par }\pard \qc \li720\ri0\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin720\itap0\pararsid4666048 {\b\fs32\insrsid4666048 Submitted }{\b\fs32\insrsid4666048\charrsid15299609 April 2005}{\b\fs32\insrsid4666048 , }{
\b\fs32\insrsid4666048\charrsid15299609 in satisfaction of the course requirement and the third year written work requirement}{\b\fs32\insrsid4666048 
\par }\pard \ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin720\itap0\pararsid4666048 {\b\fs32\insrsid4666048 \page }{\insrsid4666048\charrsid1184873 ABSTRACT}{\insrsid4666048 :}{\b\insrsid4666048  }{\insrsid4666048 Pharmaco
genomics, the study and development of compounds according to how an individual\rquote s genes affects the body\rquote 
s response to drugs, holds enormous promise for increasing the safety and efficiency of drug development while decreasing adverse reactions and the tri
al-and-error nature of drug prescription.  However, pharmacogenomics may not be the panacea for all development and prescription problems.  This paper explores some of the obstacles to pharmacogenomic advancement including industry reluctance to pursue re
s
earch because of potentially prohibitive costs associated with developing products.  The implications pharmacogenomics has for drug research and development as well as various areas of law, such as patent law, medical liability, and insurance and discrimi
nation law, will be discussed in light of current FDA regulation and guidance and the Orphan Drug Act.  The diverse p}{\insrsid4666048\charrsid12860689 ractical, economic, legal, and ethical issues associated with genetic discoveries}{\insrsid4666048 
 within the}{\insrsid4666048\charrsid12860689  current regulatory and legal }{\insrsid4666048 regime are also considered.}{\insrsid4666048\charrsid11423499  }{\insrsid4666048 
 An ideal system will advance, rather than hinder, appropriate technological progress while protecting the rights of individuals and ensuring that they receive the best medical treatment available.  }{\b\insrsid4666048\charrsid3029798 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid4666048 {\b\insrsid4666048 
\par }\pard \qc \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid4666048 {\b\insrsid4666048 \page Table of Contents}{\b\insrsid4666048\charrsid12860689 
\par }\trowd \irow0\irowband0\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmgf\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048\charrsid13568209 INTRODUCTION}{\insrsid4666048\charrsid13568209 
\par }{\insrsid4666048 I}{\insrsid4666048\charrsid13568209 .  }{\insrsid4666048   }{\insrsid4666048\charrsid13568209 History
\par }{\insrsid4666048 II}{\insrsid4666048\charrsid13568209 .  }{\insrsid4666048  }{\insrsid4666048\charrsid13568209 Definitions
\par }{\insrsid4666048 III}{\insrsid4666048\charrsid13568209 . }{\insrsid4666048  }{\insrsid4666048\charrsid13568209 The Promise
\par }{\insrsid4666048 \tab A}{\insrsid4666048\charrsid13568209 .  Drug Development
\par }\pard \ql \fi720\li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 B.}{\insrsid4666048\charrsid13568209   Adverse Drug Reactions (ADRs)
\par }{\insrsid4666048 C}{\insrsid4666048\charrsid13568209 .  Metabolism
\par }{\insrsid4666048 D.}{\insrsid4666048\charrsid13568209   Diagnosis and Treatment 
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 IV}{\insrsid4666048\charrsid13568209 .  The Perception
\par }{\insrsid4666048 V}{\insrsid4666048\charrsid13568209 .  }{\insrsid4666048  }{\insrsid4666048\charrsid13568209 Complexity
\par }{\insrsid4666048 VI}{\insrsid4666048\charrsid13568209 .  Conclusion 
\par }{\insrsid4666048\charrsid13568209 
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048\charrsid2298633 THE SCIENCE AND PROCESS OF PHARMACOGENOMIC DRUG RESEARCH AND DEVELOPMENT}{\insrsid4666048\charrsid13568209  
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 I}{\insrsid4666048\charrsid13568209 .  }{\insrsid4666048   }{\b\insrsid4666048\charrsid9452734 The Science
\par }{\insrsid4666048 II}{\insrsid4666048\charrsid13568209 . }{\insrsid4666048  }{\insrsid4666048\charrsid13568209  }{\b\insrsid4666048\charrsid9452734 Drug Development}{\insrsid4666048\charrsid13568209 
\par }\pard \ql \fi720\li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 A}{\insrsid4666048\charrsid13568209 .  Industry Reluctance to Utilize Pharmacogenomics in its R&D
\par }{\insrsid4666048 B}{\insrsid4666048\charrsid13568209 .  Advantages of U}{\insrsid4666048 sing}{\insrsid4666048\charrsid13568209  Pharmacogenomics in Drug Development
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 \tab \tab 1}{\insrsid4666048\charrsid13568209 .  Cost-Saving Measures 
\par }\pard \ql \fi720\li720\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin720\pararsid4666048 {\insrsid4666048 2}{\insrsid4666048\charrsid13568209 .  Saving Shelved Drugs
\par }{\insrsid4666048 3}{\insrsid4666048\charrsid13568209 .  Avoiding Negative Press
\par }\pard \ql \fi720\li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 C}{\insrsid4666048\charrsid13568209 .  The Move from Public to Private Sector
\par }{\insrsid4666048 D}{\insrsid4666048\charrsid13568209 .  Private/Private and Private/Public Collaborations
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid13568209 
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048\charrsid2298633 REGULATORY AND LEGAL ISSUES ASSOCIATED WITH PHARMACOGENOMICS 
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 I}{\insrsid4666048\charrsid13568209 .  }{\insrsid4666048   }{\b\insrsid4666048\charrsid9452734 The FDA}{\insrsid4666048\charrsid13568209 

\par }\pard \ql \fi720\li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 A}{\insrsid4666048\charrsid13568209 .  The Guidance
\par }{\insrsid4666048 B}{\insrsid4666048\charrsid13568209 .  Additional Guidance 
\par }{\insrsid4666048 C}{\insrsid4666048\charrsid13568209 .  Other Possible FDA Approaches to Pharmacogenomics 
\par }\pard \ql \fi720\li720\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin720\pararsid4666048 {\insrsid4666048 1}{\insrsid4666048\charrsid13568209 .  Increased Phase IV Monitoring
\par }{\insrsid4666048 2}{\insrsid4666048\charrsid13568209 .  Off-Label Use
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 II}{\insrsid4666048\charrsid13568209 .  }{\insrsid4666048  }{\b\insrsid4666048\charrsid9452734 The Orphan Drug Act (ODA)
\par }{\insrsid4666048 III}{\insrsid4666048\charrsid13568209 .  }{\b\insrsid4666048\charrsid9452734 Implications of Patent Law for Pharmacogenomics
\par }{\insrsid4666048 \tab A}{\insrsid4666048\charrsid13568209 .  Criticism of Patent Protection
\par }{\insrsid4666048 \tab B}{\insrsid4666048\charrsid13568209 .  Arguments }{\insrsid4666048\charrsid9452734 for}{\insrsid4666048\charrsid13568209  Patent Protection and the PTO\rquote s Stance
\par }\pard \ql \fi720\li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 C}{\insrsid4666048\charrsid13568209 .  Exceptions to the Patent Law
\par }{\insrsid4666048 D}{\insrsid4666048\charrsid13568209 .  Alternatives to Patent Protection
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 IV}{\insrsid4666048\charrsid13568209 .  }{\b\insrsid4666048\charrsid9452734 Legal Liability}{\insrsid4666048\charrsid13568209  
\par }\pard \ql \fi720\li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 A}{\insrsid4666048\charrsid13568209 .  Liability Against Physicians 
\par }\pard \ql \li1440\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin1440\pararsid4666048 {\insrsid4666048 1}{\insrsid4666048\charrsid13568209 .  Liability for Not Utilizing Pharmacogenomic Discoveries in the Practice of Medicine
\par }{\insrsid4666048 2}{\insrsid4666048\charrsid13568209 .  Liability for Using Pharmacogenomic Discoveries in the Practice of Medicine
\par }\pard \ql \li1440\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin1440\pararsid4666048 {\insrsid4666048 3}{\insrsid4666048\charrsid13568209 .  Off-Label Prescription
\par }{\insrsid4666048 4}{\insrsid4666048\charrsid13568209 .  Education of Physicians 
\par }\pard \ql \fi720\li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 B}{\insrsid4666048\charrsid13568209 .  Liability Against Pharmaceutical Companies
\par }\pard \ql \fi720\li720\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin720\pararsid4666048 {\insrsid4666048 1.}{\insrsid4666048\charrsid13568209   Direct-to-Consumer Advertising 
\par }\pard \ql \li720\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin720\pararsid4666048 {\insrsid4666048 C.}{\insrsid4666048\charrsid13568209   Causation
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid13568209 
\par }{\b\insrsid4666048\charrsid2298633 ETHICAL ISSUES}{\insrsid4666048\charrsid13568209 
\par }{\insrsid4666048 I}{\insrsid4666048\charrsid13568209 . }{\insrsid4666048   }{\insrsid4666048\charrsid13568209  }{\b\insrsid4666048\charrsid9452734 Insurance }{\insrsid4666048\charrsid13568209 
\par }{\insrsid4666048 II}{\insrsid4666048\charrsid13568209 .  }{\insrsid4666048  }{\b\insrsid4666048\charrsid9452734 Privacy/Genetic Tests}{\insrsid4666048\charrsid13568209 
\par }{\insrsid4666048 III}{\insrsid4666048\charrsid13568209 .  }{\b\insrsid4666048\charrsid9452734 Race/Ethnicity}{\insrsid4666048\charrsid13568209 
\par }\pard \ql \fi720\li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 A}{\insrsid4666048\charrsid13568209 .  Dispelling Historical Categories
\par }{\insrsid4666048 B.}{\insrsid4666048\charrsid13568209   Reinforcing Racial and Ethnic Categorizations
\par }{\insrsid4666048 C}{\insrsid4666048\charrsid13568209 .  Usefulness of Race/Ethnicity in Pharmacogenomic Research
\par }{\insrsid4666048 D}{\insrsid4666048\charrsid13568209 .  Access to Pharmacogenomic Discoveries
\par }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid13568209 
\par }{\b\insrsid4666048\charrsid2298633 CONCLUSION}{\insrsid4666048\charrsid13568209 
\par }{\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {
\b\insrsid4666048 \trowd \irow0\irowband0\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmgf\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row 
}\trowd \irow1\irowband1\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 1\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow1\irowband1\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 2\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow2\irowband2
\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 4\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow3\irowband3\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 4\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow4\irowband4
\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 6\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow5\irowband5\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 8\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow6\irowband6
\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 9\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow7\irowband7\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 12\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow8\irowband8
\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 13\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow9\irowband9\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 16\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow10\irowband10\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow11\irowband11\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow12\irowband12
\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow13\irowband13\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 18\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow14\irowband14\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 21\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow15\irowband15\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 21\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow16\irowband16\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 24\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow17\irowband17\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 24\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow18\irowband18\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 29\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow19\irowband19\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 32\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow20\irowband20\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 32\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow21\irowband21\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 34\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow22\irowband22\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow23\irowband23\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow24\irowband24
\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow25\irowband25\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 38\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow26\irowband26\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 41\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow27\irowband27\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 50\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow28\irowband28\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 51\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow29\irowband29\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 54\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow30\irowband30\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 56\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow31\irowband31\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 57\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow32\irowband32\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 63\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow33\irowband33\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 64\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow34\irowband34\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 66\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow35\irowband35\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 68\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow36\irowband36\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 68\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow37\irowband37\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 69\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow38\irowband38\ts35\trgaph108\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row 
}\trowd \irow39\irowband39\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 70\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow39\irowband39\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 
\clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 71\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow40\irowband40\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow41\irowband41\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 
\clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 72\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow42\irowband42\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow43\irowband43\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 
\clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 75}{\insrsid4666048\charrsid9452734 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow44\irowband44\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 75\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow45\irowband45\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 
\clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 7}{\insrsid4666048 8}{\insrsid4666048\charrsid9452734 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow46\irowband46\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 80}{\insrsid4666048\charrsid9452734 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow47\irowband47\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 8}{
\insrsid4666048 1}{\insrsid4666048\charrsid9452734 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow48\irowband48\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl
\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow49\irowband49\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 
\clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow50\irowband50
\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048 83}{
\insrsid4666048\charrsid9452734 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow51\irowband51\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb
\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol 
\clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr
\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 8}{\insrsid4666048 4}{\insrsid4666048\charrsid9452734 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow52\irowband52\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 86\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow53\irowband53\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 88\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow54\irowband54\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 
\clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 88\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow55\irowband55\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 89\cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow56\irowband56\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 
\clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 91\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow57\irowband57\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 \cell 
}\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow58\irowband58\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 
\clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\insrsid4666048\charrsid9452734 93\cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 
\trowd \irow59\irowband59\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow60\irowband60\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow61\irowband61
\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 
\clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow62\irowband62\ts35\trgaph108\trrh219\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 
\cltxlrtb\clftsWidth3\clwWidth1368\clshdrawnil \cellx8748\row }\trowd \irow63\irowband63\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv
\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl
\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow63\irowband63\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt
\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {
\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow64\irowband64\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 
\trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol 
\clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow65\irowband65
\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb
\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow66\irowband66\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt
\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {
\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow67\irowband67\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 
\trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol 
\clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow68\irowband68
\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb
\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow69\irowband69\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt
\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {
\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow70\irowband70\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 
\trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol 
\clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow71\irowband71
\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb
\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow72\irowband72\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt
\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {
\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow73\irowband73\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 
\trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol 
\clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow74\irowband74
\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb
\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow75\irowband75\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh
\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt
\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {
\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow76\irowband76\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 
\trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol 
\clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow77\irowband77
\ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 \trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 
\trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb
\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0\pararsid4666048 {\b\insrsid4666048 \cell }\pard 
\ql \li0\ri0\widctlpar\intbl\aspalpha\aspnum\faauto\adjustright\rin0\lin0 {\b\insrsid4666048 \trowd \irow78\irowband78\lastrow \ts35\trgaph108\trrh276\trleft-108\trbrdrt\brdrs\brdrw10 \trbrdrl\brdrs\brdrw10 \trbrdrb\brdrs\brdrw10 \trbrdrr\brdrs\brdrw10 
\trbrdrh\brdrs\brdrw10 \trbrdrv\brdrs\brdrw10 \trftsWidth1\trftsWidthB3\trftsWidthA3\trwWidthA1368\trautofit1\trpaddl108\trpaddr108\trpaddfl3\trpaddft3\trpaddfb3\trpaddfr3\tbllkhdrrows\tbllklastrow\tbllkhdrcols\tbllklastcol \clvmrg\clvertalt\clbrdrt
\brdrs\brdrw10 \clbrdrl\brdrs\brdrw10 \clbrdrb\brdrs\brdrw10 \clbrdrr\brdrs\brdrw10 \cltxlrtb\clftsWidth3\clwWidth7488\clshdrawnil \cellx7380\row }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid4666048 {
\b\insrsid4666048\charrsid12860689 
\par 
\par }\pard \ql \fi720\li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid4666048 {\b\insrsid4666048\charrsid12860689 
\par }\pard \ql \li1440\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin1440\itap0\pararsid4666048 {\b\insrsid4666048 
\par }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid4666048 {\insrsid4666048 
\par }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid14043728 {\b\insrsid4666048 \sect }\sectd \pgnrestart\linex0\endnhere\titlepg\sectlinegrid360\sectdefaultcl\sectrsid4666048\sftnbj {\footer \pard\plain 
\s24\ql \li0\ri0\widctlpar\tqc\tx4320\tqr\tx8640\pvpara\phmrg\posxc\posy0\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3892126 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs25\insrsid4666048 
\par }\pard \s24\ql \li0\ri0\widctlpar\tqc\tx4320\tqr\tx8640\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\insrsid4666048\charrsid4666048 \tab - }{\field{\*\fldinst {\insrsid4666048\charrsid4666048  PAGE }}{\fldrslt {
\lang1024\langfe1024\noproof\insrsid1670862 94}}}{\insrsid4666048\charrsid4666048  -}{\insrsid4666048 
\par }}\pard\plain \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid14043728 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\b\insrsid12857176\charrsid12860689 INTRODUCTION}{\b\insrsid14043728 
\par }{\b\insrsid14043728\charrsid14043728 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid605740\charrsid12860689 The last few decades have witnessed }{\insrsid3636821 remarkable}{\insrsid605740\charrsid12860689  advancement
}{\insrsid5863533 s}{\insrsid605740\charrsid12860689  in the fields of genetics and genomics.  The }{\insrsid10101694 highlight}{\insrsid605740\charrsid12860689  was the successful completion}{\insrsid5716799\charrsid12860689  of the }{
\insrsid6040410\charrsid12860689 map of the human genome in 2003.  }{\insrsid12857176\charrsid12860689 With this achievement came scientific possibilities that}{\insrsid10101694 , only a few decades earlier,}{\insrsid12857176\charrsid12860689 
 seemed more \'93science fiction\'94 }{\insrsid10101694 than reality}{\insrsid12857176\charrsid12860689 .  One of these developments, pharmacogenomics, is hailed by man}{\insrsid8213273 y}{\insrsid12857176\charrsid12860689  as }{\insrsid8213273 a}{
\insrsid12857176\charrsid12860689  panacea for problems associated with }{\insrsid8213273 pharmaceutical }{\insrsid12857176\charrsid12860689 drug}{\insrsid8213273  use and}{\insrsid12857176\charrsid12860689  development.  It promises to allow
 physicians to tailor a patient\rquote s prescription according to his or her genetic profile, reducing painful and sometimes deadly side effects, ensuring }{\insrsid7149582\charrsid12860689 appropriate}{\insrsid12857176\charrsid12860689 
 dosage decisions, and targeting specific disease pathways.  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid12857176\charrsid12860689 However, pharmacogenomics is unlikely to fulfill the }{\insrsid7149582\charrsid12860689 promise}{
\insrsid12857176\charrsid12860689  of providing \'93miracle }{\insrsid7149582\charrsid12860689 drugs}{\insrsid12857176\charrsid12860689 \'94 to all.  The pharmaceutical industry may be }{\insrsid7149582\charrsid12860689 reluctant}{
\insrsid12857176\charrsid12860689  to pursue pharmacogenomic developments}{\insrsid15607780  because of the costs associated with developing products for a segmented patient population}{\insrsid12857176\charrsid12860689 , and the curren
t regulatory and legal regime may be ill-}{\insrsid7149582\charrsid12860689 prepared}{\insrsid12857176\charrsid12860689  to deal with the practical, economic, legal, and }{\insrsid7149582\charrsid12860689 ethical issues}{\insrsid12857176\charrsid12860689 
 associated with genetic }{\insrsid7149582\charrsid12860689 discoveries}{\insrsid12857176\charrsid12860689 .  This paper }{\insrsid11430146 e}{\insrsid12857176\charrsid12860689 xplore}{\insrsid11430146 s}{\insrsid12857176\charrsid12860689 
 many dimensions }{\insrsid15607780 of}{\insrsid12857176\charrsid12860689  the legal and ethical problems }{\insrsid7149582\charrsid12860689 associated}{\insrsid15607780  with pharmacogenomic}{\insrsid12857176\charrsid12860689  }{
\insrsid7149582\charrsid12860689 discoveries}{\insrsid12857176\charrsid12860689  and consider}{\insrsid11430146 s}{\insrsid12857176\charrsid12860689  the future of this exciting and complex field.
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 I}{\b\insrsid11944523 .  }{\b\insrsid12857176\charrsid12860689 History
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid2848337\charrsid12860689 The history of pha}{\insrsid15607780 rmacogenetic}{\insrsid2848337\charrsid12860689 s}{\insrsid15607780 
 and pharmacogenomics}{\insrsid2848337\charrsid12860689  started in the early twentieth century with a scientific concentration on Mendelian effects on drug response}{\insrsid1913448 .}{\cs16\super\insrsid2848337\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 David B. Goldstein, Sarah K. Tate, and Sanjay M. Sisodiya, }{\i\insrsid4156601\charrsid11755622 Pharmacogenetics Goes Genomic}{\insrsid4156601\charrsid11755622 , 4 Nature Reviews 937 (2003) (Gregor Mendel \'93discovered\'94
 the laws of genetics in 1865 with his famous studies of the heredity of traits in pea pod plants.  His discoveries were generally ignored until the next century, when they were \'93rediscovered\'94 and applied over a number of disciplines).}}}{
\insrsid15606905  }{\insrsid1913448   The}{\insrsid15606905  }{\insrsid5587316\charrsid12860689 concept}{\insrsid4146235\charrsid12860689  of pharmacogenetics was first articulated by Arno Motulsky in 1957}{\insrsid15479969\charrsid12860689 , who a}{
\insrsid4146235\charrsid12860689 sserted that \'93otherwise innocuous genetic traits\'94 might underlie variation among individuals in drug response, based on individual differences in enzyme structure and function.}{
\cs16\super\insrsid15479969\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 I}{\insrsid4156601\charrsid4935731 d}{\i\insrsid4156601 .}{\insrsid4156601\charrsid11755622  (}{\i\insrsid4156601\charrsid11755622 citing }{
\insrsid4156601 A. Motulsky,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Drug }{\i\insrsid4156601 R}{\i\insrsid4156601\charrsid11755622 eactions, Enzymes and Biochemical Genetics}{\insrsid4156601\charrsid11755622 , 165 }{
\insrsid4156601\charrsid11755622 JAMA}{\insrsid4156601\charrsid11755622 , 835-837 (1957)).}}}{\insrsid15479969\charrsid12860689  }{\insrsid15552539\charrsid12860689  }{\insrsid3023423\charrsid12860689 
Technically, pharmacogenetics precedes pharmacogenomics, the former }{\insrsid2848337\charrsid12860689 discipline }{\insrsid3023423\charrsid12860689 coined in the 1950\rquote s when scientists became aware of the relationship between }{
\insrsid2848337\charrsid12860689 genetics }{\insrsid3023423\charrsid12860689 and drug therapy.}{\cs16\super\insrsid3023423\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  PL Bullock, }{
\i\insrsid4156601\charrsid11755622 Pharmacogenetics and its Impact on Drug Development}{\insrsid4156601\charrsid11755622 , 11 Drug Benefit Trends, 1: 53 (1999).}}}{\insrsid3023423\charrsid12860689   }{\insrsid3023423\charrsid12860689 
As early as 1979, it was suggeste}{\insrsid4720537 d that as many as one in every hundred}{\insrsid3023423\charrsid12860689  bases within the genome exhibit}{\insrsid2848337\charrsid12860689 s}{\insrsid3023423\charrsid12860689  variance.}{
\cs16\super\insrsid3023423\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  David Housman and Fred Ledley, }{\i\insrsid4156601\charrsid11755622 Why Pharmacogenomics?  Why Now? }{\insrsid4156601\charrsid11755622 
16 Nature Biotechnology 1, 2 (1998) (}{\i\insrsid4156601\charrsid11755622 citing }{\insrsid4156601\charrsid11755622 A.J. Jeffreys, 18 }{\insrsid4156601\charrsid11755622 Cell}{\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid11755622 1, }{
\insrsid4156601\charrsid11755622 1 (1979)).}}}{\insrsid3023423\charrsid12860689  }{\insrsid2848337\charrsid12860689  Although t}{\insrsid3023423\charrsid12860689 he field of pharmacogenetics is }{\insrsid2848337\charrsid12860689 relatively }{
\insrsid3023423\charrsid12860689 well-established}{\insrsid2848337\charrsid12860689 ,}{\insrsid3023423\charrsid12860689  it }{\insrsid2848337\charrsid12860689 ha}{\insrsid3023423\charrsid12860689 s only recently }{\insrsid2848337\charrsid12860689 had}{
\insrsid3023423\charrsid12860689  a significant impact on the pharmaceutical industry.}{\cs16\super\insrsid3023423\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid3023423\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 II}{\b\insrsid11944523 .  }{\b\insrsid7633072\charrsid12860689 Definitions
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid4720537 T}{\insrsid13923666\charrsid12860689 he Human Genome Project and associated research}{\insrsid4720537  have demonstrated}{
\insrsid13923666\charrsid12860689  that all human beings share 99.9% of their DNA.  Pharmacogenomics, and other genetic disc}{\insrsid4720537 iplines}{\insrsid13923666\charrsid12860689 , focus on the 0.1% d}{\insrsid2848337\charrsid12860689 
ifference between individuals.  First, it is important }{\insrsid4720537 to}{\insrsid2848337\charrsid12860689  }{\insrsid15955935 ensure}{\insrsid2848337\charrsid12860689  that p}{\insrsid2848337\charrsid12860689 harmacogenomic}{\insrsid4720537 s }{
\insrsid2848337\charrsid12860689 not be confused with predisposition or predictive testing, the latter of which \'93provide statistical inferences concerning the risk of a disease or its prognosis.\'94}{\cs16\super\insrsid2848337\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid13923666\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\i\insrsid13311197\charrsid4720537 Genomics}{\insrsid13311197\charrsid12860689  can be defined as}{\insrsid16062832\charrsid12860689 
 the study of the function and structure of genes and gene products.}{\cs16\super\insrsid16062832\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Michael J. Meurer, }{\i\insrsid4156601\charrsid11755622 
Pharmacogenomics, Genetic Tests, and Patent-Based Incentives}{\insrsid4156601\charrsid11755622 , Boston Univ. School of Law Working Paper (2003), }{\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid15872827 
http://www.bu.edu/law/faculty/papers}{\insrsid4156601\charrsid11755622 .}}}{\insrsid16062832\charrsid12860689  }{\insrsid13311197\charrsid12860689  }{\i\insrsid9583942\charrsid4720537 Pharmacogenomics,}{\insrsid9583942\charrsid12860689  a f
ield within genomics, can be defined as the }{\insrsid15955935 development of drugs according to a }{\insrsid9583942\charrsid12860689 characterization of an individual\rquote s genetic makeup}{\insrsid4720537 , focusing on one\rquote s}{
\insrsid9583942\charrsid12860689  susceptibility to disease and response to drug therapies.  More specifically}{\insrsid2848337\charrsid12860689  within pharmacogenomics}{\insrsid9583942\charrsid12860689 , }{\i\insrsid9583942\charrsid4720537 phar
macokinetics}{\insrsid9583942\charrsid12860689  is defined as the study of the variation in drug metabolism, while }{\i\insrsid9583942\charrsid4720537 pharmacodynamics}{\insrsid9583942\charrsid12860689  is the mechanism of a drug on its target.}{
\cs16\super\insrsid9583942\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Andrew Marshall, }{\i\insrsid4156601\charrsid11755622 Laying the Foundation for Personalized Medicine, }{\insrsid4156601\charrsid11755622 16 Nature Bio
tech. 1 Supp. 6 (1998).}}}{\insrsid9583942\charrsid12860689   However, throughout the paper I will refer to pharmacogenomics generally. 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid1769622 {\insrsid14968440\charrsid12860689 Although}{\insrsid6488845\charrsid12860689  the terms }{\insrsid4720537 pharmacogenetics and pharmacogenomics }{
\insrsid6488845\charrsid12860689 are often used interchangeably, it is helpful to understand the distinction.  }{\insrsid873026\charrsid12860689 Jai Shah }{\insrsid9583942\charrsid12860689 provides a usef}{\insrsid5337727 
ul, and according to the author, relevant}{\insrsid9583942\charrsid12860689  distinction between pharmacogenetics and pharmacogenomics.}{\insrsid14892720  }{\insrsid14892720\charrsid12860689  }{\insrsid9583942\charrsid12860689 
Shah explains that pharmacogenetics only applies to the reaction of genetically diverse patients to a particular medicine (\'93one drug across many genomes\'94)}{\insrsid15823965\charrsid12860689 , while p}{\insrsid9583942\charrsid12860689 
harmacogenomics encompasses pharmac}{\insrsid873026\charrsid12860689 ogenetics, but also applies at }{\insrsid9583942\charrsid12860689 earlier phase}{\insrsid873026\charrsid12860689 s}{\insrsid9583942\charrsid12860689  of drug development, }{
\insrsid873026\charrsid12860689 whe}{\insrsid1769622 n }{\insrsid873026\charrsid12860689 it is}{\insrsid9583942\charrsid12860689  determine}{\insrsid873026\charrsid12860689 d}{\insrsid9583942\charrsid12860689  wh}{\insrsid873026\charrsid12860689 ich}{
\insrsid9583942\charrsid12860689  compounds will be most effective to a particular genome (i.e.}{\insrsid1769622 ,}{\insrsid4609084  \'93many drugs across one genome}{\insrsid9583942\charrsid12860689 \'94).}{\cs16\super\insrsid15823965\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622 Jai Shah, }{\i\insrsid4156601\charrsid11755622 Concept and Putative Application of Pharmacogenetics and Pharmacogenomics}{\insrsid4156601\charrsid11755622 
. 12 Health Law Review  2: 3 (2004).  The World Health Organization provides the following distinction in definitions between the two: \'93Pharmacogene
tics refers to the study of DNA sequence variation as it relates to differential drug response in individuals, i.e. the use of genomics to determine an individual\rquote 
s response.  Pharmacogenomics refers to the use of DNA-based genotyping in order to target pharmaceutical agents to specific patient populations in the design of drugs.\'94 }{\insrsid4156601\charrsid11755622 WHO Drug Information, Vol. 16, No.}{
\insrsid4156601  }{\insrsid4156601\charrsid11755622 1, 2002.
\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 {\insrsid4156601\charrsid11755622 Another article distinguishes between the two in that pharmacogenetics}{\insrsid4156601\charrsid11755622  is the \'93
application of single gene sequence or a limited number of multiple gene sequences to study variations in DNA sequences related to drug action or drug disposition\'94 while pharmacogenomics is the \'93
application of genome-wide single-nucleotide polymorphism maps and genome-wide gene expression analysis to study variations that influence drug action.\'94 Jack E. Urquhart, C. Kelvin Adams and Laura E. De Santos, }{\i\insrsid4156601\charrsid11755622 
The Duty to Use Pharmacogenetics and Pharmacogenomics to Reduce the Risk of Idiosyncratic Drug-Induced Liver Injury,}{\insrsid4156601\charrsid11755622  Drug Recall Litigation Reporter (2004), a}{\i\insrsid4156601\charrsid11755622 vailable at }{
\insrsid4156601\charrsid15872827 http://library.lp.findlaw.com/articles/file/00093/009455/title/Subject/topic/Health_Drugs%20and%20Medical%20Devices/filename/health_2_3858}{\insrsid4156601\charrsid11755622  (last visited 1/04/05). (}{
\i\insrsid4156601\charrsid11755622 citing }{\insrsid4156601\charrsid11755622 Lesko et al, }{\i\insrsid4156601\charrsid11755622 Pharmacogenetics and Pharmacogenomics in Drug Development and Re
gulatory Decisions Making: Report of the First FDA-PWG-PhRMA-Drug Safe Workshop,}{\insrsid4156601\charrsid11755622  43 J. Clin. Pharmacol., 342 (2003)).}}}{\insrsid873026\charrsid12860689   Shah explains that }{\insrsid9583942\charrsid12860689 
pharmacogenetics could be applied immediately to }{\insrsid1769622 currently}{\insrsid873026\charrsid12860689  }{\insrsid9583942\charrsid12860689 existing }{\insrsid11601522\charrsid12860689 drugs and development programs }{
\insrsid9583942\charrsid12860689 because it }{\insrsid4609084 is most useful for}{\insrsid9583942\charrsid12860689  already-available drugs, }{\insrsid11601522\charrsid12860689 while \'93}{\insrsid9583942\charrsid12860689 
pharmacogenomics will exert its impact at the drug discovery stage and will thus appear in products over the long term.\'94}{\cs16\super\insrsid9583942\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .}}}{\insrsid9583942\charrsid12860689   }{\insrsid14747523\charrsid12860689 However, }{\insrsid16017423 others}{\insrsid14747523\charrsid12860689  merely define pharmacogenomics as the ensuing \'93
broadening\'94 of pharmacogenetics.}{\cs16\super\insrsid14747523\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid14747523\charrsid12860689   }{\insrsid9583942\charrsid12860689 Generally, 
I will use}{\insrsid13500904\charrsid12860689  the terms}{\insrsid12681208  }{\insrsid9583942\charrsid12860689 pharmacogenomic}{\insrsid13500904\charrsid12860689 s}{\insrsid12681208  and }{\insrsid9583942\charrsid12860689 pharmacogenetic}{
\insrsid13500904\charrsid12860689 s}{\insrsid9583942\charrsid12860689  interchangeably}{\insrsid1324433 .  R}{\insrsid11550887 egardless of their }{\insrsid16017423 specific}{\insrsid11550887  definitions, the goals of both are the same: 
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid11550887 {\insrsid16017423 [T]}{\insrsid11550887 o improve the diagnosis of genetic disease; to develop drugs to fight genetic disease; to make clinic
al testing of drugs more efficient by identifying populations in which the drugs are likely to be }{\insrsid144414 especially}{\insrsid11550887  efficacious\'85; and, using genetic information about }{\insrsid144414 patients}{\insrsid11550887 
, to maximize therapeutic benefit and minimize harmful side effects by prescribing drugs to targeted patient populations.}{\cs16\super\insrsid11550887 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Lori B. Andrews, Maxwell J. Mehlman, and Mark A. Rothman, }{
\i\insrsid4156601 Genetics: Ethics, Law and Policy, }{\insrsid4156601 West Group, St. Paul, MN, 2002 at 423. }}}{\insrsid9583942 
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid11550887 {\insrsid11550887\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\tx7455\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 III}{\b\insrsid11944523 .  }{\b\insrsid14644702\charrsid12860689 The Promise}{\b\insrsid11550887 \tab 
}{\b\insrsid15883187\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\insrsid16272184\charrsid12860689 \tab }{\b\insrsid14054882 A}{\b\insrsid11944523\charrsid11944523 .}{\insrsid11944523   }{
\b\insrsid679502\charrsid12860689 Drug Development
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid16017423 In the area of drug discovery and development, }{\insrsid16392615\charrsid12860689 pharmacogenomics }{\insrsid11944523 
promises to }{\insrsid9786919\charrsid12860689 offer better matching between patients and the appropriat}{\insrsid5787956\charrsid12860689 e drugs}{\insrsid11944523  and}{\insrsid5787956\charrsid12860689  }{\insrsid5066125\charrsid12860689 to }{
\insrsid5787956\charrsid12860689 reduce}{\insrsid9786919\charrsid12860689  or eliminat}{\insrsid5787956\charrsid12860689 e}{\insrsid9786919\charrsid12860689  adverse effects, enabling correct dosage according to one\rquote s}{
\insrsid5787956\charrsid12860689  particular metabolism}{\insrsid9786919\charrsid12860689 .}{\insrsid3935865\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid679502 {\insrsid16392615\charrsid12860689 The promise most commonly associated with pharmacogenomics is }{\insrsid5787956\charrsid12860689 
the advancement of new \'93designer drugs\'94 that may be developed to meet }{\insrsid6685439 an}{\insrsid5787956\charrsid12860689  individual\rquote s particular needs.  }{\insrsid14836478\charrsid12860689 \'93Individualized medicine\'94
 is one terms often associated with the results of the Human Genome Project.}{\cs16\super\insrsid14836478\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Henry T. Greely, }{\i\insrsid4156601\charrsid11755622 
Pharmacogenomics: Promise, Prospects, and Potential Problems}{\insrsid4156601\charrsid11755622 , 9(1) Medical Ethics 1, 2 (2002).}}}{\insrsid14836478\charrsid12860689   }{\insrsid5787956\charrsid12860689 Dean Hamer and Peter Copeland, in their book }{
\i\insrsid5787956\charrsid12860689 Living with Our Genes}{\insrsid5787956\charrsid12860689 , note the imprecise nature of current pharmacological methods and suggest,}{\insrsid679502\charrsid12860689  }{\insrsid5787956\charrsid12860689 \'93
Why not start backwards and build a drug that addresses the problem?  Individual DNA sequences, combined with existing computer modeling techniques, would allow drugs to be as precise as a key in a lock.\'94}{\cs16\super\insrsid5787956\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Dean Hamer and Peter Copeland, Living with Our Genes: Why They Matter More than You Think}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  304}{\i\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid11755622 
(New York: NY: Doubleday, 1998).}}}{\insrsid5787956\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid14836478\charrsid12860689 The authors of \'93Pharmacogenetics Goes Genomic\'94 provide a table of pharmacogenetic variants that \'93
have been significantly associated with drug response in at least two studies.\'94}{\cs16\super\insrsid14836478\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Goldstein, Tate, and Sisodiya, }{\i\insrsid4156601 supra }{\insrsid4156601 note 1 at 940.}}}{
\insrsid14836478\charrsid12860689   These drug targets or pathway proteins are examples of potential objectives for pharmacogenomic drug development.   For example, one gene (GNB3) is assoc
iated with a response to antidepressants, while another (AGT) is associated with reduction of blood pressure with anti-hypertensive treatment.  Likewise, certain genes have an impact o}{\insrsid2505741 n}{\insrsid14836478\charrsid12860689 
 metabolic rates.}{\cs16\super\insrsid14836478\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id. at 941.}}}{\insrsid14836478\charrsid12860689   For example, one (DRD2) is associated with the metabolism of certain antipsychotics. 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\i\insrsid1772256\charrsid6685439 Science}{\insrsid1772256\charrsid12860689 
 magazine provides an updated table on genetic polymorphisms of human drug-metabolizing enzymes and transporters (those genetic variations that are currently known to be susceptible to drug variations).}{\cs16\super\insrsid8466304\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 See }{\insrsid4156601\charrsid11755622 William E. Evans and Mary V. Relling,}{\cs18\b\insrsid4156601\charrsid11755622  }{\cs18\i\insrsid4156601\charrsid11755622 
Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics,}{\insrsid4156601\charrsid11755622  Science Mag. }{\i\insrsid4156601\charrsid11755622 at }{\insrsid4156601\charrsid15872827 http://www.sciencemag.org/feature/data/1044449.shl}{
\insrsid4156601\charrsid11755622 .}}}{\insrsid16392615\charrsid12860689   This list is a jumping-off point for drug developers to }{\insrsid6685439 creat}{\insrsid12681208 e}{\insrsid16392615\charrsid12860689  products that are particular to an }{
\insrsid1403258\charrsid12860689 individual\rquote s}{\insrsid16392615\charrsid12860689  genetic profile.}{\insrsid1772256\charrsid12860689  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid6685439\charrsid12860689 Dr. Craig Venter,}{\insrsid6685439  }{\insrsid14302374 president of Celera and }{\insrsid6685439 one of the }
{\insrsid14302374 major players}{\insrsid6685439  behind the HGP,}{\insrsid6685439\charrsid12860689  predicts that eventually each of us \'93might carry some
thing similar to a bar code that identifies our genotype, and this would help us make healthcare decisions.\'94}{\cs16\super\insrsid6685439\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid6685439 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  
Salvatore Giorgianni, ed., The }{\i\insrsid4156601\charrsid11755622 Genome on Main Street: How Genetic Research Will Change Our Lives,}{\insrsid4156601\charrsid11755622  The Pfizer Jour}{\insrsid4156601 .}{\i\insrsid4156601\charrsid11755622  }{
\insrsid4156601\charrsid11755622 96 (1998).}}}{\insrsid6685439   }{\insrsid14836478\charrsid12860689 One of the first examples}{\insrsid14302374  of \'93effective\'94 pharmacogenomic}{\insrsid14836478\charrsid12860689  prescrip}{\insrsid12681208 
tion is Herceptin, a drug for }{\insrsid5783525 metastatic}{\insrsid12681208  }{\insrsid14836478\charrsid12860689 breast cancer.}{\cs16\super\insrsid14836478\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Tom Hollon, }{
\i\insrsid4156601\charrsid11755622 The Making of the Pharmacogenomic Prescription}{\insrsid4156601\charrsid11755622 , GeneLetter (Jan. 2, 2001) }{\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid15872827 
http://www.geneletter.org/01-02-01/features/pharmacogenomics.html}{\insrsid4156601\charrsid11755622 . }}}{\insrsid14836478\charrsid12860689   It is especially effective for approximately thirty pe}{\insrsid14302374 rcent of breast cancer patients,}{
\insrsid14836478\charrsid12860689  those whose tumors express abnormally high amounts of the HER2/neu protein.}{\cs16\super\insrsid14836478\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Shah,}{
\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 9.}{\insrsid4156601\charrsid11755622  }}}{\insrsid14836478\charrsid12860689 
  The drug, which has been shown to shrink tumors and extend the lives of those with the illness, was one of the first drugs for which tests }{\insrsid14302374 we}{\insrsid14836478\charrsid12860689 re performed \'93
to predict whether it will work in a particular patient }{\i\insrsid14836478\charrsid12860689 prior to drug prescription}{\i\insrsid14836478\charrsid3219331 .}{\insrsid14836478\charrsid12860689 \'94}{\cs16\super\insrsid14836478\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid14836478\charrsid12860689   The use of Herceptin illustrates the ability to identify drugs according to an individual\rquote s genetic profile, and although }{\insrsid14302374 it was }{
\insrsid14836478\charrsid12860689 only placed on the market in 1998,}{\insrsid14302374  it}{\insrsid14836478\charrsid12860689  is \'93now }{\insrsid13199228 considered the standard of care}{\insrsid14836478\charrsid12860689 \'94}{\insrsid13199228 
 for that particular form of breast cancer.}{\cs16\super\insrsid14836478\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  PK Manasco, and TE Arledge, }{\i\insrsid4156601\charrsid11755622 Drug Development Strategies}{
\insrsid4156601\charrsid11755622 , in Pharmacogenomics: Social, Ethical, and Clinical Dimensions 114 (Mark A. Rothstein, ed., Hoboken, NJ: John Wiley & Sons) (2003).}}}{\insrsid14836478\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid16125156\charrsid12860689 Alzheimer\rquote s disease has }{\insrsid679502\charrsid12860689 also }{\insrsid16125156\charrsid12860689 
been cited as a promising illness for pharmacogenomics, and the discipline is used widely in Alzheimer\rquote s research, now in research and hopefully later in treatment options.  A }{\i\insrsid16125156\charrsid16273347 Nature Biotechnology}{
\insrsid16125156\charrsid12860689  author discusses a study by McGill University researchers Judes Poirer and colleagues, who investigated the relationship between Alzheimer\rquote s patients\rquote  genotype
s and their response to certain already-existing drugs, and found that a certain gene is a good predictor of response to tacr}{\insrsid2253861\charrsid12860689 ine, a cholinesterase inhibitor}{\insrsid16125156\charrsid12860689 .}{
\cs16\super\insrsid16125156\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Andrew Marshall, }{\i\insrsid4156601\charrsid11755622 Getting the Right Drug into the Right Patient,}{\insrsid4156601\charrsid11755622 
 16 Nature Biotech. Supplement, 9 (1998) (}{\i\insrsid4156601\charrsid11755622 citing}{\insrsid4156601\charrsid11755622  J. Poirer et al. }{\i\insrsid4156601\charrsid11755622 
Apolipoprotein E4 Allele as a Predictor of Cholinergic Deficits and Treatment Outcome in Alzheimer's Disease}{\insrsid4156601\charrsid11755622 . 92 }{\insrsid4156601\charrsid11755622 Proc. Natl. Acad. Sci.}{\i\insrsid4156601\charrsid11755622  }{
\insrsid4156601\charrsid11755622 12260-12264 (1995)).}}}{\insrsid16125156\charrsid12860689  
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 B}{\b\insrsid16273347 .  }{\b\insrsid679502\charrsid12860689 Adverse Drug Reactions (ADR}{
\b\insrsid5976879 s}{\b\insrsid679502\charrsid12860689 )
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid679502 {\insrsid679502\charrsid12860689 The second promise of pharmacogenomics is t}{\insrsid13244632 o reduce adverse drug reactions (ADRs).}{
\insrsid679502\charrsid12860689   }{\insrsid13244632 Fatal ADRs are considered to be between the fourth and sixth leading causes of death.}{\cs16\super\insrsid13244632 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid11755622 
J. Lazarou, B.H. Pomeranz, and P.N. Corey.  }{\i\insrsid4156601\charrsid11755622 Incidence of Adverse Drug Reactions in Hospitalized Patients: a Meta-Analysis of Prospective Studies,}{\insrsid4156601\charrsid11755622  279(15) JAMA 1200 (1998)}{
\insrsid4156601 .}}}{\insrsid679502\charrsid12860689   According }{\insrsid7149582\charrsid12860689 to}{\insrsid679502\charrsid12860689 
 a 1998 study, ADRs are responsible for 100,000 drug-related deaths and 2.2 million hospitalizations each year in the U.S.}{\cs16\super\insrsid679502\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Pharmacogenomics}{\insrsid4156601\charrsid11755622 , Human Genome Project Information, }{\i\insrsid4156601\charrsid11755622 available at}{\insrsid4156601\charrsid11755622 
\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 {\insrsid4156601\charrsid15872827 http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml}{\insrsid4156601\charrsid11755622 
 (last visited 1/05/05). (}{\i\insrsid4156601\charrsid11755622 citing }{\insrsid4156601\charrsid11755622 J}{\insrsid4156601 . }{\insrsid4156601\charrsid11755622 Lazarou,}{\insrsid4156601  Pomeranz, and Corey,}{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601 supra }{\insrsid4156601 note 24 }{\insrsid4156601\charrsid11755622 (\'93We have found that serious ADRs are frequent and more so than generally recognized}{\insrsid4156601 \'85}{\insrsid4156601\charrsid11755622 
 Their incidence has remained stable over the last 30 years.\'94)).}}}{\insrsid679502\charrsid12860689   }{\insrsid5125208 Moreover, i}{\insrsid679502\charrsid12860689 t is estimated that ADRs cost society an estimated }{\insrsid4068852 one hundred}{
\insrsid679502\charrsid12860689  billion}{\insrsid4068852  dollars}{\insrsid679502\charrsid12860689  a year.}{\cs16\super\insrsid679502\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Faith Lagay, Genethics: Pharmacogenomics: Revolution in a Bottle? AMA (Virtual Mentor) Genethics, available at }{\insrsid4156601\charrsid15872827 www.ama-assn.org/ama/pub/category/7459.html}{\insrsid4156601\charrsid11755622  (last visited 1/06/05).  

\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 {\insrsid4156601\charrsid11755622 It is ex
plained that underdosing, overdosing, or missed doses currently cost the US more than $100 billion a year in increased hospital admissions, lost productivity, and premature death.  Marshall, }{\i\insrsid4156601\charrsid2111073 
Getting the Right Drug into the Right Patient}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 23}{\insrsid4156601\charrsid11755622  (cit
ing a PhRMA statistic).  Another article cites annual cost estimates for ADRs at $30.1 to $136.8 billion. David J. Wu, A Pharmacogenomics Standard for FDA Drug Approval: Arbitrary and Capricious or Safe and Effective? 23 Biotechnology L. Rep. 733 (2004). 
 Another study estimates that quantified Adverse}{\insrsid4156601  }{\insrsid4156601\charrsid11755622 Drug Reactions (ADR) cost to be $76.6 billion in 1992.  Sam Tetlow, }{\i\insrsid4156601\charrsid7489573 Successful Pharmacogenomics Business Models}{
\insrsid4156601\charrsid11755622 , Cambridge Healthtech Institute (2002) at 4, available at http://www.chadvisors.com/services/pharmacogenomics_business/sample.pdf.}}}{\insrsid679502\charrsid12860689  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\tx5492\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid679502 {\insrsid12133167\charrsid12860689 According to many, }{\insrsid5125208 pharmacogenomic discoveries will cause }{
\insrsid679502\charrsid12860689 the drug prescription}{\insrsid12133167\charrsid12860689  process}{\insrsid679502\charrsid12860689  }{\insrsid5125208 to }{\insrsid679502\charrsid12860689 
change.  Instead of determining dosages by weight, age, and other proxies, physicians will }{\insrsid5125208 also }{\insrsid679502\charrsid12860689 be able to prescribe according to an individual\rquote s genetic}{\insrsid14827251  makeup}{
\insrsid679502\charrsid12860689 , thereby \'93maximiz[ing] the therapy\rquote s value and decreas[ing] the likelihood of overdose.\'94}{\cs16\super\insrsid679502\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  David J. Wu, }{
\i\insrsid4156601\charrsid5262996 A Pharmacogenomics Standard for FDA Drug Approval: Arbitrary and Capricious or Safe and Effective?}{\insrsid4156601\charrsid11755622  23 Biotechnology L. Rep. 733 (2004).}}}{\b\insrsid679502\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid6378728 {\insrsid679502\charrsid12860689 An apt example of the use}{\insrsid5125208  of pharmacogenomics in preven}{\insrsid679502\charrsid12860689 
tive medicine is the identification of the V Leiden allele, which confers a higher than average risk for venous thrombosis.}{\cs16\super\insrsid5125208 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid11755622 Muin J. Khoury and Jill Morris, 
}{\i\insrsid4156601\charrsid5125208 Pharmacogenomics and Public Health: The Promise of Targeted}{\i\insrsid4156601\charrsid11755622  Disease Prevention, }{\insrsid4156601\charrsid11755622 CDC, }{\i\insrsid4156601\charrsid11755622 available at }{
\insrsid4156601\charrsid11755622 http://}{\insrsid4156601\charrsid15872827 www.cdc.gov/genomics/info/factshts/pharmacofs.htm}{\insrsid4156601\charrsid11755622  (last visited 1/11/05}{\insrsid4156601 ).}}}{\insrsid679502\charrsid12860689 
  The use of oral contraceptives by women with the factor V Leiden allele greatly increases the risk.  Thus, it might be possible to test all women for the 
allele before prescribing oral contraception.  However, as will be discussed further, such an approach}{\insrsid14827251  may not be cost-effective for}{\insrsid679502\charrsid12860689  drug companies.}{\cs16\super\insrsid679502\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid679502\charrsid12860689   }{\insrsid12133167\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid12133167 {\insrsid14827251 On the other hand}{\insrsid12133167\charrsid12860689 , there are also studies that }{\insrsid7622050 demonstrate that }{
\insrsid12133167\charrsid12860689 pharmacogenomics is unlikely to have a}{\insrsid7622050 s}{\insrsid12133167\charrsid12860689  intense an impact on the reduction of adverse events }{\insrsid7622050 as}{\insrsid12133167\charrsid12860689  might appear.  }{
\insrsid14827251 In response to}{\insrsid12133167\charrsid12860689  the }{\insrsid7622050 British }{\insrsid12133167\charrsid12860689 Nuffield Council on Bioethics report\rquote s }{\insrsid13386001 constructive }{\insrsid12133167\charrsid12860689 
discussion regarding the reduction of adverse events due to pharmacogenomic advances}{\insrsid13386001 , one critic points out that the Council might have}{\insrsid12133167\charrsid12860689  failed to consider other significant va}{\insrsid6771936 
riables, including age and sex.}{\cs16\super\insrsid12133167\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Oonagh Patricia Corrigan, }{\i\insrsid4156601\charrsid11755622 
Pharmacogenetics, Ethical Issues: Review of the Nuffield Council on Bioethics}{\insrsid4156601\charrsid11755622 , 8.}}}{\insrsid12133167\charrsid12860689   
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 C}{\b\insrsid7622050 .  }{\b\insrsid12482009\charrsid12860689 Metabolism
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13643396 {\insrsid679502\charrsid12860689 Genetics}{\insrsid5066125\charrsid12860689  could clarify why people respond differently to }{
\insrsid12977733 specific}{\insrsid5066125\charrsid12860689  medications and how a person\rquote s body metabolizes }{\insrsid281864 particular compound}{\insrsid5066125\charrsid12860689 s.}{\cs16\super\insrsid5066125\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Marion Jones, }{\i\insrsid4156601\charrsid11755622 Genetic Profiles May Help Doctors Match Drugs to Patients}{\insrsid4156601\charrsid11755622 , Fox News (April 19, 2000).}}}{\insrsid5066125\charrsid12860689   }{\insrsid679502\charrsid12860689 Up to }{
\insrsid10354790 thirty percent}{\insrsid679502\charrsid12860689  of patients do not respond optimally to certain drugs.  }{\insrsid13643396 If an individual\rquote s rate of}{\insrsid13643396\charrsid12860689  metabolism }{\insrsid13643396 
is too high, a }{\insrsid13643396\charrsid12860689 patient will be undertreated because the drugs will not be delivered in an efficacious manner.  If metabolism is }{\insrsid13643396 too low,}{\insrsid13643396\charrsid12860689  it 
could lead to an overdose because the site will be overdelivered.}{\cs16\super\insrsid13643396\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13643396 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Greely,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 13.}{\b\insrsid4156601  }{
\insrsid4156601\charrsid11755622  }}}{\insrsid13643396\charrsid12860689   Thus, ultra-rapid metabolism of a drug can cause it to be ineffective, and slow or non-metabolism can result in the accumulation of toxic amounts}{\insrsid13643396  of a drug}{
\insrsid13643396\charrsid12860689  in the body.
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid679502\charrsid12860689 Pharmacogenomics could potentially increase the probability of optimal dosage.}{
\cs16\super\insrsid679502\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nusrat Khaleeli and Dennis Fernandez, }{\i\insrsid4156601\charrsid11755622 Patent Prosecution in Pharmacogenomics,}{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid15872827 http://www.iploft.com}{\insrsid4156601\charrsid11755622  (last visited 1/05/05).}}}{\insrsid679502\charrsid12860689   }{\insrsid5066125\charrsid12860689 
The manner in which an individual metabolizes certain}{\insrsid13643396  compounds}{\insrsid5066125\charrsid12860689  may depend on a set of genes separate }{\insrsid679502\charrsid12860689 and unrelated }{\insrsid5066125\charrsid12860689 from those }{
\insrsid679502\charrsid12860689 correlated to any particular}{\insrsid5066125\charrsid12860689  illness that is present throughout the population}{\insrsid679502\charrsid12860689 .  }{\insrsid5066125\charrsid12860689 
As the Nuffield Council on Bioethics explains, these genes do not necessarily have an effect on an individual\rquote s susceptibility to disease, but how the person absorbs, metabolizes, and excretes }{\insrsid679502\charrsid12860689 compound}{
\insrsid5066125\charrsid12860689 s.}{\cs16\super\insrsid5066125\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nuffield Council on Bioethics}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Pharmacogenetics: Ethical Issues, }{\insrsid4156601\charrsid11755622 The Nuffield Trust, London, }{\insrsid4156601 (2003) }{\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid15872827 
www.nuffieldbioethics.org/go/browseablepublications/pharmacogenetics/report_122}{\insrsid4156601\charrsid11755622 .}}}{\insrsid5066125\charrsid12860689   Physicians could modify an individual\rquote 
s prescription according to multiple sets of genes and their interactions.}{\cs16\super\insrsid5066125\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id. at 88}{\insrsid4156601\charrsid11755622 .}}}{\insrsid5066125\charrsid12860689 
\par }{\insrsid1967193\charrsid12860689 According to one study, 59% of drugs are metabolized by at least one enzyme that has a variant allele }{\insrsid10354790 known to cause poor metabolism.}{\cs16\super\insrsid1967193\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 D. Melzer, A Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  DE Detmer, T Ling, and RL Zimmern, }{\i\insrsid4156601\charrsid11755622 My Very Own Medicine: What Must I Know: Information Policy for Pharmacogenetics}{
\insrsid4156601\charrsid11755622 , The Wellcome Trust, 53 (2003).  }}}{\insrsid1967193\charrsid12860689   If an individual, for example, carries the
 variant cytochrome P450 gene, CYP2D6, which encodes a metabolic liver enzyme, he or she cannot metabolize certain drugs, which could }{\insrsid10354790 therefore allow}{\insrsid1967193\charrsid12860689  lethal amounts }{\insrsid2955983 of }{
\insrsid1967193\charrsid12860689 the drug to accumulate in his or her body.}{\cs16\super\insrsid1967193\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Wu, }{\i\insrsid4156601 supra }{\insrsid4156601 note 27.  }}}{\insrsid1967193\charrsid12860689   }{
\insrsid679502\charrsid12860689 Other examples}{\cs18\insrsid679502\charrsid12860689  of prescribing particular dosages according to one\rquote s metabolism in order to reduce adverse event}{\cs18\insrsid2955983 s}{\cs18\insrsid679502\charrsid12860689 
 include risk reduction strategies}{\b\insrsid679502\charrsid12860689  }{\insrsid679502\charrsid12860689 such as HIV resistance testing and optimized dosing for HCV.}{\cs16\super\insrsid679502\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lawrence Lesko, 
}{\i\insrsid4156601\charrsid11755622 Pharmacogenomics: A Critical Path Opportunity, }{\insrsid4156601\charrsid11755622 FDA (March 18, 2004) }{\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid15872827 
http://www.fda.gov/oc/initiatives/criticalpath/Lesko/Lesko.html}{\insrsid4156601\charrsid11755622 .}}}{\insrsid679502\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid679502\charrsid12860689 According to Janet Woodcock, Director of the FDA\rquote s Center for Drug Evaluation and Research
 (CDER), the variability in how individuals metabolize compounds is }{\cs26\insrsid679502\charrsid12860689 \'93a huge problem, because what\rquote s considered a normal dose of a drug can be toxic for some people.\'94}{\cs16\super\insrsid2955983 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\cs26\insrsid4156601\charrsid11755622 
Tracy }{\insrsid4156601\charrsid11755622 Hampton, }{\i\insrsid4156601\charrsid11755622 FDA Seeks Genome-Based Drug Data,}{\insrsid4156601\charrsid11755622  291 }{\cs27\insrsid4156601\charrsid11755622 JAMA.}{\insrsid4156601\charrsid11755622  32 (2004).}}}{
\cs26\insrsid679502\charrsid12860689  }{\cs26\insrsid12546512  }{\cs26\insrsid679502\charrsid12860689 She praises the us}{\cs26\insrsid12546512 e of pharmacogenomics, stating that dosing }{\cs26\insrsid679502\charrsid12860689 according to a patient}{
\cs26\insrsid12546512 \rquote }{\cs26\insrsid679502\charrsid12860689 s genetic profile}{\cs26\insrsid12546512  would be advantageous}{\cs26\insrsid679502\charrsid12860689 .}{\cs16\super\insrsid679502\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\cs26\insrsid4156601 Id.}}}{\cs26\insrsid679502\charrsid12860689   }{\insrsid10768431\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 D}{\b\insrsid12546512 .  }{\b\insrsid8804748\charrsid12860689 Diagnosis and Treatment 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8804748 {\insrsid8804748\charrsid12860689 
Although the major focus of this paper is the effect of pharmacogenomics on the development of drugs for the treatment of illness, diagnosis is another area in which genetic discoveries c
ould have a positive impact.  Currently, diagnosis of illness can be quite haphazard, and the trial-and-error method common in the experience of most physicians and patients can take its toll.  Take, for instance, the example of bipolar disorder, a mental
 illness that affects 1.2% of the American population, or approximately 2.2 million men and women.}{\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\super\insrsid4156601\charrsid11755622  }{
\insrsid4156601\charrsid11755622 David Kahn, Ruth Ross, David Printz, and Gary Sachs, }{\i\insrsid4156601\charrsid11755622 Treatment of Bipolar Disorder: A Guide for Patients and Families,}{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Medication }{\insrsid4156601\charrsid11755622 Treatment of Bipolar Disorder (2000).}}}{\insrsid8804748\charrsid12860689   It is one of the most fatal of all illnesses, with a suicide rate of up to twenty percent.}{
\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Peter Brigham, }{\i\insrsid4156601\charrsid11959164 The Psychopharmacology of Bipolar Disorder}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601\charrsid11755622 
available at}{\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid15872827 http://home.comcast.net/~pmbrig/BP_pharm.html}{\insrsid4156601\charrsid11755622  (last visited 1/11/05).}}}{\insrsid8804748\charrsid12860689 
  One survey found that although twenty-eight percent of adults may have some sort of mental illness within a given year, only eight percent receive any diagnosis or treatment.}{\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Alison Ashton, }
{\i\insrsid4156601\charrsid11755622 It\rquote s All in Your Head}{\insrsid4156601\charrsid11755622 , Copley News Service}{\i\insrsid4156601\charrsid11755622 , }{\insrsid4156601\charrsid11755622 July 3, 2000.}}}{\insrsid8804748\charrsid12860689 
  This low rate of success is telling of the current needle-in-a-haystack process of diagnosis.
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8804748 {\insrsid8804748\charrsid12860689 The isolation of genes that predispose certain i
ndividuals to particular illnesses will lead to an improvement in the understanding of the causes and mechanisms of the illnesses themselves.  For example, mental health physicians began to see this improvement during the revisions of the Diagnostic and S
tatistical Manual of Mental Disorders (DSM-III) in the 1980\rquote s, as the definitions shifted \'93away from psychoanalytic assumptions toward an approach increasingly based on biology.\'94}{\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Dorothy Nelkin and M. Susan Levee, The DNA Mystique (New York, NY: W.H. Freeman and Company, 1995).}}}{\insrsid8804748\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8804748 {\insrsid8804748\charrsid12860689 The increase in our knowledge of the biology underlying illness could occur
 through the identification of susceptibility genes, which might lead to an understanding of gene products.  This, in turn, would trigger greater awareness of the role of individual proteins in causing illness, thereby leading to further appreciation of t
he interaction of these proteins with other substances, as well as the effect of the environment on protein levels and function.}{\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Nick Craddock and Ian Jones}{\i\insrsid4156601\charrsid11755622 , Genetics of Bipolar Disorder}{\insrsid4156601\charrsid11755622 , 36 J. Med. Genet}{\i\insrsid4156601\charrsid11755622 . }{\insrsid4156601\charrsid11755622 585 (1999).}}}{
\insrsid8804748\charrsid12860689   Thus, genetic discoveries would also help elucidate how genes interact with environmental factors.  Such developments would as
sist the creation of new forms of diagnosis, treatment, and possibly prevention of many illnesses and disorders.
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8804748 {\insrsid467708\charrsid12860689 Since many illnesses are }{\insrsid11958893 currently }{\insrsid467708\charrsid12860689 treated not }{
\insrsid11958893 according to}{\insrsid467708\charrsid12860689  the underlying disease, but }{\insrsid467708 the symptoms}{\insrsid15892270  of that illness}{\insrsid467708 , the }{\insrsid467708\charrsid12860689 process of finding th
e right dosage and combination of medications can be extraordinarily slow and discouraging, and it can take months, or even years, to determine the correct combinations and dosages.}{\cs16\super\insrsid467708\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid467708 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Kimberly Bailey and Marcia Purse, }{\i\insrsid4156601\charrsid11755622 The Trial and Error Terror }{\insrsid4156601\charrsid11755622 (Oct. 22, 2000) }{\insrsid4156601\charrsid15872827 http://bipolar.about.com/cs/whatme/l/bl_titration.htm}{
\insrsid4156601\charrsid11755622  (last visited 1/11/05).}}}{\insrsid467708\charrsid12860689   The Surgeon General\rquote s Office reported that approximately thirty to fifty percent of patients do not respond to their original medication.}{
\cs16\super\insrsid467708\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid467708 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Mental Health: A Report of the Surgeon General- Chapter 4,}{\insrsid4156601\charrsid11755622  Office of the Surgeon General}{
\i\insrsid4156601\charrsid11755622 .}{\insrsid4156601\charrsid11755622  http://www.surgeongeneral.gov/library/mentalhealth/home.html (1999) (last visited 1/5/05).}}}{\insrsid467708 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8804748 {\insrsid8804748\charrsid12860689 
For example, cancer is generally diagnosed and treated according to the location at which it is found, rather than any underlying biological causes.  With the eventual discover}{\insrsid14164145 y}{\insrsid8804748\charrsid12860689  of genes th
at confer vulnerability to }{\insrsid4476814 an illness, all individuals with the same }{\insrsid8804748\charrsid12860689 symptom}{\insrsid4476814 s}{\insrsid8804748\charrsid12860689 
 would no longer be diagnosed with the same illness.  It has been argued that genetic discoveries will allow us to develop a \'93molecular taxonomy of disease,\'94}{\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622  }}}{\insrsid8804748\charrsid12860689  or \'93a rational aetiology-based classification of\'85
 disorders which will almost certainly provide a much better guide to treatment and prognosis than do current classifications.\'94}{\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Craddock and Jones}{\i\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 45.  }}}{\insrsid8804748\charrsid12860689   Indeed, future research could establish diverse and multiple biological causes for the same sympt
oms, thus creating new categories of an overarching illness.  Many believe that \'93
it is likely that some conditions which are now considered to be single disorders, with a common set of symptoms, will be discovered to be more heterogeneous, with several different biochemical disorders leading to a common set of clinical features.\'94}{
\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34}{\insrsid4156601\charrsid11755622 .}}}{
\insrsid8804748\charrsid12860689   These subcategories could have diverse molecular and environmental causes, but are all manifested in similar physical or behavioral (in the case of mental illness) symptoms.  Thu
s, utilizing the example of cancer, the categories of breast and lung cancer may become obsolete, as the understanding of the molecular biology of illness improves.  }{\insrsid14164145 In the future}{\insrsid8804748\charrsid12860689 
, cancer diagnosis could be categorized by the individual\rquote s biological interactions or their predetermined reactions to medicine.  }{\insrsid14164145 P}{\insrsid8804748\charrsid12860689 
harmacogenomic discoveries may blur the lines between existing disease classifications.}{\cs16\super\insrsid8804748\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Thomas White, Chief Scientific Officer of Celera Diagnostics, illustrates this possibility: \'93\'85
perhaps a drug that is currently used in the treatment of cancer, like a kinase inhibitor, with a known safety profile may actually have a role in treating certain inflammatory diseases based on its activity on a nontarget kinase th
at has now been shown to play a role in the new disease in a way that is testable both mechanistically and preclinical in clinical trials.\'94
  Thomas White, Targeted Medicine: From Concept to Clinic, Luncheon Keynote with Lawrence J. Lesko at Scientific American, }{\i\insrsid4156601\charrsid11755622 at }{\insrsid4156601\charrsid11755622 2004 WL 99524302 (Nov. 11, 2004).}}}{
\insrsid8804748\charrsid12860689   Thus, }{\insrsid4476814 diagnosis and }{\insrsid8804748\charrsid12860689 treatment might become more effective as physicians are able to hone their prescriptions to the specific genetic variation an individual possesses.

\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 IV}{\b\insrsid10621753 .  }{\b\insrsid150282\charrsid12860689 The Perception}{
\b\insrsid3935865\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid12858816\charrsid12860689 A common }{\insrsid1403258\charrsid12860689 sentiment}{\insrsid12858816\charrsid12860689 
 among the public and expert alike is a sense of optimism regarding the prospects for pharmacogenomics.  }{\insrsid1403258\charrsid12860689 A sampling of statements to this effect includes}{\insrsid12858816\charrsid12860689 :
\par {\listtext\pard\plain\f3\insrsid3935865\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \ql \fi-360\li720\ri0\widctlpar\jclisttab\tx720\aspalpha\aspnum\faauto\ls2\adjustright\rin0\lin720\itap0\pararsid8923281 {\insrsid3935865\charrsid12860689 
\'93Imagination is the only limitation to the potential benefits of pharmacogenenetics and pharmacogenomics.\'94}{\cs16\super\insrsid3935865\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Jack E. Urquhart, C. Kelvin Adams and Laura E. De Santos, }{\i\insrsid4156601\charrsid11755622 The Duty to Use Pharmacogenetics and Pharmacogenomics to Reduce the Risk of Idiosyncratic Drug-Induced Liver Injury,}{\insrsid4156601\charrsid11755622 
 Drug Recall Litigation Reporter (2004), a}{\i\insrsid4156601\charrsid11755622 vailable at }{\insrsid4156601\charrsid15872827 
http://library.lp.findlaw.com/articles/file/00093/009455/title/Subject/topic/Health_Drugs%20and%20Medical%20Devices/filename/health_2_3858}{\insrsid4156601\charrsid11755622  (last visited 1/04/05).}}}{\insrsid3935865\charrsid12860689 
\par {\listtext\pard\plain\f3\insrsid12858816\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \ql \fi-360\li720\ri0\widctlpar\jclisttab\tx720\aspalpha\aspnum\faauto\ls2\adjustright\rin0\lin720\itap0\pararsid8923281 {
\insrsid12858816\charrsid12860689 \'93Doctors will treat disease like cancer and diabetes before the symptoms even begin, using medications that boost or counteract the effect of individual proteins\'85
 and they will know right from the start how to select the best medicine to suit each patient.\'94}{\cs16\super\insrsid12858816\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Khoury and Morris, }{\i\insrsid4156601 supra }{\insrsid4156601 note 28}{\insrsid4156601\charrsid11755622  (}{\i\insrsid4156601\charrsid11755622 citing Time Magazine }{\insrsid4156601\charrsid11755622 January 15, 2001).}}}{
\insrsid9859791\charrsid12860689 
\par {\listtext\pard\plain\f3\insrsid9859791\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \ql \fi-360\li720\ri0\widctlpar\jclisttab\tx720\aspalpha\aspnum\faauto\ls2\adjustright\rin0\lin720\itap0\pararsid8923281 {\insrsid9859791\charrsid12860689 
\'93Pharmacogenomics is here to stay because it means making medicines that are safer, better targeted, and more efficacious.\'94}{\cs16\super\insrsid9859791\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Andrew Marshall, }{\i\insrsid4156601\charrsid11755622 One Drug Does Not Fit All}{\insrsid4156601\charrsid11755622 , 1 Nature Biotechnology 16, Supplement 1 (1998).}}}{\insrsid9859791\charrsid12860689 
\par {\listtext\pard\plain\f3\insrsid9859791\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}Pharmacogenomic research is likely to become a routine part of the drug discovery process.}{\cs16\super\insrsid9859791\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Meurer, }{\i\insrsid4156601 supra }{\insrsid4156601 note 7.}}}{\insrsid9859791\charrsid12860689   
\par {\listtext\pard\plain\f3\insrsid9859791\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \ql \fi-360\li720\ri0\widctlpar\jclisttab\tx720\aspalpha\aspnum\faauto\ls2\adjustright\rin0\lin720\itap0\pararsid8923281 {\insrsid9859791\charrsid12860689 
\'93Pharmacogenomics is a logical progression of medicine}{\insrsid4476814 \'85}{\insrsid9859791\charrsid12860689  It will render health care increasingly rational, address the economic challenge of infinite demand versus limited resources. By ide
ntifying the relatively small proportion of the population that accounts for high costs, it will bring about a profound shift from reactive to proactive treatment.\'94}{\cs16\super\insrsid9859791\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Andrew Marshall, }{\i\insrsid4156601 supra }{\insrsid4156601 note 23 (}{\insrsid4156601\charrsid4476814 citing}{\i\insrsid4156601  }{\insrsid4156601\charrsid12860689 SmithKline Beecham\rquote s (London) chief science and te}{\insrsid4156601 
chnology officer, George Poste).}}}{\insrsid16457587\charrsid12860689 
\par {\listtext\pard\plain\f3\insrsid1403258\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \ql \fi-360\li720\ri0\widctlpar\jclisttab\tx720\aspalpha\aspnum\faauto\ls2\adjustright\rin0\lin720\itap0\pararsid16272184 {
\insrsid1403258\charrsid12860689 A \'93number}{\insrsid16457587\charrsid12860689  of influential proponents argued that pharmacogenetics would revolutionise drug marketing and prescribing.\'94}{\cs16\super\insrsid16457587\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36.  }}}{\insrsid16457587\charrsid12860689  }{
\insrsid8923281\charrsid12860689 
\par }\pard \ql \li360\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin360\itap0\pararsid16272184 {\insrsid16272184\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid16457587\charrsid12860689 However, others hold a less optimistic view of the promise of pharmacogenomics: 
\par {\listtext\pard\plain\f3\insrsid16457587\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \ql \fi-360\li720\ri0\widctlpar\jclisttab\tx720\aspalpha\aspnum\faauto\ls3\adjustright\rin0\lin720\itap0\pararsid8923281 {
\insrsid16457587\charrsid12860689 \'93The complexity of human responses to medicines makes it prudent not to overestimate the probable impact of pharmacogenomics.\'94}{\cs16\super\insrsid10621753 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10621753 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\i\insrsid4156601\charrsid15668283 
Ethical, Legal and Social Implications (ELSI) of Human Genomics: Pharmacogenomics}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  World Health Organization. }{\i\insrsid4156601\charrsid11755622 Available at 
\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\insrsid4156601\charrsid15872827 http://www.who.int/genomics/elsi/pharmacogenomics/en/}{\insrsid4156601 .}}}{\insrsid14168363\charrsid12860689 
\par {\listtext\pard\plain\f3\insrsid14168363\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}\'93[I]t is clear that pharmacogenetics will neither be universally applicable or perfectly predictive.\'94}{\cs16\super\insrsid14168363\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 56.}{\insrsid4156601\charrsid11755622   }}}{
\insrsid6322602\charrsid12860689 
\par {\listtext\pard\plain\f3\insrsid6322602\charrsid12860689 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \ql \fi-360\li720\ri0\widctlpar\jclisttab\tx720\aspalpha\aspnum\faauto\ls3\adjustright\rin0\lin720\itap0\pararsid8923281 {\insrsid6322602\charrsid12860689 
\'93[P]harmacogenetics is not a panacea, and the benefits arising from pharmacogenetics (purported by industry advocates and largely accepted by the Report authors) have been arguably been exaggerated.\'94}{\cs16\super\insrsid6322602\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Corrigan, }{\i\insrsid4156601 supra }{\insrsid4156601 note 30 }{\insrsid4156601\charrsid11755622 (}{\i\insrsid4156601\charrsid11755622 citing}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 
her own work in}{\insrsid4156601\charrsid11755622  B. Williams-Jones, OP Corrigan, }{\i\insrsid4156601\charrsid11755622 Rhetoric and Hype: Where\rquote s the \lquote Ethics\rquote  in Pharmacogenomics? }{\insrsid4156601\charrsid11755622 3(6) American Jour
}{\insrsid4156601 .}{\insrsid4156601\charrsid11755622  of Pharmacogenomics (2003)).}}}{\insrsid6322602\charrsid12860689  
\par }\pard \ql \li360\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin360\itap0\pararsid8923281 {\insrsid8923281\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid10439170 {\insrsid5463365\charrsid12860689 
Regardless of how optimistic one is regarding the future of pharmacogenomics, it is anticipated that the introduction of pharmacogenetics products will be incremental.}{\cs16\super\insrsid5463365\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{
\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 28.}}}{\b\insrsid3935865\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 V}{\b\insrsid10880679 .  }{\b\insrsid3817714\charrsid12860689 Complexity}{\insrsid3817714\charrsid12860689 

\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3817714 {\insrsid3817714\charrsid12860689 At this juncture, an important disclaimer is necessary.  }{\insrsid15276277\charrsid12860689 The promises of p
}{\insrsid3817714\charrsid12860689 harmacogenomics}{\insrsid15276277\charrsid12860689  are}{\insrsid3817714\charrsid12860689  further complicated by a number of other fact}{\insrsid16272184\charrsid12860689 ors}{\insrsid3817714\charrsid12860689 
; it is not as simple as finding that one\rquote s genetic makeup affects drug dosage and prescription.  }{\insrsid16272184\charrsid12860689 The uncertainties related to pharmacogenomics }{\insrsid3817714\charrsid12860689 contradict the optimism e}{
\insrsid16272184\charrsid12860689 xpressed by many, particularly once}{\insrsid3817714\charrsid12860689 
 the notion of tailor-made drugs has lost its novelty.  First, it has been pointed out that is important to understand that pharmacogenomics does not promise }{\insrsid1339390 perfectly }{\insrsid4661547 individualized}{\insrsid3817714\charrsid12860689 
 medicine, but will}{\insrsid16272184\charrsid12860689  only}{\insrsid3817714\charrsid12860689  accelerate the process in that direction.}{\cs16\super\insrsid3817714\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  TM Luhrmann, }{
\i\insrsid4156601\charrsid11755622 Of Two Minds: The Growing Disorder in American Psychiatry }{\insrsid4156601\charrsid11755622 (New York, NY: Alfred A. Knopf, 2000), p 48.  }}}{\insrsid16272184\charrsid12860689   As researchers }{
\insrsid3817714\charrsid12860689 have focused}{\insrsid16272184\charrsid12860689  on the }{\insrsid3817714\charrsid12860689 probabilistic nature of genetics, it is }{\insrsid16272184\charrsid12860689 becoming more and more clear}{
\insrsid3817714\charrsid12860689  that the most common illnesses, if genetic, are \'93influenced by many genes of low penetrance, plus environmental factors.\'94}{\cs16\super\insrsid3817714\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{
\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 53.  }{\i\insrsid4156601\charrsid11755622 See also }{\insrsid4156601\charrsid11755622 Pat Buckley and Ross A. McKinnon, 
}{\i\insrsid4156601\charrsid11755622 Pharmacogenomics, Ethics, and the Community, }{\insrsid4156601\charrsid11755622 23 Pharmacist 1 (2004). \'93
The probabilistic nature of pharmacogenomics needs to be appreciated when considering whether its application will increase inequalities in the provision of health care.  Ph
armacogenomic tests are unlikely to indicate that a particular medicine will definitely be effective or ineffective in a particular patient.  Rather, they are likely to provide probabilistic information\'85\'94 }}}{\insrsid3817714\charrsid12860689 
  The complexity of genetic information is augmented by other }{\insrsid3944688 causes}{\insrsid3817714\charrsid12860689 , such as drug }{\insrsid16272184\charrsid12860689 interactions and }{\insrsid3817714\charrsid12860689 
environmental and physiological factors suc}{\insrsid10880679 h as nutrition, ag}{\insrsid3817714\charrsid12860689 ing, liver and kidney function.}{\cs16\super\insrsid3817714\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id. at 51.  The focus on the interaction between genetics and nutrition was recently highlighted in a Newsweek cover story.  The authors explain, \'93It isn\rquote t just what you eat that can kill you, and it isn\rquote 
t just your DNA that can save you\emdash it\rquote s how they interact.\'94  Anne Underwood and Jerry Adler, }{\i\insrsid4156601 Diet and Genes, }{\insrsid4156601 Newsweek (Jan. 17, 2005).}{\insrsid4156601\charrsid11755622   }}}{
\insrsid3817714\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid3944688 {\insrsid3817714\charrsid12860689 The}{\insrsid16272184\charrsid12860689  }{\insrsid3817714\charrsid12860689 FDA guidance to industry regarding the su
bmission of pharmacogenomic data is clear on the interaction between genes, the environment, and other assorted factors, stating, \'93}{\insrsid3944688 
In most instances, a genotype or particular gene expression profile is likely to be one of a number of factors that affects t
he probability of an adverse event or a favorable response. For this reason, pharmacogenomic biomarkers can ordinarily be handled like other non-genomic predictive markers in the clinical arena.}{\insrsid3817714\charrsid12860689 \'94}{
\cs16\super\insrsid3817714\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological Health (CDRH), FDA, }{
\i\insrsid4156601\charrsid11755622 Guidance for Industry: Pharmacogenomic Data Submissions.}{\insrsid4156601\charrsid11755622  (}{\insrsid4156601 March 2005}{\insrsid4156601\charrsid11755622 ).  }}}{\insrsid3817714\charrsid12860689 
  Another author explains, \'93More often than not, several genes, rather than one, interact with environmental factors to result in a particular variation in drug action.\'94}{\cs16\super\insrsid3817714\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Marshall, }{
\i\insrsid4156601\charrsid11755622 Laying the Foundation for Personalized Medicine, }{\i\insrsid4156601 supra }{\insrsid4156601 note 8.}{\insrsid4156601\charrsid11755622 \tab }}}{\insrsid3817714\charrsid12860689 
  William Haseltine, CEO of Human Genome Sciences, warns that diagnostic tests can be unreliable because environmental factors have a significant influence on drug behavior.}{\cs16\super\insrsid3817714\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\cs19\insrsid4156601\charrsid11755622 Stix, G., }{\cs19\i\insrsid4156601\charrsid11755622 Personal Pills: Genetic Differences May Dictate how Drugs are Prescribed}{\cs19\insrsid4156601\charrsid11755622 , Scientific American, (1998).}}}{
\insrsid3817714\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3817714 {\insrsid3817714\charrsid12860689 
Some authors assert that the application of pharmacogenomics is likely much more complicated than the media and members of the public claim.  For example, Oonagh Patricia Corrigan, in a critique of the British Nuffield Council on Bioethic\rquote 
s report on pharmacogenetics, cites a study regarding the implications of pharmacogenomics, and found that \'93expert opinion is less optimistic as the complexities of gene-gene, and gene-environment interactions have become more apparent.\'94}{
\cs16\super\insrsid3817714\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Corrigan, }{\i\insrsid4156601 supra }{\insrsid4156601 note 30.}}}{\insrsid3817714\charrsid12860689   }{\insrsid3817714 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13176573 {\insrsid13176573\charrsid12860689 As 
genetic discoveries occur, it becomes increasingly significant to educate society about the concept of statistics, predispositions, and predictability.  }{\insrsid13176573 G}{\insrsid13176573\charrsid12860689 enetic information is quite complex, and it }{
\insrsid1792628 can}{\insrsid13176573\charrsid12860689  therefore }{\insrsid1792628 be}{\insrsid13176573\charrsid12860689  easy to fall back on a genetic deterministic viewpoint.  Thus, it is necessary to }{\insrsid13176573 make the }{
\insrsid13176573\charrsid12860689 probabilistic nature of genetics}{\insrsid13176573  clear}{\insrsid13176573\charrsid12860689 , rather than}{\insrsid13176573  allow the public to rely on}{\insrsid13176573\charrsid12860689 
 the standard one-gene-one-trait notion of genetics.}{\cs16\super\insrsid13176573\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13176573 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 51}{\insrsid4156601\charrsid11755622 .  }}}{\insrsid13176573\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3817714 {\insrsid13176573\charrsid12860689 Since almost all illnesses are genetically heterogeneous, particular pr
oblems exist for those who are found to carry }{\insrsid13176573 a }{\insrsid13176573\charrsid12860689 predisposition to such illnesses.  Nancy Wexler, a renowned scientist best known for her work towards finding a cure for Huntington}{\insrsid13176573 
\rquote }{\insrsid13176573\charrsid12860689 s disease, worries that the concept of variable penetrance may be too complex for the general public.}{\cs16\super\insrsid13176573\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13176573 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nancy Wexler, }{
\i\insrsid4156601\charrsid11755622 The Oracle of DNA, }{\insrsid4156601\charrsid11755622 Molecular Genetics of Neuromuscular Disease}{\i\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid11755622 (Oxford: Oxford University Press, 1989).}}}{
\insrsid13176573\charrsid12860689   As the science becomes more complex, the need for appropriate public education becomes more pressing, particularly because in the absence of education elsewhere, \'93
there will be a reliance on industry and patient advocate groups to supply the information, with some inherent bias.\'94}{\cs16\super\insrsid13176573\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13176573 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{
\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36.}}}{\insrsid13176573 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13386707 {\insrsid13386707\charrsid12860689 
Obviously, education is an integral part of making pharmacogenomics discoveries benefit the greatest number of individuals.  In order to further this aim, the FDA has developed a number of science forums}{\insrsid13386707 .  For example, }{
\insrsid13386707\charrsid12860689 the 11th Annual FDA Science Forum entitled }{\i\insrsid13386707\charrsid9648509 Personalizing Your Healthcare: The Best Consumer is an Educated Consumer}{\insrsid13386707\charrsid12860689 , will be held }{\insrsid6102696 
free to the public }{\insrsid13386707\charrsid12860689 in April, 2005.}{\cs16\super\insrsid13386707\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13386707 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  11th Annual FDA Science Forum, April 27-28, 2005, Washington, DC Convention Center}{
\i\insrsid4156601\charrsid11755622 .  Information available at}{\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid10158083 http://www.cfsan.fda.gov/~frf/forum05/sxsf05pr.html}{\insrsid4156601\charrsid11755622 .}}}{
\insrsid13386707\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 VI}{\b\insrsid10880679 .  }{\b\insrsid7149582\charrsid12860689 Conclusion}{
\b\insrsid12132278\charrsid12860689  }{\b\insrsid3935865\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid6635737 {\insrsid14436897\charrsid12860689 The targeted nature of }{\insrsid16151277 pharmacogenomics}{\insrsid14436897\charrsid12860689  may make it s}
{\insrsid5243569\charrsid12860689 eem, upon first blush, that }{\insrsid16151277 the discipline}{\insrsid5243569\charrsid12860689  }{\insrsid14436897\charrsid12860689 does not }{\insrsid5243569\charrsid12860689 present the same sort of }{
\insrsid1403258\charrsid12860689 worrisome}{\insrsid5243569\charrsid12860689  ethical }{\insrsid13129762\charrsid12860689 and legal }{\insrsid5243569\charrsid12860689 dilemmas }{\insrsid13129762\charrsid12860689 that are }{
\insrsid5243569\charrsid12860689 generally expected from genetic discoveries}{\insrsid14436897\charrsid12860689 .  }{\insrsid7368861\charrsid12860689 As we have seen, }{\insrsid7368861\charrsid12860689 
the ultimate promise of personalized, tailor-made medicine, with fewer side effects, more appropriate dosage, and prescription of drugs according to one\rquote s particular drug sensitivity}{\insrsid10880679  is tantalizing}{
\insrsid7368861\charrsid12860689 .  }{\insrsid14436897\charrsid12860689 However}{\insrsid5243569\charrsid12860689 , there are a number of dilemmas that must be considered in order }{\insrsid3751568\charrsid12860689 to proactively}{
\insrsid5243569\charrsid12860689  approach and anticipate potential innovations and their implications rather than \'93trying to implement retroactive changes.\'94}{\cs16\super\insrsid5243569\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Barbara Ann Binzak, }{\i\insrsid4156601\charrsid11755622 How Pharmacogenomics Will Impact the Federal Regulation of Clinical Trials and the New Drug Approval Process}{\insrsid4156601\charrsid11755622 , 58 Food Drug. L.J. 102, 103 (2003).}}}{
\insrsid5243569\charrsid12860689  }{\insrsid6635737\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid6635737\charrsid12860689 
Many of the problems encountered when considering the impact of pharmacogenomics on society are multilayered and complex, and involve ethical, legal, and public-policy-related }{\insrsid10880679 issue}{\insrsid6635737\charrsid12860689 
s.  When possible, these problems will be separated out, but it is inevitable that legal issues will come up in the conversation regarding the ethical dimensions of pharmacogenomics, and vice versa.  }{\insrsid9717014\charrsid13310513 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid13129762\charrsid12860689 This paper }{\insrsid3751568\charrsid12860689 primarily}{\insrsid13129762\charrsid12860689  deals with }{
\insrsid1462823\charrsid12860689 the }{\insrsid13129762\charrsid12860689 role of industr}{\insrsid1462823\charrsid12860689 y in furthering pharmacogenomic}{\insrsid13129762\charrsid12860689 
 developments, and the dimensions of current regulatory and legislative decision-making}{\insrsid10880679  in the discipline}{\insrsid13129762\charrsid12860689 .  }{\insrsid10880679 T}{\insrsid13129762\charrsid12860689 
he discussion of the impact of pharmacogenomics would be incomplete if the influence of patent law on the burgeoning field of pharmacogenomics, as well as }{\insrsid14183866\charrsid12860689 
how theories of liability may change, or be changed, by pharmacogenomic developments}{\insrsid10880679  were not considered}{\insrsid14183866\charrsid12860689 .  }{\insrsid10880679 In addition, t}{\insrsid14183866\charrsid12860689 he }{\insrsid13310513 
final}{\insrsid14183866\charrsid12860689  section will consider }{\insrsid13129762\charrsid12860689 the impact that the}{\insrsid16127030\charrsid12860689 se}{\insrsid13129762\charrsid12860689  }{\insrsid2310118\charrsid12860689 scientific }{
\insrsid13129762\charrsid12860689 developments will have on issues of privacy, insurance, and the need for education.}{\cs16\super\insrsid13266421 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid12860689 
Throughout the paper, it might appear as if I am giving short shrift to issues related to genetic testing, such as privacy and consent.  However, I have chosen to focus more on the impact of pharmacogenomics in
 terms of drug development.  Testing does become pertinent particularly during discussion of test-drug combination products, and I will therefore spend some time considering the ethical issues generally associated with genetic testing in later sections.  
However, genetic testing is an enormous topic which would be better dealt with separately.}{\insrsid4156601\charrsid13266421  }{\insrsid4156601 
For a detailed account of the myriad issues associated with genetic testing, specifically in light of pharmacogenomics, }{\i\insrsid4156601 see }{\insrsid4156601 Lars Noah, }{\i\insrsid4156601 The Coming Pharmacogenomics Rev
olution: Tailoring Drugs to Fit Patients\rquote  Genetic Profiles}{\insrsid4156601 \'b8 43 Jurimetrics J. 1 (2002).  }{\insrsid4156601\charrsid11755622 Moreover, an excellent paper was submitted for this same class in 2003:}{
\cs15\insrsid4156601\charrsid11755622  }{\cs15\i\insrsid4156601\charrsid11755622 See }{\insrsid4156601\charrsid11755622 Anna E. Lumelsky}{\i\insrsid4156601\charrsid11755622 ,}{\cs15\i\insrsid4156601\charrsid11755622  G}{
\cs30\i\insrsid4156601\charrsid11755622 enetic Testing and Government Regulation: The Growing Significance of Pharmacogenomics}{\insrsid4156601\charrsid11755622  (2003 Third Year Paper).  }}}{\insrsid13129762\charrsid12860689 
\par }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3541397 {\insrsid3541397 \page }{\b\insrsid15024846\charrsid12860689 THE SCIENCE AND PROCESS OF }{\b\insrsid12132278\charrsid12860689 PHARMACOGENOMIC }{
\b\insrsid15024846\charrsid12860689 DRUG }{\b\insrsid8784707 RESEARCH AND }{\b\insrsid15024846\charrsid12860689 DEVELOPMENT }{\b\insrsid6126054 
\par }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10229876 {\b\insrsid10229876\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 I}{\b\insrsid10880679 .  }{\b\insrsid16272184\charrsid12860689 The Science
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16272184 {\insrsid16272184\charrsid12860689 The Human Genome Project (HGP), one of the most industrious scientific endeavors of the late twentieth 
century, has had an enormous effect on subsequent discoveries relating to genome-based research.  Pharmacogenomics is based on discovering \'93mistaken pairings,\'94
 in which the basic pairing of nucleotide bases in DNA (or mRNA) are reversed  (i.e., where adenine (referred to simply as A) does not, as it usually does, bond with thymine (T), or cytosine (C) does}{\insrsid6102696  }{\insrsid16272184\charrsid12860689 n
}{\insrsid6102696 o}{\insrsid16272184\charrsid12860689 t bond with guanine (G)).  These \'93mistakes\'94 in base pairs cause mutations in the DNA.  If a mutation occurs in more than one percent of the population,
 it is referred to as a single nucleotide polymorphism (SNP).}{\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Binzak, }{\i\insrsid4156601 supra }{\insrsid4156601 note 73 at 109.  }}}{\insrsid16272184\charrsid12860689 
  These SNPs are \'93found sprinkled throughout the population\'94 so that it is possible, by looking at groups with shared traits, }{\insrsid4735685 to identify}{\insrsid16272184\charrsid12860689  shared SNPs.  There are approximately eleven million SNP
s in the human population, with an average of one every 1,300 base pairs.}{\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Pharmacogenomics}{\insrsid4156601\charrsid11755622 
, American Medical Association, a}{\i\insrsid4156601\charrsid11755622 vailable at }{\insrsid4156601\charrsid10158083 http://www.ama-assn.org/ama/pub/category/2306.html}{\insrsid4156601\charrsid11755622  (last visited 1/7/05).}}}{
\insrsid16272184\charrsid12860689   SNPs may \'93give rise to disease, increased susceptibility to disease, sensitivity or insensitivity to certain drug treatments, or adverse side effects from those treatments.  Altern
atively, SNPs may mark the presence of disease-causing genes or indicate disease susceptibilities or drug sensitivities.\'94}{\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 AC Nunnally, SA Brown, and GA Cohen}{\i\insrsid4156601\charrsid11755622 , Intellectual Property and Commercial Aspects of Pharmacogenomics}{\insrsid4156601\charrsid11755622 
 in Pharmacogenomics: Social, Ethical, and Clinical Dimensions 114 (Mark A. Rothstein, ed., Hoboken, NJ: John Wiley & Sons) (2003).}}}{\insrsid16272184\charrsid12860689 
  Drug companies can put pharmacogenomics to use by acquiring DNA samples from within a population in order to \'93connect drug toxicity and ineffectiveness to SNPs.\'94}{\cs16\super\insrsid16272184\charrsid12860689  \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Binzak, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 73 at 103.}}}{\insrsid16272184\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16272184 {\insrsid16272184\charrsid12860689 
Pharmacogenomics may be particularly useful for drug development and treatment decisions because of its ability to generate biological mark}{\insrsid348963 ers, or \'93biomarkers.\'94  The FDA}{\insrsid16272184\charrsid12860689  guidance}{
\insrsid13836550  on pharmacogenomics}{\insrsid16272184\charrsid12860689 , releas}{\insrsid13836550 ed in }{\insrsid348963 March 2005 (after having been available}{\insrsid13836550  for comment}{\insrsid348963  since November 2003)}{\insrsid13836550 ,}{
\insrsid16272184\charrsid12860689  defines a biomarker as \'93a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.\'94}{
\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological Health (CDRH), FDA, }{
\i\insrsid4156601\charrsid11755622 Draft Guidance for Industry: Pharmacogenomic Data Submissions.}{\insrsid4156601\charrsid11755622  (Nov. 2003) (}{\i\insrsid4156601\charrsid11755622 citing }{\insrsid4156601\charrsid11755622 
Biomarkers Definitions Working Group, }{\i\insrsid4156601\charrsid11755622 Biomarkers and Surrogate Endpoints: Preferred Definitions and Conceptual Framework}{\insrsid4156601\charrsid11755622 , 69(3) Clinical Pharm. & Therapeutics (2001)). }}}{
\insrsid16272184\charrsid12860689   It defines a valid biomarker as a \'93
biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates
 the physiologic, toxicologic, pharmacologic, or clinical significance of the test results.\'94}{\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 FDA, }{\i\insrsid4156601\charrsid11755622 Guidance for Industry: P}{\i\insrsid4156601 harmacogenomic Data Submissions, supra }{\insrsid4156601 note 65.   }}}{\insrsid6102696   }{\insrsid1720629 With pharmacogenomic advances such as these}{
\insrsid12452262 , d}{\insrsid7149582\charrsid12860689 rug}{\insrsid16272184\charrsid12860689  developers }{\insrsid12452262 may be able to}{\insrsid16272184\charrsid12860689  design products that are effective and eliminate adverse drug }{
\insrsid7149582\charrsid12860689 reactions}{\insrsid12452262  utilizing these biomarkers. }{\insrsid16272184\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16272184 {\insrsid16272184\charrsid12860689 One }{\insrsid12452262 product }{\insrsid16272184\charrsid12860689 
development option involves creating genetic test and drug combinations.  }{\insrsid13839713\charrsid12860689 However, }{\insrsid16272184\charrsid12860689 SNP-mapping from }{\cs18\insrsid16272184\charrsid12860689 whole genome scans}{
\insrsid16272184\charrsid12860689  could be another significant innovation for drug development research.}{\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\super\insrsid4156601\charrsid11755622  }{
\insrsid4156601\charrsid11755622 Lesko, }{\i\insrsid4156601 supra }{\insrsid4156601 note 38.  }}}{\insrsid16272184\charrsid12860689   Thus, it is possible to imagine }{\insrsid1720629 a }{\insrsid9839000 comprehensive}{\insrsid8338877 
 genetic test that tests for a number of different products rather than }{\insrsid1720629 the popular }{\insrsid16272184\charrsid12860689 
one-test, one-drug scenario.  In fact, developers may not, in the future, have to develop a genetic test to go along with every drug developed via pharmacogenomics, but instead be able t}{\insrsid2766260 o conduct a single }{
\insrsid16272184\charrsid12860689 genome scan to determine all of the information necessary for the prescriptions an individual may need over the course of his or her lifetime.}{\insrsid7685238\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16272184 {\insrsid16272184\charrsid12860689 Microarray technology may be useful in advancing the promises of phar
macogenomics by eliminating the need for multiple independent genetic tests to find information about an individual\rquote s disease susceptibility or metabolism.  One }{\i\insrsid16272184\charrsid9450237 New York Times}{\insrsid16272184\charrsid12860689 
 reporter maintains that the current \'93needle-in-a-haystack process could take many years using test tubes and petri dishes but is accelerated a thousandfold by biochip technology.\'94}{\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Lawrence Fisher, }{\i\insrsid4156601\charrsid11755622 Biology Meets High Technology}{\insrsid4156601\charrsid11755622 , N.Y. Times, Dec. 21, 1999.}}}{\insrsid16272184\charrsid12860689   Simple blood tests that produce a readout }{\insrsid2766260 
would be in the form of a micro}{\insrsid16272184\charrsid12860689 array, or GeneChip, which contains a person\rquote s entire genetic profile.}{\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  \'93
GeneChip Technology,\'94 }{\i\insrsid4156601\charrsid11755622 Affymetrix. }{\insrsid4156601\charrsid10158083 http://www.affymetrix.com/technology/dna_analysis/index.affx}{\insrsid4156601\charrsid11755622  (visited 1/5/05).}}}{
\insrsid9315852\charrsid12860689   Such}{\insrsid16272184\charrsid12860689  chips could be inserted into a \'93PC-sized analytical instrument\'94 which could predict the person\rquote s susceptibility to developing particular disorders}{
\insrsid7538444\charrsid12860689  or one\rquote s metabolism.}{\cs16\super\insrsid16272184\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Fisher, }{\i\insrsid4156601 supra }{\insrsid4156601 note 82.}}}{\insrsid16272184\charrsid12860689   }{
\insrsid9450237 Roche Diagnostics}{\insrsid7538444\charrsid12860689  recently developed the AmpliChip CYP450,}{\insrsid9450237  claiming that it is \'93the world\rquote }{\insrsid7538444\charrsid12860689 
s first pharmacogenomic microarray designed for clinical applications.\'94}{\field\fldedit{\*\fldinst {\insrsid7538444\charrsid12860689  INCLUDEPICTURE "http://www.roche-diagnostics.com/images/1pix_trans.gif" \\* MERGEFORMATINET }}{\fldrslt {
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\lang1024\langfe1024\noproof\insrsid1670862 94}}}{\insrsid4666048\charrsid4666048  -}{\insrsid4666048 
\par }}{\cs16\super\insrsid7538444\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Product Detail, AmpliChip CYP450 Test}{\insrsid4156601\charrsid11755622 , Roche Diagnostics, }{\i\insrsid4156601\charrsid11755622 
at }{\insrsid4156601\charrsid11755622 http://www.roche-diagnostics.com/products_services/amplichip_cyp450.html.}}}{\insrsid7538444\charrsid12860689   }{\insrsid8338877 This product}{\insrsid7538444\charrsid12860689 
 is intended to identify and analyze variations for two genes that are ass}{\insrsid7538444\charrsid12860689 ociated with the metabolism of approximately a quarter of all prescription drugs.}{\cs16\super\insrsid7538444\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .  \'93Results are obtained and interpreted by computer analysis performed on a scan showing the pattern of hybridization of the patient sample to a series of probes (arrayed on 
the glass substrate) that are specifically complementary to either wild-type or mutant sequences.\'94}}}{\insrsid7538444\charrsid12860689   The product, which is powered by Affymetrix microarray technology, received FDA }{\insrsid548638\charrsid12860689 
clearance}{\insrsid7538444\charrsid12860689  in }{\insrsid548638\charrsid12860689 January}{\insrsid7538444\charrsid12860689  2005.}{\cs16\super\insrsid7538444\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Roche\rquote s AmpliChip CYP450 Test Receives FDA Clearance,}{\insrsid4156601\charrsid11755622  Roche Diagnostics}{\i\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid11755622 
(Jan. 11, 2005), at http://www.roche-diagnostics.us/press_room/2005/011105.htm.}}}{\insrsid7538444\charrsid12860689   
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid16272184\charrsid12860689 
Instead of subjectively interpreting symptoms, pharmacogenomics promises to help physicians understand an individual\rquote s illness at the molecular level.  It is anticipated that \'93
[a]s DNA microarray technology is developed further, SNP screening in the doctor\rquote s office to determine a patient\rquote s response to a drug, prior to drug prescription, will be commonplace.\'94}{\cs16\super\insrsid16272184\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\super\insrsid4156601\charrsid11755622  }{\cs20\i\insrsid4156601\charrsid11755622 Just the Facts: A Basic Introduction to the Science Underlying NCBI Resources}{\cs20\insrsid4156601\charrsid11755622 , National Center for Biotechnology Information, }{
\cs20\i\insrsid4156601\charrsid11755622 a}{\i\insrsid4156601\charrsid11755622 vailable at}{\insrsid4156601\charrsid11755622  }{\field\flddirty{\*\fldinst {\insrsid4156601\charrsid11755622  HYPERLINK "http://www.ncbi.nlm.nih.gov/About/primer/pharm.html" }{
\insrsid4156601\charrsid11755622 {\*\datafield 
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000000}}}{\fldrslt {\cs17\insrsid4156601\charrsid11755622 http://www.ncbi.nlm.nih.gov/About/primer/pharm.html}}}{\insrsid4156601\charrsid11755622  (last visited 1/29/05).}}}{\insrsid8725941\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 II}{\b\insrsid9450237 .  }{\b\insrsid8725941\charrsid12860689 Drug Development
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 A}{\b\insrsid9450237 .  }{\b\insrsid15550035 Industry }{\b\insrsid11930460\charrsid12860689 R}{
\b\insrsid4733528\charrsid12860689 eluctance}{\b\insrsid15550035  to Utilize Pharmacogenomics in its R&D}{\b\insrsid4733528\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid9450237\charrsid12860689 There are conflicting opinions regarding the prospects for pharmacogenomics }{\insrsid6166433 with}{
\insrsid9450237\charrsid12860689 in the pharmaceutical industry.}{\insrsid9450237   }{\insrsid14238861\charrsid12860689 Big }{\insrsid10044921\charrsid12860689 pharmaceutical}{\insrsid14238861\charrsid12860689  companies may be }{
\insrsid11274775\charrsid12860689 hesitant}{\insrsid14238861\charrsid12860689  to pursue pharmacogenomics at all, for any drug or illness, because they may see it as inherently unprofitable. }{\insrsid2888255\charrsid12860689 Some }{\insrsid8474921 
critics assert}{\insrsid2888255\charrsid12860689  that c}{\insrsid14238861\charrsid12860689 ompanies who s}{\insrsid8474921 ell the most products that are, in fact, }{\insrsid14238861\charrsid12860689 ineffective}{\insrsid2125014\charrsid12860689 
 for many}{\insrsid8474921  consumers/patients}{\insrsid14238861\charrsid12860689 , have the least incentive to do research to identify }{\insrsid2125014\charrsid12860689 more }{\insrsid14238861\charrsid12860689 effective drugs.}{
\cs16\super\insrsid2888255\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  BJ Evans, DA Flockhart, EM Meslin, }{\i\insrsid4156601\charrsid11755622 Creating Incentives for Genomics Research to Improve Targeting of Therapies,}{
\insrsid4156601\charrsid11755622  10 Nature Med. 1289, 1289 (2004).}}}{\insrsid14238861\charrsid12860689  }{\insrsid13923643\charrsid12860689 
  They claim that companies who are successful with their blockbuster drugs will be hesitant to pursue pharmacogenomic research because alternative drugs may \'93serve only a small portion of the population.\'94}{
\cs16\super\insrsid13923643\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Pharmacogenomics}{\insrsid4156601\charrsid11755622 , Human Genome Project Information, }{\i\insrsid4156601 supra }{\insrsid4156601 
note 25.  }}}{\insrsid15684490\charrsid12860689   The \'93stratification\'94 of groups of patients by their genetic predispositions could lead companies to bypass the development of potentially beneficial drugs and therapies because }{\insrsid8474921 
of the }{\insrsid6166433 limited size of the }{\insrsid8474921 targeted patient population}{\insrsid15684490\charrsid12860689 .}{\cs16\super\insrsid15684490\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nuffield
 Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622  }}}{\insrsid15684490\charrsid12860689   }{\insrsid6166433 Income e}{\insrsid9983032\charrsid12860689 
stimates for these smaller patient markets run }{\insrsid2766260 three hundred to\~five hundred}{\insrsid9983032\charrsid12860689  million}{\insrsid2766260  dollars}{\insrsid9983032\charrsid12860689  rather than }{\insrsid8474921 the }{
\insrsid2125014\charrsid12860689 one}{\insrsid9983032\charrsid12860689  billion}{\insrsid8474921  dollars}{\insrsid2125014\charrsid12860689  generally associated with one-size-fits-all drugs}{\insrsid9983032\charrsid12860689 .}{
\cs16\super\insrsid9983032\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Wu, }{\i\insrsid4156601 supra }{\insrsid4156601 note 27}{\insrsid4156601\charrsid11755622  (}{\i\insrsid4156601\charrsid11755622 citing}{
\insrsid4156601\charrsid11755622  Gina-Louise Monari, From }{\i\insrsid4156601\charrsid11755622 Blockbusters to Multibusters: Personalized Medicine May Diminish the Importance of the Outrageously Successful Drug,\~
Triggering a More Profitable Drug-Development Model,}{\insrsid4156601\charrsid11755622  22 Med. Ad. News (Jun. 1, 2003)).}}}{\insrsid10644497\charrsid12860689   }{\insrsid273851\charrsid12860689 Thus, there is concern that ph}{
\insrsid12806265\charrsid12860689 armacogenomic developments could lead to market segmentation by increasing R&D costs without raising profits.}{\cs16\super\insrsid7426351\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Corrigan, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 30.}}}{\insrsid15684490\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid10439170 {\insrsid2888255\charrsid12860689 However, }{\insrsid14238861\charrsid12860689 if other companies manufacture a drug that is obviously more effective}{
\insrsid2125014\charrsid12860689  than the current blockbuster}{\insrsid273851\charrsid12860689  drug}{\insrsid14238861\charrsid12860689 , people }{\insrsid2888255\charrsid12860689 may}{\insrsid14238861\charrsid12860689  stop buying the ineffective one}{
\insrsid2888255\charrsid12860689 , thereby forcing }{\insrsid2125014\charrsid12860689 sponsors of big-name drugs }{\insrsid2888255\charrsid12860689 to compete in the }{\insrsid16663215\charrsid12860689 market.}{\insrsid8002727\charrsid12860689  }{
\insrsid6891652  }{\insrsid1051419 D}{\insrsid1051419\charrsid12860689 ifferentiating drugs according to effectiveness in sub-populations may lead to increas}{\insrsid4662408 ed}{\insrsid1051419\charrsid12860689  competition among companies.}{
\insrsid1051419   }{\insrsid15216827 Evans, Flockhart, and Meslin, t}{\insrsid15216827\charrsid12860689 he authors of \'93Creating Incentives for Genomics Research to Improve Targeting of Therapies,\'94 }{\insrsid15216827 point}{
\insrsid15216827\charrsid12860689  out big pharmaceutical companies\rquote  reluctance to en}{\insrsid15216827 ter the pharmacogenomics market.  However, they}{\insrsid15216827\charrsid12860689  concede that although \'93
increased attention to cost effectiveness tends to reward well-targeted therapies for their low rates of treatment failure\'85 drugs need only outperform a standard or reference drug, which could itself be poorly targeted.\'94}{
\cs16\super\insrsid15216827\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15216827 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1290.  }}}{
\insrsid15216827\charrsid12860689   }{\insrsid14238861\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid7808596\charrsid12860689 Pharmaceutical companies, as we will see in more detail in }{\insrsid6891652 the section on legal liability}{
\insrsid7808596\charrsid12860689 , may be reluctant to
 pursue pharmacogenomic research because of a fear of increased liability, as greater precision may shift the standard of care such that companies could be held responsible for ineffective treatment or ADRs in ways that they are not under the current regi
me. }{\insrsid2125014\charrsid12860689  }{\insrsid10099105\charrsid12860689 Treatment effectiveness and side effects, which were previously uncontrollable, }{\insrsid4662408 would}{\insrsid10099105\charrsid12860689  now }{\insrsid4662408 be }{
\insrsid10099105\charrsid12860689 within the drug manufacturers\rquote  control}{\insrsid8667738\charrsid12860689 .}{\cs16\super\insrsid10099105\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid10099105\charrsid12860689   }{\insrsid9390398\charrsid12860689 Companies are aware of this, and therefore t}{\insrsid10048450\charrsid12860689 he standard of care may already be changing.  For example, one company, N
orvartis, has offered customers a money-back guarantee on two of its antihypertensives}{\insrsid8722281\charrsid12860689 , demonstrating behavior more like that of other }{\insrsid6360595\charrsid12860689 industrie}{\insrsid8722281\charrsid12860689 
s than the drug }{\insrsid7808596\charrsid12860689 industry}{\insrsid10048450\charrsid12860689 .}{\cs16\super\insrsid6360595\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.  }}}{\insrsid5713265\charrsid12860689   However, }{\insrsid1051419 Evans, Flockhart, and Meslin}{\insrsid1051419\charrsid12860689  }{\insrsid5713265\charrsid12860689 caution that encouraging behavior like that of Novartis would \'93
be an extreme approach to the desired incentive structure}{\insrsid144414 \'85}{\insrsid1051419  }{\insrsid5713265\charrsid12860689 rife with ethical, social, industry and community concerns, even if science were fully ready to support it.\'94}{
\cs16\super\insrsid5713265\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid8736112 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11409746 {\insrsid11409746\charrsid12860689 Even as it might fight it, the industry is anticipating change.  Although some industry repre}{
\insrsid11409746 sentatives will admit that \'93[t]}{\insrsid11409746\charrsid12860689 he era of the blockbuster is ending,\'94 it is unclear how \'93the drug industry will metamorphose itself.\'94}{\cs16\super\insrsid11409746\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11409746 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Pamela Sherrid, }{\i\insrsid4156601\charrsid11755622 Is There a Market for Personal Medicine?}{\insrsid4156601\charrsid11755622  56 U.S. News & World Rep. (1/20/03) (quoting Dorman
 Followwill, head of life sciences at research firm Frost & Sullivan).}}}{\insrsid11409746\charrsid12860689  }{\insrsid16389222  }{\insrsid11409746\charrsid12860689 
In fact, the configuration of the industry may shift so much that Robert Freeman, head of public policy at AstraZeneca, admits, \'93We simply don\rquote t know what kind of business model is necessary to commercialize personalized\~medicine.\'94}{
\cs16\super\insrsid11409746\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11409746 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid11409746\charrsid12860689  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11409746 {\insrsid11409746\charrsid12860689 Some pharmaceutical companies have actively begun pursuing pharmacogenomic research}{\insrsid4662408 
.  For example, GlaxoSmithKline}{\insrsid11409746\charrsid12860689  \'93has 
played a prominent role in promoting pharmacogenetics, with company scientists producing a number of scientific papers in high profile science and medical journals urging the uptake of pharmacogenetics.\'94}{\cs16\super\insrsid11409746\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11409746 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Corrigan, }{\i\insrsid4156601 supra }{\insrsid4156601 note 30 at 5.}}}{\insrsid11409746\charrsid12860689   }{\insrsid4662408 By 1998, three major companies --}{\insrsid11409746\charrsid12860689 Genset in Paris, 
Celera Genomics in Maryland, and Incy}{\insrsid16067922 te Genetics }{\insrsid4662408 in California --}{\insrsid16067922  had }{\insrsid11409746\charrsid12860689 
begun preparation to undertake systematic searches of the genome for variants or SNPs, and a number of }{\insrsid12454601 other }{\insrsid11409746\charrsid12860689 companies had been created in order to develop molecular diagnostics.}{
\cs16\super\insrsid11409746\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11409746 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Marshall, }{\i\insrsid4156601\charrsid11755622 One Drug Does Not Fit All}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 54.  }}}{
\insrsid11409746\charrsid12860689   }{\insrsid4662408\charrsid12860689 Interesting}{\insrsid4662408 ly}{\insrsid4662408\charrsid12860689 , in the past, companies have sought to }{\insrsid4662408 downplay}{\insrsid4662408\charrsid12860689 
 news of adverse events related to their drugs.  However, \'93such incidences are now being highlighted as rationales for the promotion of pharmacogenetics.\'94}{\cs16\super\insrsid4662408\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid4662408 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Corrigan, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 30 at 7.}}}{\insrsid11409746\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 B}{\b\insrsid7029336 .  }{\b\insrsid10581199\charrsid12860689 Advantages}{\b\insrsid14818623  of U}{
\b\insrsid8748061 s}{\b\insrsid14818623 ing Pharmacogenomics in Drug Development}{\b\insrsid2125014\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid2125014\charrsid12860689 \tab }{\b\insrsid2823497\charrsid12860689 \tab }{\b\insrsid14054882 1}{\b\insrsid7029336 .  }
{\b\insrsid2125014\charrsid12860689 Cost-}{\b\insrsid8784707 S}{\b\insrsid2125014\charrsid12860689 aving }{\b\insrsid8784707 M}{\b\insrsid2125014\charrsid12860689 easures}{\b\insrsid10581199\charrsid12860689  }{\b\insrsid14238861\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid7497177 {\insrsid5652455 An}{\insrsid4029898  oft-quoted}{\insrsid2125014\charrsid12860689 
 study by the Boston Consulting Group asserts that companies that are hesitant }{\insrsid11666227 to}{\insrsid2125014\charrsid12860689  enter the \'93genomics revolution head on\'94 will suffer}{\insrsid7474840  the}{\insrsid2125014\charrsid12860689 
 consequences, }{\insrsid7474840 rendering them }{\insrsid2125014\charrsid12860689 \'93unable to compete\'94}{\insrsid14483942  in the market}{\insrsid9141262  with those that do}{\insrsid14483942 .}{\cs16\super\insrsid2125014\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 A Revolution in R&D: How Genomics and Genetics are Transforming the Biopharmaceutical Industry,}{\insrsid4156601\charrsid11755622  The Boston Consulting Group at 21 (2001),}{
\i\insrsid4156601\charrsid11755622  available at }{\insrsid4156601\charrsid10158083 http://www.bcg.com/publications/files/eng_genomicsgenetics_rep_11_01.pdf}{\insrsid4156601\charrsid11755622 .}}}{\insrsid2125014\charrsid12860689    Moreover, }{
\insrsid9392939\charrsid12860689 the pharmaceutical industry is aware of}{\insrsid2125014\charrsid12860689  }{\insrsid9392939\charrsid12860689 many of the }{\insrsid2125014\charrsid12860689 (albeit speculative and long-term) }{
\insrsid9392939\charrsid12860689 advantages pharmacogenomics may have to offer.}{\cs16\super\insrsid2125014\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{
\insrsid4156601 note 89 at 1289.  }}}{\insrsid803550\charrsid12860689   }{\insrsid11274775\charrsid12860689 Currently, drug research and development is extremely expensive and }{\insrsid545567 relatively haphazard}{\insrsid11274775\charrsid12860689 .  }{
\insrsid10044921\charrsid12860689 In 2003, members of P}{\insrsid5769827\charrsid12860689 harmaceutical Research and Manufacturers of America (P}{\insrsid10044921\charrsid12860689 hRMA}{\insrsid5769827\charrsid12860689 )}{
\insrsid10044921\charrsid12860689  spent an estimated $33.2 billion on pharmaceutical R&D.}{\cs16\super\insrsid10044921\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\i\insrsid4156601\charrsid11755622 
 Pharmaceutical Industry 2004,}{\insrsid4156601\charrsid11755622  Pharmaceutical Research and Manufacturers of America (PhRMA), at vii (2004), }{\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid10158083 
http://www.phrma.org/publications/publications//2004-03-31.937.pdf}{\insrsid4156601\charrsid11755622 .}}}{\insrsid10044921\charrsid12860689   }{\insrsid7497177\charrsid12860689 Dr. Barbara J. Evans, one of the authors of a recent article in }{
\i\insrsid7497177\charrsid11409746 Nature Medicine}{\insrsid7497177\charrsid12860689 , described the current cost of drug development as well as the optimism about pharmacogenomics that is shared by many.  She explained,
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid7497177 {\insrsid7497177\charrsid12860689 
In 2002, overall prescription drug spending in the U.S. was $162 billion.  A back-of-the-envelope calculation suggests that up to $65 billion (or 40% o
f this total) may have been spent on drugs that, for one reason or another, did not help the patient get well.  Pharmacogenomics only addresses some of these treatment failures\emdash 
those that have genetic roots.  Still, the numbers are so large that even a small improvement in targeting could save billions of dollars.}{\cs16\super\insrsid7497177\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Pharmacogenomics Has the Potential to Spark a Major, Technology-Driven Restructuring of the Health Care and Pharmaceutical Industries,}{\insrsid4156601\charrsid11755622  News-Medical.Net (Dec. 21, 2004), }{
\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid11755622 http:// }{\insrsid4156601\charrsid10158083 www.news-medical.net/?id=6979}{\insrsid4156601\charrsid11755622  (last visited 1/05/05) (reviewing Evans, Flockhart, }{
\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1290}{\insrsid4156601\charrsid11755622 ).}}}{\insrsid7497177\charrsid12860689  
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid7497177 {\insrsid7497177\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid10439170 {\insrsid10044921\charrsid12860689 It}{\insrsid8615479  currently}{\insrsid10044921\charrsid12860689  takes an average of }{\insrsid5769827\charrsid12860689 ten to fifteen
}{\insrsid10044921\charrsid12860689  years}{\insrsid5769827\charrsid12860689  for a company}{\insrsid10044921\charrsid12860689  to develop a drug, and it costs more }{\insrsid8615479 than eight hundred}{\insrsid10044921\charrsid12860689  million}{
\insrsid8615479  dollars}{\insrsid10044921\charrsid12860689  to advance a potential new medicine from a research idea to a treatment approved by the FDA.}{\cs16\super\insrsid10044921\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Pharmaceutical Industry 2004,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 105.}{\insrsid4156601\charrsid11755622  }{\insrsid4156601  }{\i\insrsid4156601\charrsid11755622 See also }
{\insrsid4156601\charrsid11755622 Sam Tetlow, }{\i\insrsid4156601\charrsid7421013 Successful Pharmacogenomics Business Models, }{\insrsid4156601\charrsid11755622 Cambridge Healthtech Institute (2002) at 3, }{\i\insrsid4156601\charrsid11755622 available at
}{\insrsid4156601\charrsid11755622  http://www.chadvisors.com/services/pharmacogenomics_business/sample.pdf.}}}{\insrsid5769827\charrsid12860689  }{\insrsid10044921\charrsid12860689  }{\insrsid8615479 The time and financial burdens mean that}{
\insrsid5769827\charrsid12860689  }{\insrsid9392939\charrsid12860689 \'93}{\insrsid5769827\charrsid12860689 [f]}{\insrsid9392939\charrsid12860689 
ailure at the clinical trial stage could completely nullify 15 years of painstaking work by pharmaceutical research company scientists.\'94}{\cs16\super\insrsid9392939\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .}}}{\insrsid9392939\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5769827\charrsid12860689 Moreover, since most drugs do not make it far enough in the }{\insrsid11274775\charrsid12860689 development}{
\insrsid5769827\charrsid12860689  process, the profits from one product must make up for the losses incurred for failed compounds.  PhRMA states that }{\insrsid9392939\charrsid12860689 \'93}{\insrsid5769827\charrsid12860689 [o]}{
\insrsid9392939\charrsid12860689 nly 3 out of every 10 marketed Rx drugs produce revenues that ma}{\insrsid5769827\charrsid12860689 tch or exceed average R&D costs.}{\insrsid9392939\charrsid12860689 \'94}{\cs16\super\insrsid9392939\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id. at 31.}}}{\insrsid9392939\charrsid12860689  }{\insrsid5769827\charrsid12860689  }{\insrsid11274775\charrsid12860689 Furthermore}{\insrsid5769827\charrsid12860689 , }{\insrsid9392939\charrsid12860689 
only one of }{\insrsid9392939\charrsid12860689 60,000 compounds synthesized by pharmaceutical companies can be considered \'93highly successful.\'94}{\cs16\super\insrsid9392939\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 CE Reeder and WM Dickson, }{\i\insrsid4156601\charrsid11755622 Economic Implications of Pharmacogenomics}{\insrsid4156601\charrsid11755622 , in Pharmacogenomics: Social, Ethical, and Clinical Dimensions}{\insrsid4156601 ,}{
\insrsid4156601\charrsid11755622  230 (Mark A. Rothstein, ed., Hoboken, NJ: John Wiley & Sons) (2003) (}{\i\insrsid4156601\charrsid11755622 citing}{\insrsid4156601\charrsid11755622  H. Redwood, }{\i\insrsid4156601\charrsid11755622 
New Drugs in the World Market: Incentives and Impediments to Innovation}{\insrsid4156601\charrsid11755622 , 4(4) Am. Enterprise 72 (1993)).}}}{\insrsid9392939\charrsid12860689   Success is currently measured by the amount }{
\insrsid10044921\charrsid12860689 earned}{\insrsid5769827\charrsid12860689 ;}{\insrsid9392939\charrsid12860689  }{\insrsid5769827\charrsid12860689 \'93highly successful\'94 }{\insrsid9392939\charrsid12860689 blockbust}{\insrsid5769827\charrsid12860689 er 
}{\insrsid9392939\charrsid12860689 drugs have global sales over $100 million.}{\cs16\super\insrsid9392939\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622  (}{\i\insrsid4156601\charrsid11755622 citing}{
\insrsid4156601\charrsid11755622  H. Redwood, }{\i\insrsid4156601\charrsid11755622 New Drugs in the World Market: Incentives and Impediments to Innovation}{\insrsid4156601\charrsid11755622 
, 4(4) Am. Enterprise 72 (1993)).  As we will see, the measurement of \'93success\'94 may have to change as drug companies focus more on smaller \'93niche\'94 medicines rather than blockbuster drugs.}}}{\insrsid9392939\charrsid12860689   }{
\insrsid5769827\charrsid12860689 
\par }{\insrsid9973349 Generally, the most costly phases of drug research and development are at the beginning }{\insrsid15143106 s}{\insrsid9973349 tages and the larger phase III clinical trials.  }{\insrsid8850803\charrsid12860689 
In a study of all PhRMA members in 2002, 33.8% of all }{\insrsid8850803\charrsid12860689 domestic R&D was spent on p}{\insrsid8850803\charrsid12860689 rehuman/preclinical research (the
 research conducted between synthesis of a compound to first testing in humans, often includes animal testing and IRB oversight), while 4.8% was spent on Phase I, 9.6% on Phase II, 20.2}{\insrsid8850803 % }{\insrsid8850803\charrsid12860689 
on Phase III, 7.9% on FDA approval (the time spent between new drug application (NDA) submission to NDA approval), and 12.4% on Phase IV.}{\cs16\super\insrsid8850803\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Pharmaceutical Industry 2004,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 105 at 43.}{\insrsid4156601\charrsid11755622 
\par The FDA phases are as follows:
\par {\listtext\pard\plain\s15 \f3\fs20\insrsid4156601\charrsid11755622 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \s15\ql \fi-288\li864\ri0\widctlpar\jclisttab\tx864\aspalpha\aspnum\faauto\ls19\adjustright\rin0\lin864\itap0\pararsid11755622 {
\insrsid4156601\charrsid11755622 Phase I: escalating doses to determine toxicity}{\insrsid4156601 
\par {\listtext\pard\plain\s15 \f3\fs20\insrsid4156601\charrsid11755622 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}{\insrsid4156601\charrsid11755622 Phase II: larger # of people to determine o}{\insrsid4156601 ptimum amount (titration study)
\par {\listtext\pard\plain\s15 \f3\fs20\insrsid4156601\charrsid11755622 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}{\insrsid4156601\charrsid11755622 Phase III: large population study (whi}{\insrsid4156601 ch is often the most expensive)
\par {\listtext\pard\plain\s15 \f3\fs20\insrsid4156601\charrsid11755622 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}{\insrsid4156601\charrsid11755622  \'93Phase IV}{\insrsid4156601 :\'94 }{\insrsid4156601\charrsid11755622 post approval testing for at-risk groups}}}{
\insrsid8850803\charrsid12860689   }{\insrsid3880412 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid15756574\charrsid12860689 According to one estimate, \'93pharmacogenomics could save up to 45% of }{\insrsid3880412 
clinical drug development costs,}{\insrsid13044946 \'94}{\insrsid3880412  leading t}{\insrsid3880412\charrsid12860689 o a reduction in the cost and time of drug development}{\insrsid3880412 .}{\cs16\super\insrsid15756574\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Reeder and Dickson, }{\i\insrsid4156601 supra }{\insrsid4156601 note 110. }{\insrsid4156601\charrsid11755622 (citing S. Aldridge, }{\i\insrsid4156601\charrsid11755622 Customizing Drugs to Individual Genetic Profiles}{
\insrsid4156601\charrsid11755622 , 21(14) Genet. Eng. News, 29, 67 (2001)).}}}{\insrsid15756574\charrsid12860689  }{\insrsid5834685\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid14699362\charrsid12860689 The}{\insrsid2059047\charrsid12860689  Boston Consulting Group}{\insrsid7888530\charrsid12860689 
 study mentioned }{\insrsid11549302 earlier}{\insrsid5834685\charrsid12860689  found that}{\insrsid2059047\charrsid12860689  the cost of developing a new medicine could be reduced dramatically, to about }{\insrsid13044946 sixty percent}{
\insrsid2059047\charrsid12860689  of the $880 million usually required to develop a }{\insrsid1406534 drug}{\insrsid2059047\charrsid12860689 .}{\cs16\super\insrsid2059047\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Revolution in R&D: How Genomics and Genetics are Transforming the Biopharmaceutical Industry,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 103.}}}{\insrsid12454601 
  The study found that genomic}{\insrsid2059047\charrsid12860689  technologies could save drug companies an average of }{\insrsid13044946 three hundred}{\insrsid2059047\charrsid12860689  }{\insrsid7425817 million}{\insrsid13044946  dollars}{
\insrsid7425817  }{\insrsid2059047\charrsid12860689 and two years per new drug as a result of increased efficiency.}{\cs16\super\insrsid2059047\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622   Another study estimates that a twenty-five percent reduction in phase length can trim costs by $129 million. Sam Tetlow}{\i\insrsid4156601\charrsid662027 
, Successful Pharmacogenomics Business Models,}{\insrsid4156601\charrsid11755622  Cambridge Healthtech Institute (2002) at 3, }{\i\insrsid4156601\charrsid11755622 available at}{\insrsid4156601\charrsid11755622 
 http://www.chadvisors.com/services/pharmacogenomics_business/sample.pdf.}}}{\insrsid5914059\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11274775\charrsid12860689 Pharmacogenomics can be applied at every phase along the drug development process, }{
\cs18\insrsid11274775\charrsid12860689 and companies may be able to save substantial R&D c
osts and speed the drug approval process because of the ability to reduce the population in which the drug would be tested, leading to more reliable findings and safer trials}{\insrsid11274775\charrsid12860689 .}{
\cs16\super\insrsid11274775\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  \'93Jay Lichter, senior director of diagnostics and pharmacogen
etics at Sequana Therapeutics (La Jolla, CA),  believes that pharmacogenomics can benefit every stage of clinical development, even before the final phase III and beyond.  He stated, \'93
Genes that were linked with drug metabolism in preclinical studies could be genotyped in patients recruited for phase I trials.\'94
 Any genotype that correlates with adverse effects could then be used to screen out relevant patients in subsequent trials. Furthermore, Lichter suggests, if efficacy data are collected during phase I
 trials, polymorphisms in the drug target gene could be typed in phase I participants to assess whether they are linked with side effects or with variations in drug response. That analysis could obviously be further refined in phase II trials, enabling co
mpanies to undertake phase III trials in a subgroup of patients that responds well and exhibits lesser side effects. The resultant drugs would be expected not only to have better efficacy, but also a better safety profile.\'94 Marshall, }{
\i\insrsid4156601\charrsid11755622 Getting the Right Drug into the Right Patient,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 23. }}}{\insrsid11274775\charrsid12860689   }{\insrsid15756574\charrsid12860689 
Pharmaceutical companies could \'93conduct phase 2 trials with well-phenotyped patients to identify high density }{\cs18\insrsid15756574\charrsid12860689 SNP profiles predicting efficacy}{\cs18\insrsid9656072\charrsid12860689 .}{
\cs18\insrsid15756574\charrsid12860689 \'94}{\cs16\super\insrsid15756574\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{\i\insrsid4156601 supra }{\insrsid4156601 note 38.  }}}{\cs18\insrsid5834685\charrsid12860689  }{
\cs18\insrsid9656072\charrsid12860689  }{\insrsid15756574\charrsid12860689 Individuals for whom the drug in question }{\insrsid6701351 is}{\insrsid15756574\charrsid12860689 
 less likely to be effective, or those for whom the drug may have deleterious side effects, can be excluded from later stages of clinical trials, thereby improving the protection of participants in human research.}{
\cs16\super\insrsid15756574\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622  }}}{
\insrsid15756574\charrsid12860689   Moreover, the \'93selection of smaller groups of genetically homogenous participants in clinical trials may be advantageous, leading to more robust and reliable scientific findings regar
ding the group of patients who might eventually be prescribed the medicine.\'94}{\cs16\super\insrsid15756574\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid15756574\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid13450249\charrsid12860689 FDA ap}{\insrsid9656072\charrsid12860689 proval }{\insrsid15358335 may}{\insrsid9656072\charrsid12860689 
 be less costly for }{\insrsid13450249\charrsid12860689 blockbuster drugs, }{\insrsid15358335 since}{\insrsid13450249\charrsid12860689  phase III trials will be cheaper because adverse responders and non-responders would already have been identified i
n the first two phases, thereby decreasing the number of individuals necessary to ensure safety and efficaciousness.}{\cs16\super\insrsid13450249\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  L}{
\insrsid4156601\charrsid9049716 agay}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 26.}{\insrsid4156601\charrsid11755622   }{\i\insrsid4156601\charrsid11755622 See also }{
\insrsid4156601\charrsid11755622 Binzak, }{\i\insrsid4156601 supra }{\insrsid4156601 note 73 at 113.  }}}{\insrsid13450249\charrsid12860689   }{\insrsid15756574\charrsid12860689 In addition, firms can conduct phase IV}{\insrsid4002133  trials}{
\insrsid15756574\charrsid12860689 , }{\insrsid81899\charrsid12860689 or }{\insrsid15756574\charrsid12860689 post-marketing surveillance}{\insrsid81899\charrsid12860689 ,}{\insrsid15756574\charrsid12860689  using whole genome scans to identify }{
\cs18\insrsid15756574\charrsid12860689 adverse event SNP profiles.}{\cs16\super\insrsid15756574\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{\i\insrsid4156601 supra }{\insrsid4156601 note 38.  }}}{\insrsid11930460\charrsid12860689   }{
\insrsid12780380 The authors of \'93Pharmacogenetics Goes Genomic\'94}{\insrsid12780380\charrsid12860689  }{\insrsid12780380 summarize the increased efficiency and cost-effectiveness of applying pharmacogenomics to the drug R&D process:}{
\insrsid11930460\charrsid12860689 
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid9656072 {\insrsid13450249\charrsid12860689 One motivation for pharmacogenetic testing during drug development is that the stratifi
cation of patients by genotype might allow the identification of responses that would have been missed in an unselected cohort.  This could allow efficacy for subgroups to be shown in drugs that might not have been considered effective in general populati
ons, which could potentially improve the success rate of compounds.  Because of the huge costs per patient of clinical trials, it has been suggested that such streamlining might reduce the average cost of developing new compounds.}{
\cs16\super\insrsid13450249\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Goldstein, Tate, and Sisodiya, }{\i\insrsid4156601 supra }{\insrsid4156601 note 1 at 945.}}}{\insrsid11292718\charrsid12860689   }{\insrsid6554490\charrsid12860689 

\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid9656072 {\insrsid9656072\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid1395490\charrsid12860689 Reducing the failure rate could \'93far outweigh the\~negatives of market segmentation,\'94
 according to Nicholas Dracopoli, head of}{\insrsid7149582\charrsid12860689 \~pharmacogenomics}{\insrsid1395490\charrsid12860689  at Bristol-Myers Squibb.}{\cs16\super\insrsid1395490\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Sherrid, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 98.  }}}{\insrsid1395490\charrsid12860689  }{\insrsid11930460\charrsid12860689 A drug guaranteed to work on the forty percent}{\insrsid81899\charrsid12860689  of the population}{
\insrsid11930460\charrsid12860689  for whom other drugs are ineffective or cause harmful side effects will return steady revenue at a premium price.}{\cs16\super\insrsid11930460\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  L}{
\insrsid4156601\charrsid8600549 agay}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 26.}{\insrsid4156601\charrsid11755622     }}}{\insrsid11930460\charrsid12860689  }{\insrsid81899\charrsid12860689  
}{\insrsid12548363\charrsid12860689 Because of the smaller target population, companies may pursue \'93mini-busters\'94 that have been developed utilizing pharmacogenomics.  }{\insrsid11930460\charrsid12860689 Thus, a}{\insrsid11292718\charrsid12860689 
mong the advantages of incorporating pharmacogenomic research into a company\rquote s drug R&D is the ability to charge premium prices because of higher reliability}{\insrsid11930460\charrsid12860689 .}{\cs16\super\insrsid11292718\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1289.}}}{\insrsid11292718\charrsid12860689   }{\insrsid11930460\charrsid12860689 
One example that is already in the market is the breast cancer drug, H}{\insrsid12780380 erceptin, which is an expensive}{\insrsid11930460\charrsid12860689  but very effective drug for particular }{\insrsid10044921\charrsid12860689 patients}{
\insrsid11930460\charrsid12860689 .  }{\insrsid11292718\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid16139604 An}{\insrsid12780380  example of }{\insrsid2125014\charrsid12860689 blockbuster drug}{\insrsid12780380 s}{
\insrsid2125014\charrsid12860689  that could be replaced by new, more genome-specific drugs are Statins, currently the biggest\~source of revenue for many drug companies.  }{\insrsid6831802 In a recent Brigham and Women\rquote }{
\insrsid16389222\charrsid12860689 s study, patients with a\~certain common genetic variant had }{\insrsid16389222 a twenty-two percent}{\insrsid16389222\charrsid12860689  smaller drop in total cholesterol and a }{\insrsid16389222 nineteen percent}{
\insrsid16389222\charrsid12860689  smaller drop in LDL or \'93bad\'94 cholesterol than those patients without the variant.}{\cs16\super\insrsid16389222\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16389222 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Genes Play Role In Who Benefits From Statin}{\insrsid4156601\charrsid11755622 , Wall St. J. at D1 (6/16/04).}}}{\insrsid16389222\charrsid12860689   }{\insrsid16389222 P}{\insrsid2125014\charrsid12860689 
harmacogenomic discoveries \'93threaten[ ] to shake up the lucrative $26 billion market for\~Statins -- the big-selling products that help lower cholesterol in the blood\~and reduce the risk of heart attacks and strokes.\'94}{
\cs16\super\insrsid2125014\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid2125014\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11930460\charrsid12860689 
However, the commonly-held view that pharmacogenomics will lead to more efficacious and safe clinical trials because of more targeted trial studies is not unanimous.  For example, some believe that \'93
the small size of pharmacogenetics studies renders them unconvincing.\'94}{\cs16\super\insrsid81899\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 33.}}}{\insrsid11930460\charrsid12860689   }{\insrsid81899\charrsid12860689 In addition, t}{\insrsid11930460\charrsid12860689 he restricted trial populations will limit the claims }{
\insrsid15358335\charrsid12860689 a company can make}{\insrsid15358335  }{\insrsid15358335\charrsid12860689 on a drug}{\insrsid15358335  to the FDA.  This may affect the licenses FDA may grant, because a}{\insrsid1797257 pproval}{
\insrsid11930460\charrsid12860689  will only be related to the particular population in the \'93pivotal trials.\'94}{\cs16\super\insrsid11930460\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622   }}}{\insrsid11930460\charrsid12860689   The restriction of FDA approval to specific patient groups could implicate a significant problem already plaguing FDA}{\insrsid12454601 , that of}{
\insrsid81899\charrsid12860689  }{\insrsid11930460\charrsid12860689 off-label prescription.  Problems with off-label use will be discussed in further detail in the section on FDA regulation.
\par }\pard \ql \fi720\li720\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin720\itap0\pararsid16733115 {\b\insrsid14054882 2}{\b\insrsid1844610 .  }{\b\insrsid14307018 Saving Shelved D}{\b\insrsid11368522\charrsid12860689 
rugs
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid16065829\charrsid12860689 One often-noted potential advantage of pharmacogenomics is the ability to remarket \'93shelved\'94
 drugs that }{\insrsid10581199\charrsid12860689 are no longer being prescribed }{\insrsid15422489 due to the}{\insrsid10581199\charrsid12860689  inability to determine for whom the drugs will work or because they cause adverse reactions in others.}{
\cs16\super\insrsid10581199\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Greely,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 13.}{\b\insrsid4156601  }{\insrsid4156601\charrsid11755622  }}}{
\insrsid11368522\charrsid12860689  }{\insrsid16065829\charrsid12860689  }{\insrsid1464802\charrsid12860689 Between January 1, 1971, and April 30, 2004, FDA approved 780 new molecular entities.  Of these, there were }{\insrsid3953376 twenty-two}{
\insrsid1464802\charrsid12860689  safety-based drugs withdrawals, in which the approved drugs were taken off the market because of unacceptable side effects.}{\cs16\super\insrsid1464802\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 CDER Report to the Nation: 2003}{\insrsid4156601\charrsid11755622 .  }{\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid10158083 http://www.fda.gov/cder/reports/rtn/2003/rtn2003-3.HTM#Withdraw}{
\insrsid4156601\charrsid11755622 .  }}}{\insrsid1464802\charrsid12860689   }{\insrsid11368522\charrsid12860689 Developing genetic tests will allow companies to market}{\insrsid14746420  these and other already-}{\insrsid11368522\charrsid12860689 
patented and approved drugs}{\insrsid3481962 . }{\insrsid11368522\charrsid12860689  Thus, genetic tests may be able to resuscitate patented drugs that were abandoned because of problems with adverse reactions.}{
\cs16\super\insrsid11368522\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Meurer, }{\i\insrsid4156601 supra }{\insrsid4156601 note 7.}}}{\insrsid11368522\charrsid12860689  }{\insrsid16065829\charrsid12860689  The identification }{
\insrsid7551059\charrsid12860689 of}{\insrsid16065829\charrsid12860689  a \'93unique population\'85 that benefits from a drug that once experienced lagging sales because of its ineffectiveness in the larger overall population\'94 could mean that \'93
the postmarketing use of pharmacogenomics data may be quite useful to a drug company.\'94}{\cs16\super\insrsid16065829\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Binzak, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 73 at 126.}}}{\insrsid16065829\charrsid12860689   }{\insrsid11368522\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid13450249\charrsid12860689 The authors of \'93Pharmacogenetics Goes Genomic\'94 highlight the anti-epileptic drug felbamate in orde
r to clarify the use of pharmacogenomics to reduce adverse drug reactions.}{\cs16\super\insrsid13450249\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Goldstein, Tate, and Sisodiya, }{\i\insrsid4156601 supra }{\insrsid4156601 note 1 at 945.}}}{
\insrsid13450249\charrsid12860689   The drug was approved in 1993, after it was demonstrated that }{\insrsid3481962 it}{\insrsid13450249\charrsid12860689 
 helped control seizures.  During clinical investigation, there was no evidence of clinically significant blood or liver disorder}{\insrsid3481962 s}{\insrsid13450249\charrsid12860689  related to use of the drug.  However, }{
\insrsid13522444\charrsid12860689 thirty-four}{\insrsid13450249\charrsid12860689  }{\insrsid13522444\charrsid12860689 cases of aplastic anaemia and twenty-three}{\insrsid13450249\charrsid12860689  cases of hepatic failure, with }{
\insrsid13522444\charrsid12860689 eighteen}{\insrsid13450249\charrsid12860689  reported fatalities, were reported in the first year after licensing.}{\cs16\super\insrsid13450249\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid13450249\charrsid12860689   It is believed that these ADRs and associated deaths were relate}{\insrsid753298 d to the metabolism of the drug}{\insrsid13450249\charrsid12860689 .  The authors contend that \'93
[t]he ability to reliably predict which patients might be at risk of such reactions to felbamate might allow greater confidence in its use, and again make available a 
potentially valuable AED [anti-epileptic drug] for patients with epilepsy that can itself be life threatening.\'94}{\cs16\super\insrsid13450249\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid13450249\charrsid12860689   This example is }{\insrsid15235920 illustrative}{\insrsid13450249\charrsid12860689 
 of the optimism many have for FDA-approved drugs that have been subsequently shelved due to adverse reactions.  The authors claim that the economic incen}{\insrsid5914059\charrsid12860689 tives for \'93unshelving\'94 the drug}{\insrsid12025426 
 could be well worth it, }{\insrsid13450249\charrsid12860689 explaining that \'93if pharmacogenetic predictors of adverse events could prevent the exposure of genetically vulnerable patients and so preserve even a single dru
g, the costs of any large-scale research effort in pharmacogenenetics could be fully recovered.\'94}{\cs16\super\insrsid13450249\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid13450249\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid9372797\charrsid12860689 However, the }{\insrsid10503486 British }{\insrsid9372797\charrsid12860689 
Nuffield Council on Bioethics is not convinced that pharmacogenomics research will be conducted for drugs already on the market, because 
private sector companies may not have the incentives to do the research since the drugs are no longer protected by patent.}{\cs16\super\insrsid9372797\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622  Although much of the Nuffield Council\rquote 
s report is particular to the dynamics of the British system, there are a number of instances that can be extended to the American system.}}}{\insrsid9372797\charrsid12860689 
  Moreover, companies may be reluctant to narrow the number of patients who currently use their drugs.  }{\insrsid8469685 SmithKline Beecham\rquote }{\insrsid8469685\charrsid12860689 s (London)
 chief science and technology officer, George Poste, has stated, \'93With opportunities so fecund in discovery at the moment, there is little need [for big pharmaceutical companies] to go back to old drugs.\'94}{
\cs16\super\insrsid8469685\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8469685 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Marshall, }{\i\insrsid4156601\charrsid11755622 Getting the Right Drug into the Right Patient,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{
\insrsid4156601 note 23.  }}}{\insrsid8469685   }{\insrsid9372797\charrsid12860689 Thus, the Council recommends that pharmaceutical companies be encouraged, via public sector }{\insrsid1442800\charrsid12860689 funding}{\insrsid9372797\charrsid12860689 
 and support, to conduct such research on existing drugs for which there is a reasonable belief that efficacy and safety could be improved.}{\cs16\super\insrsid11034412\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622  }}}{\insrsid9372797\charrsid12860689   }{\insrsid721945\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid10046853\charrsid12860689 Moreover, }{\insrsid16139707 like those products that were shelved }{\i\insrsid16139707 after }{
\insrsid16139707 FDA approval, }{\insrsid10046853\charrsid12860689 drugs that had not made it through the approval process may}{\insrsid16139707  also }{\insrsid10046853\charrsid12860689 be given a second chance}{\insrsid5914059\charrsid12860689 . }{
\insrsid10046853\charrsid12860689  }{\insrsid1447208\charrsid12860689 Companies may take advantage of \'93Lazarus\'94 programs, which }{\insrsid2110442\charrsid12860689 are}{\insrsid1447208\charrsid12860689 
 programs in which drugs which had failed FDA approval because of high levels of ADR}{\insrsid2054874 s}{\insrsid1447208\charrsid12860689  or low efficacy may be \'93resurrected and used to treat genetically selected responders.\'94}{
\cs16\super\insrsid1447208\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Marshall, }{\i\insrsid4156601\charrsid11755622 One Drug Does Not Fit All}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 54 at 1.}}
}{\insrsid2110442\charrsid12860689   }{\insrsid5914059\charrsid12860689 Thus, \'93previously failed drug candidates may be revived as they are matched with the niche population they serve.\'94}{\cs16\super\insrsid5914059\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Pharmacogenomics}{\insrsid4156601\charrsid11755622 , Human Genome Project Information, }{\i\insrsid4156601 supra }{\insrsid4156601 note 25.  }}}{\insrsid5914059\charrsid12860689   }{
\insrsid2110442\charrsid12860689 Companies can save or \'93rescue\'94 drugs in Phase III }{\insrsid3697593 trials }{\insrsid2110442\charrsid12860689 beca
use of the new ability to reduce the rate of toxicity or adverse events in the identified testing population.}{\cs16\super\insrsid2110442\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{
\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 31.}}}{\insrsid16204641\charrsid12860689   }{\insrsid2110442\charrsid12860689 It has been}{
\insrsid1447208\charrsid12860689  predict}{\insrsid2110442\charrsid12860689 ed}{\insrsid1447208\charrsid12860689  that although the big pharmaceutical companies may abandon these drugs (\'93why try to rescue a failed compound when pipeline
s are overflowing with leads?\'94), such drugs may present desirable opportunities for smaller biotech companies who choose to }{\insrsid3697593 pursue }{\insrsid1447208\charrsid12860689 licens}{\insrsid3697593 ing}{\insrsid1447208\charrsid12860689 .}{
\cs16\super\insrsid1447208\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Marshall, }{\i\insrsid4156601\charrsid11755622 One Drug Does Not Fit All}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 54 at 1.}}
}{\insrsid2110442\charrsid12860689  
\par }\pard \ql \fi720\li720\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin720\itap0\pararsid16733115 {\b\insrsid14054882 3}{\b\insrsid5662583 .  Avoiding Negative Press}{\b\insrsid662058\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid790295\charrsid12860689 Moreover, companies may be }{\insrsid15226686\charrsid12860689 
able to avoid scandals like that currently associated with the drug Vioxx}{\insrsid11938437 .  }{\insrsid11938437\charrsid12860689 Recently, Merck}{\insrsid14042889  & Co.}{\insrsid11938437\charrsid12860689 
 conducted the largest voluntary drug recall in history after a study confirmed that Vioxx raises the risk of heart attack and stroke.}{\cs16\super\insrsid11938437\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11938437 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Inside the Industry Merck: Vioxx Recall Leads to New Questions on FDA Effectiveness,}{\insrsid4156601\charrsid11755622  10 American Political Network 9 (Oct. 4, 2004).}}}{\insrsid11938437\charrsid12860689   }{
\insrsid11938437 Drugs companies like Merck}{\insrsid15226686\charrsid12860689  may be }{\insrsid790295\charrsid12860689 less likely to lose money late in trials due to safety and efficacy problems (or even after FDA has already approve}{
\insrsid15226686\charrsid12860689 d}{\insrsid1716032\charrsid12860689 ), and will therefore be able to avoid the }{\insrsid7808596\charrsid12860689 withdrawal}{\insrsid1716032\charrsid12860689  of a drug from the market and all the }{
\insrsid7808596\charrsid12860689 negative}{\insrsid1716032\charrsid12860689  }{\insrsid7808596\charrsid12860689 press}{\insrsid1716032\charrsid12860689  and profit-loss associated with it}{\insrsid15226686\charrsid12860689 .}{
\cs16\super\insrsid5966976\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1289.}}}{
\insrsid15226686\charrsid12860689   }{\insrsid12869998\charrsid12860689 The recall has incensed FDA critics, who have accused the FDA of lacking aggressiveness and \'93foot-dragging\'94 once a drug has entered the market.}{
\cs16\super\insrsid1716032\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Inside the Industry Merck: Vioxx Recall Leads to New Questions on FDA Effectiveness,}{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601 supra }{\insrsid4156601 note 145.}}}{\insrsid3371788\charrsid12860689   }{\insrsid12869998\charrsid12860689 Agency response}{\insrsid2913478\charrsid12860689  to the Vioxx debacle has}{\insrsid12869998\charrsid12860689  include}{
\insrsid2913478\charrsid12860689 d}{\insrsid12869998\charrsid12860689  a focus on pharmacogenomics}{\insrsid662058\charrsid12860689 .  }{\insrsid12869998\charrsid12860689 Steven Galson, acting director of FDA's Center for Drug Evaluation and Research, }{
\insrsid11938437 has }{\insrsid12869998\charrsid12860689 said that FDA is \'93
focusing on improving data-mining of adverse events by using electronic filing to process reports, examining health care provider data, improving the design of clinical trials and promoting research on pharmacogenetics to help identify people who m}{
\insrsid4543301\charrsid12860689 ight react adversely to drugs.\'94}{\cs16\super\insrsid4543301\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622 
  As we will see in the discussion of off-label prescription, FDA may need to im
pose stricter phase IV monitoring requirements for certain drugs, particularly those developed utilizing pharmacogenomics, in order to be more proactive it its regulation of new technologies.}}}{\insrsid1447208\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 C}{\b\insrsid14641708 .  }{\b\insrsid14307018 The }{\b\insrsid11930460\charrsid12860689 Move from }{
\b\insrsid14307018 P}{\b\insrsid11930460\charrsid12860689 ublic to }{\b\insrsid14307018 P}{\b\insrsid11930460\charrsid12860689 rivate}{\b\insrsid15298575\charrsid12860689  }{\b\insrsid14307018 S}{\b\insrsid15298575\charrsid12860689 ector}{
\b\insrsid11930460\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid6164102 {\insrsid10896021\charrsid12860689 There has been intense focus on where the resources for pharmacogenomics will come from.  }{\insrsid14823734 It}{
\insrsid10896021\charrsid12860689  is believed that generally, \'93}{\insrsid2964119 fe}{\insrsid2964119\charrsid12860689 deral subsidies and public sect
or research currently play significant roles stimulating the development of the first generation of genetic tests designed to customize drug therapy}{\insrsid10896021\charrsid12860689 .\'94}{\cs16\super\insrsid10896021\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10896021 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Meurer, }{\i\insrsid4156601 supra }{\insrsid4156601 note 7.}}}{\insrsid10896021\charrsid12860689   }{\insrsid14823734 Although}{\insrsid10896021  s}{\insrsid11930460\charrsid12860689 ome}{\insrsid10896021  observers}{\insrsid11930460\charrsid12860689 
 predict that much of pharmacogenomic research will shift from the public to the private sector, \'93[t]hus far, public sector funding and R&D have been critical to the creation and deployment of pharmacogenomic innovations.\'94}{
\cs16\super\insrsid11930460\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .}}}{\insrsid11930460\charrsid12860689  }{\insrsid6164102  }{\insrsid6164102\charrsid12860689 
It may be important to either incentivize private sponsorship of drug development, or provi}{\insrsid6164102 de greater federal subsidies.  }{\insrsid15935158 A PhRMA report explained,}{\insrsid6164102 
\par }\pard \ql \li720\ri720\widctlpar\faauto\rin720\lin720\itap0\pararsid6164102 {\insrsid6164102\charrsid12860689 
According to the National Institutes of Health (NIH), public dollars are not funding the research leading to new medicines. In fact, only 4 of the 47 topselling drugs considered by NIH in its study to determine if Ameri
can public investments were funding new drug development were developed in part with NIH funding, and none was developed solely with public funds.}{\cs16\super\insrsid6164102\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid6164102 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Pharmaceutical Industry 2004,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 105 at 5.}}}{\insrsid6164102  }{\insrsid11930460 
\par }\pard \ql \li720\ri720\widctlpar\faauto\rin720\lin720\itap0\pararsid6164102 {\insrsid6164102\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid2964119 {\insrsid12798376 Michael Meurer, }{\insrsid2964119 quoted }{\insrsid14042889 earlier}{\insrsid11930460\charrsid12860689 
, after a series of mathematical models}{\insrsid12798376  stated}{\insrsid11930460\charrsid12860689  that }{\insrsid2964119 \'93}{\insrsid2964119\charrsid12860689 [i]f pharmacogenomics f
ulfills its promise, then we should expect that as this sector of the pharmaceutical industry matures, most of the R&D on genetic tests will shift to the private sector}{\insrsid11930460\charrsid12860689 .}{\insrsid2964119 \'94}{
\cs16\super\insrsid11930460\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Meurer, }{\i\insrsid4156601 supra }{\insrsid4156601 note 7}{\insrsid4156601\charrsid11755622 .}}}{\insrsid11930460\charrsid12860689  }{\insrsid2517555\charrsid12860689 

\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11930460\charrsid12860689 However, public sector funding of pharmacogenomics will still be necessary.  }{\insrsid3023361 Such}{
\insrsid11930460\charrsid12860689  funding may be most needed where genetic tests \'93
are not widely adopted, when tests are designed for use with substitute drugs manufactured by different companies, or when the private cost of test development is high because of licensing costs.\'94}{\cs16\super\insrsid11930460\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.  }{\insrsid4156601\charrsid11755622 The author recommends a number of options for the type of public subsidies that should be offered: \'93
Presently, federal grants directly support public sector pharmacogenomic research, and indirectly support 
pharmacogenomics through subsidies encouraging the production of research inputs (like gene data) that are used in the development of genetic tests. The government can encourage adoption of genetic tests through drug law and health insurance regulation.  
Finally, the drug laws may be used to subsidize the
\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 {\insrsid4156601\charrsid11755622 development of drugs designe}{\insrsid4156601 d to treat \lquote orphan genotypes.\rquote \'94}}}{
\insrsid11930460\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15422804 {\insrsid15422804 Thus,}{\insrsid15422804\charrsid12860689  pub
lic sector support may be necessary to encourage the private sector to develop tests for existing drugs.  There are a number of possibilities for public sector support: federal grants directly supporting such research, indirect support through subsidies e
ncouraging the production of research imputs (like gene data) that are used in the development of products, encouraging }{\insrsid12989976 the utilization}{\insrsid12989976\charrsid12860689  of }{\insrsid12989976 the }{\insrsid12989976\charrsid12860689 
use of drugs and drug tests through drug law and health insurance regulation, }{\insrsid12989976 and the use of}{\insrsid12989976\charrsid12860689  \'93orphan drug\'94 laws to incentivize such drug development}{\insrsid15422804\charrsid12860689 .}{
\cs16\super\insrsid15422804\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15422804 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid15422804\charrsid12860689   The authors of a }{\i\insrsid15422804\charrsid15422804 Nature Medicine}{\insrsid15422804\charrsid12860689 
 article, \'93Creating Incentives for Genomics Research to Improve Targeting of Therapies,\'94 explore issues of whether the private sector has appropriate incentives to }{\insrsid12989976 pursue R&D}{\insrsid15422804\charrsid12860689 .}{
\cs16\super\insrsid14823734\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid14823734 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1289.}}}{
\insrsid14823734\charrsid12860689  }{\insrsid15422804\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 D}{\b\insrsid7560466 .  }{\b\insrsid14307018 Private/P}{\b\insrsid6041850\charrsid12860689 rivate and }
{\b\insrsid14307018 P}{\b\insrsid13458818\charrsid12860689 rivate}{\b\insrsid14307018 /Public C}{\b\insrsid6041850\charrsid12860689 ollaboration}{\b\insrsid14307018 s}{\b\insrsid7043820\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid7560466 {\insrsid7560466\charrsid12860689 The authors of \'93Pharmacogenetics Goes Genomic\'94
 are concerned that economic considerations could lead to a differentiation between the research focus in the industrial and academic sectors.}{\cs16\super\insrsid7560466 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid7560466 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid11755622 
Goldstein, Tate, and Sisodiya, }{\i\insrsid4156601 supra }{\insrsid4156601 note 1 at 945.}}}{\insrsid7560466\charrsid12860689   They recommend that
 cooperation between sectors be ensured through the appropriate regulatory mechanisms, in order to facilitate the transfer of information and the development of pharmacogenomic technology.   }{\insrsid7560466 Likewise}{\insrsid7560466\charrsid12860689 
, the British Nuffield Council on Bioethics recommends that public-private partnerships be encouraged.}{\cs16\super\insrsid7560466\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid7560466 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622  }}}{\insrsid7560466\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid4683758 There are a few public-private collaborations already in the works.  }{\insrsid4206107\charrsid12860689 The SNP Consortium, a}
{\insrsid4206107\charrsid12860689  non-profit foundation, was founded to provide public genomic data online, thereby facilitating genomic research.}{\insrsid15624811\charrsid12860689  }{\insrsid14823734  }{\insrsid15624811\charrsid12860689 Phar
maceutical and technology companies, academic research centers, and the Wellcome Trust all entered into a partnership to publish a high-density SNP map of the human genome.}{\cs16\super\insrsid15624811\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Celia M. Henry, 
}{\i\insrsid4156601\charrsid11755622 Pharmacogenomics}{\insrsid4156601\charrsid11755622 , 79 Chemical and Engineering News 33: 37-42 (Aug. 13, 2001), }{\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid13786787 
http://pubs.acs.org/cen/coverstory/7933/7933pharmacogenomics.html}{\insrsid4156601\charrsid11755622  (last visited 1/29/05). }{\i\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid11755622 Although the consortium's original 
goal was to map 300,000 SNPs, it already has a publicly available map of more than a million SNPs.}}}{\insrsid12924017\charrsid12860689   The database of over one million SNPS is }{\insrsid15624811\charrsid12860689 maintained by Cold Spring Harbor Laborat
ory}{\insrsid2775846 .  In addition,}{\insrsid14098552\charrsid12860689  th}{\insrsid7031132 e Functional Genomics Consortium is}{\insrsid14098552\charrsid12860689  a collaboration between MIT\rquote 
s Whitehead Institute for Biomedical Research and many large pharmaceutical companies, which ha}{\insrsid6167573 s a more narrow focus than the SNP Consortium}{\insrsid14098552\charrsid12860689 .}{\cs16\super\insrsid3570163\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 The Business Case for Pharmacogenomics,}{\insrsid4156601\charrsid11755622  2nd Edition (2001) }{\i\insrsid4156601\charrsid11755622 at}{\insrsid4156601\charrsid11755622  http://}{
\insrsid4156601\charrsid13786787 www.the-infoshop.com/study/av7679_pharmacogenomics.html}{\insrsid4156601\charrsid11755622 .}}}{\insrsid14098552\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10254855 {\insrsid2520794\charrsid12860689 Pharmaceutical companies are }{\insrsid13852767 also }{\insrsid2520794\charrsid12860689 
encouraged to enter agreements with biotech companies in order to}{\insrsid161531  develop test-drug combinations.}{\insrsid2520794\charrsid12860689  }{\insrsid161531  }{\insrsid10254855 O}{\insrsid10254855\charrsid12860689 
ne author argues that the resource allocation problem is not as much of an issue }{\insrsid10254855 as it may seem }{\insrsid10254855\charrsid12860689 because companies have \'93jumped on the technology, many
 of them merging with biotech companies that suddenly see a profitable product in the near future for the first time.\'94}{\cs16\super\insrsid10254855\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10254855 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  L}{
\insrsid4156601\charrsid8933749 aga}{\insrsid4156601 y}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 26.}{\insrsid4156601\charrsid11755622   }}}{\insrsid10254855   Another observer explains, \'93[w]
}{\insrsid2520794\charrsid12860689 here tests and drugs are intimately linked, as is in the case of new pharmacogenetic products, their evaluation needs to be co-ordinate}{\insrsid12989976 d}{\insrsid2520794\charrsid12860689 
 and any licensing approval issued in concert\'94 rather than separately.}{\cs16\super\insrsid2520794\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 41.}}}{\insrsid2520794\charrsid12860689   Herce}{\insrsid13852767 ptin is one example of a linked}{\insrsid2520794\charrsid12860689  test-drug combination}{\insrsid13061094\charrsid12860689 
, as it requires administration of a test before it can be prescribed.}{\cs16\super\insrsid13061094\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  However, \'93
the test is not a true pharmacogenetic test, because it measures protein expression in a tumor rather than the underlying genetic makeup of the patient, but it shows the power of such tests.\'94 }{\i\insrsid4156601\charrsid11755622 
Tailored Treatment: Test Identifies Candidates For Genentech's Herceptin, available at }{\insrsid4156601\charrsid13786787 http://pubs.acs.org/cen/coverstory/7933/7933pharmacogenomics.html}{\insrsid4156601\charrsid11755622  (last visited 1/26/05).}}}{
\insrsid2520794\charrsid12860689  }{\insrsid11433113  }{\insrsid2520794\charrsid12860689 Such combinations may become necessary for some products.  For example, the FDA recently approved a label change for the\~
drug thioguanine, used to treat patients with leukemia, alerting doctors to\~the availability of a genetic test to screen for an inherited enzyme\~deficiency linked to a potentially fatal reaction to the drug.}{\cs16\super\insrsid2520794\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3870241 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid1135332 Wylie Burke and Ron L. Zimmern}{\insrsid4156601 , }{\i\insrsid4156601 Ensuring the Appropriate Use of Genetic Tests, }{\insrsid4156601 5 Nature Reviews: Genetics 959 (2004).}}}{
\insrsid1135332   The label does not require a genetic test before use of the drug.}{\cs16\super\insrsid1135332 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3870241 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{\insrsid7276705\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13852767 {\insrsid2114819 Corrigan, a}{\insrsid13852767\charrsid12860689  critic of the Nuffield Council\rquote s report}{\insrsid6167573 
 on pharmacogenomics}{\insrsid15297170 ,}{\insrsid13852767\charrsid12860689  focuses particularly on the role of the pharmaceutical industry in development.}{\cs16\super\insrsid13852767\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13852767 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Corrigan, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 30.}}}{\insrsid13852767\charrsid12860689   She cites a r}{\insrsid14823734 ecent survey that indicates an }{\insrsid13852767\charrsid12860689 interest }{\insrsid13852767 in pharmacogenomic collaborations }{
\insrsid13852767\charrsid12860689 by both small biotech companies, who are generally involved in providing test kits and other technological innovation, and large pharmaceutical companies.}{\cs16\super\insrsid13852767\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13852767 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id. at }{\insrsid4156601\charrsid11755622 4-5}{\insrsid4156601 .}{\insrsid4156601\charrsid11755622  (}{\i\insrsid4156601\charrsid11755622 citing}{\insrsid4156601\charrsid11755622  Hedgecoe A, Martin P. }{\i\insrsid4156601\charrsid11755622 
The Drugs Don\rquote t Work: Expectations and the Shaping of Pharmacogenetics, }{\insrsid4156601\charrsid11755622 Social Studies of Science 2003; 33(3): 327-364).}}}{\insrsid13852767\charrsid12860689 
  She provides the example of a twenty million dollar alliance between the biotech company Genset and the pharmaceutical company Abbott Laboratories to analyze variations in patient responses to particular drug therapies.}{
\cs16\super\insrsid13852767\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13852767 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid13852767\charrsid12860689  }{\b\insrsid13852767\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1135332 {\insrsid10622559\charrsid12860689 Other collaborations between companies }{\insrsid7149582\charrsid12860689 include}{
\insrsid10622559\charrsid12860689  the 1997 twenty-five million}{\insrsid2114819  dollar}{\insrsid10622559\charrsid12860689  deal be}{\insrsid3412961\charrsid12860689 tween Incyte Genomics and GlaxoSmithKline to form diaDEXUS}{
\insrsid4197659\charrsid12860689  and the}{\insrsid14423950\charrsid12860689  1997 $42.5 million agreement between Genset and Abbott to develop pharmacogenomics tests for gauging drug response.}{\cs16\super\insrsid14423950\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3870241 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Lesko, }{\i\insrsid4156601 supra }{\insrsid4156601 note 38.  }}}{\insrsid14423950\charrsid12860689   In }{\insrsid4197659\charrsid12860689 1998}{\insrsid14423950\charrsid12860689 ,}{\insrsid4197659\charrsid12860689  }{
\insrsid14423950\charrsid12860689 Decode and Roche entered into }{\insrsid2114819 a two hundred million dollar }{\insrsid4197659\charrsid12860689 genomics }{\insrsid14423950\charrsid12860689 and pharmacogenomics agreement }{
\insrsid3412961\charrsid12860689 to identify disease genes through genetic analysis of the uniquely homogenous Icelandic population.}{\cs16\super\insrsid3412961\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid2648244\charrsid12860689   Mitch Martin, a resea}{\insrsid8540414 rch leader at Roche Holdings AG\rquote }{\insrsid2648244\charrsid12860689 s pharmaceutical unit, explained, \'93We\rquote 
re moving from a one-size-fits-all paradigm to a targeted par}{\insrsid4340304\charrsid12860689 adigm.}{\insrsid15297170 \'94}{\cs16\super\insrsid15297170\charrsid15297170  }{\cs16\super\insrsid15297170\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15297170 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Anna Wilde Mathews, }{\i\insrsid4156601\charrsid11755622 FDA Will Issue Rules on New Era of \'93Personalized Medicine,\'94}{\insrsid4156601\charrsid11755622  Wall St. J. at B1 (11/3/03). }}}{\insrsid4340304\charrsid12860689  }{
\insrsid2648244\charrsid12860689  }{\insrsid7304678 Accor}{\insrsid15297170 ding to Roche, the company has a number of programs to discover genetic markers related to the drugs they are developing}{\insrsid10891466 .}{\insrsid15297170  }{
\insrsid3412961\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid2979840\charrsid12860689 Even if smaller companies do not enter into collaborations with big pharma, the \'93existence of \lquote 
niche\rquote  therapeutic categories will present opportunities for smaller, genetics-based biotechnology firms to enter the market and produce the drugs.\'94}{\cs16\super\insrsid6041057\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Reeder and Dickson, }{\i\insrsid4156601 supra }{\insrsid4156601 note 110 at 233.}}}{\insrsid6041057\charrsid12860689  }{\insrsid11433113  }{\insrsid6041057\charrsid12860689 It has been}{\insrsid2979840\charrsid12860689  hypothesize}{
\insrsid6041057\charrsid12860689 d}{\insrsid2979840\charrsid12860689 , interestingly, that the pharmaceutical industry will bifurcate into two separate \'93sectors:\'94 those big pharmaceutical companies that will continue to pursue \'93blockbuster\'94
 drugs for \'93high-prevalence polymorphisms\'94 and a \'93second \lquote cottage\rquote  sector that serves the \lquote orphan drug\rquote  market.\'94}{\cs16\super\insrsid5851113\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid5851113\charrsid12860689  }{\insrsid6956622\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11015841\charrsid12860689 
It will be interesting to see how the pharmaceutical industry adapts and changes alongside pharmacogenomic advances.  Recently, the industry has been \'93in a consolidation and merger phase, with ever larger corporations emerging at a steady pace.\'94}{
\cs16\super\insrsid1389278\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Laviero Mancinelli, Maureen Cronin, and Wolfgang Sad\'e9e, }{\cs32\i\insrsid4156601\charrsid11755622 Pharmacogenomics: The Promise of Personalized Medicine,}{
\cs32\insrsid4156601\charrsid11755622  2(1) }{\insrsid4156601\charrsid11755622 AAPS PharmSci}{\insrsid4156601\charrsid11755622 . (2000).}}}{\insrsid4737555\charrsid12860689   }{\insrsid13852767 Since}{\insrsid4737555\charrsid12860689  blockbuster drugs }{
\insrsid10879186\charrsid12860689 could }{\insrsid4737555\charrsid12860689 no longer become the preferred treatment, }{\insrsid10879186\charrsid12860689 companies may hone in on \'93mini-busters,\'94
 thereby decreasing their size and the way they work with one another.}{\insrsid4340304\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\b\insrsid2979840\charrsid12860689 
\par }{\b\insrsid721945\charrsid12860689 
\par }{\b\insrsid14042310\charrsid12860689 
\par }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3411073 {\b\insrsid2957370 \page }{\b\insrsid6583447\charrsid12860689 REGULATORY AND }{\b\insrsid13199381\charrsid12860689 LEGAL ISSUES}{\b\insrsid2957370 
 ASSOCIATED WITH PHARMACOGENOMICS }{\b\insrsid14042310 
\par }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3411073 {\b\insrsid3411073 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8664551 {\insrsid741294 The utilization of pharmacogenomics in drug development is likely to have repercussions for diverse areas of the law.  }{
\insrsid8664551 This section considers the recent FDA guidance on pharmacogenomic data submission, as well as other FDA measures taken to ensure the safety and efficacy of }{\insrsid3560787 pharmacogenomic advancements.}{\insrsid12730418 
  The impact of the Orp}{\insrsid13530900 h}{\insrsid12730418 a}{\insrsid13530900 n Drug Act }{\insrsid611373 (ODA) is}{\insrsid13530900  }{\insrsid8415820 explore}{\insrsid13530900 d in light of }{\insrsid11485022 the creation }{\insrsid16717024 
of drug compounds for small targeted}{\insrsid611401  }{\insrsid16717024 populations.}{\insrsid611401  }{\insrsid16717024  }{\insrsid611401 The next section discusses pharmacogenomics in }{\insrsid1902495 the context of patent law, }{\insrsid14100509 
and concludes with a consideration}{\insrsid8415820  of legal liability for both }{\insrsid15813400 physicians}{\insrsid8415820  and the pharmaceutical industry.}{\b\insrsid741294\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 I}{\b\insrsid14823734 .  }{\b\insrsid3411073 The }{\b\insrsid12874126\charrsid12860689 FDA
\par }\pard\plain \s22\ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid11679063\charrsid12860689 
The Food, Drug, and Cosmetic Act (FDCA) authorizes the }{\insrsid11433113 FDA}{\insrsid11679063\charrsid12860689  to ensure that human and animal drugs}{\insrsid2114819 ,}{\insrsid11679063\charrsid12860689  biological products, and thera
peutic devices are safe and effective.  The FDA\rquote s \'93mission is to advance and protect public health\'85.. by helping to speed innovations that make medicines more effective, safer and more affordable.\'94}{
\cs16\super\insrsid11679063\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid11755622 Dr. Mark McClellan,}{\insrsid4156601  former FDA Commissioner in }{\i\insrsid4156601\charrsid8878203 
Improving Innovation in Medical Technology: Beyond 2002}{\insrsid4156601\charrsid11755622  and reported in the Pink Sheet, February 3, 2003.}}}{\insrsid11679063\charrsid12860689  }{\i\insrsid11679063\charrsid12860689 
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid11679063\charrsid12860689 
The drug amendment to the FDCA of 1962 authorized the FDA to take a more preemptive approach to drug development, requiring premarket approval for every new drug.}{\insrsid13777625   Thus, a}{\insrsid8019477  new drug a}{\insrsid13130766 p}{
\insrsid8602958 plicatio}{\insrsid13130766 n (NDA) will only be approved once the FDA is convinced of its safety and effectiveness.}{\insrsid13777625   In order to }{\insrsid14823734 demonstrate safety and efficacy}{\insrsid13777625 
, drug companies spend millions of dollars and years enrolling individuals in a series of clinical trials to generate the}{\insrsid14823734  necessary data.}{\insrsid8545116   Alternatively, }{\insrsid7755587 after the pioneer drug\rquote 
s patent has expired, }{\insrsid8545116 FDA can }{\insrsid12403630 approve}{\insrsid8545116  abbreviated new drug applic}{\insrsid7563327 ations (ANDA), for which a gener}{\insrsid8545116 ic drug sponsor may establish }{\insrsid1135332 
that the drug is a bioequivalent to the original product.}{\cs16\super\insrsid7563327 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  One article maintains that pharmacogenomics will facilitate the way generic drugs are approved.  \'93
Pharmacogenomic information could, therefore, provide a better basis for making comparative judgments about bioavailability and facilitate the approval and use of generic drugs in the future.  Lars Noah, }{\i\insrsid4156601 
The Coming Pharmacogenomics Revolution: Tailoring Drugs to Fit Patients\rquote  Genetic Profiles}{\insrsid4156601 \'b8 43 Jurimetrics J. 1, 18 (2002).}}}{\insrsid14823734\charrsid14823734  }{\insrsid14823734  }{\insrsid14823734\charrsid12860689 
The Center for Drug Evaluation and Research (CDER) is responsible for approving new drug applications so that a product can enter the ma
rket.  The Office of Clinical Pharmacology in Biopharmaceutics is charged with reviewing biopharmaceutic, pharmacokinetic, and pharmacodynamic data in INDs}{\insrsid7162350  (}{\insrsid15404848 Investigational New Drug applications}{\insrsid9309897 ) }{
\insrsid14823734\charrsid12860689 and NDAs.}{\insrsid14823734   }{\insrsid13130766 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2712288 {\insrsid14823734 P}{\insrsid11679063\charrsid12860689 harmacogenomics introduces new complexities to the }{\insrsid12525549 
already complicated }{\insrsid11679063\charrsid12860689 system}{\insrsid11469762  of drug development and approval}{\insrsid11679063\charrsid12860689 
.  It is unclear how pharmacogenomic data will be incorporated into the drug development and approval process.  It has been argued }{\insrsid7888366 that pharmacogenomics will}{\insrsid11679063\charrsid12860689  lead to a \'93major, technology-driven
 restructuring\'94 which would require \'93bold leadership from relevant regulatory agencies worldwide.\'94}{\cs16\super\insrsid11679063\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1290.  }}}{\insrsid2712288   }{\insrsid13129402\charrsid12860689 
\par }\pard\plain \s22\ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid5919408\charrsid12860689 In general, the FDA\rquote s}{
\insrsid8328128  approach to new technologies has}{\insrsid5919408\charrsid12860689  not}{\insrsid8328128  been}{\insrsid5919408\charrsid12860689  very proactive.  Instead, \'93}{\insrsid14042310\charrsid12860689 
the agency tends to observe and wait until the industry works out its own new paradigms before generating new regulations.\'94}{\cs16\super\insrsid5919408\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 The Business Case for Pharmacogenomics,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 159.  }}}{\insrsid721945\charrsid12860689  }{\insrsid10120491\charrsid12860689  }{
\insrsid721945\charrsid12860689 In the late 199}{\insrsid360343 0\rquote s, FDA indicated that it planned to }{\insrsid721945\charrsid12860689 maintain the drug approval}{\insrsid360343  process as it currently exists}{\insrsid721945\charrsid12860689 
, explaining that there are \'93no problem with the promise of pharmacogenomics,\'94 and }{\insrsid7888366 that }{\insrsid721945\charrsid12860689 they }{\insrsid7888366 we}{\insrsid721945\charrsid12860689 re waiting for \'93data to evaluate the results.
\'94}{\cs16\super\insrsid721945\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Binzak, }{\i\insrsid4156601 supra }{\insrsid4156601 note 73 at 105-6.}}}{\insrsid721945\charrsid12860689   As of 1998, the FDA had no plans to focus}{
\insrsid212881\charrsid12860689  any}{\insrsid721945\charrsid12860689  guidance solely on pharmacogenomics.  Nor, in 1998, were there any guidelines in Europe or Japan regarding the requirements for pharmacogenomic data.  Moreover, \'93
none of the regulatory agencies thought it likely that pharmacogenomic information would be req}{\insrsid212881\charrsid12860689 uired for all drugs,}{\insrsid721945\charrsid12860689 \'94}{\insrsid212881\charrsid12860689 
 and thus the use of pharmacogenomics and pharmacogenetics }{\insrsid7888366 wa}{\insrsid212881\charrsid12860689 s not required by the FDA}{\insrsid2439493\charrsid12860689 .}{\cs16\super\insrsid721945\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Andrew Marshall, }{\i\insrsid4156601\charrsid11755622 Pharmacogenomics: Will the Regulators Approve?}{\insrsid4156601\charrsid11755622 , 16 Nature Biotechnology Supp. 13 (1998).}}}{\insrsid3149194\charrsid12860689   }{\insrsid7823086 
\par }\pard \s22\ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid14187429 However, }{\insrsid7823086 only five years later, the 
FDA released its draft guidance to industry regarding the submission of pharmacogenomic data to the agency.  }{\insrsid14187429 Lawrence}{\insrsid14187429\charrsid12860689  Lesko, Director of the Office of Clinical Pharmacology }{\insrsid9052865 and}{
\insrsid14187429\charrsid12860689  Biopharmaceutics in CDER, stated that in the case of pharmacogenomics, the agency has been atypically proactive}{\insrsid14187429  in its promulgation of the draft}{\insrsid14909319  (and }{\insrsid9641423 final}{
\insrsid14909319 ) }{\insrsid14187429 guidance entitled, }{\i\insrsid14187429\charrsid14909319 Draft Guidance for Industry: Pharmacogenomic Data Submissions}{\insrsid14187429 , drafted in November 2003}{\insrsid14909319  and issued in March 2005}{
\insrsid1013614\charrsid12860689 .}{\cs16\super\insrsid11031460\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lawrence Lesko, Keynote speaker at Scientific American, }{\i\insrsid4156601\charrsid11755622 
Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601\charrsid11755622 at }{\insrsid4156601\charrsid11755622 2004 WL 99524302 (Nov. 11, }{\insrsid4156601 .}{\insrsid4156601\charrsid11755622 2004).  }}}{
\insrsid721945\charrsid12860689 
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid6231436 Although drug sponsors might react favorably
 to clear guidance regarding the use of genomics in drug research and development, industry}{\insrsid8464831  more}{\insrsid6231436  often prefers a hands-off approach.  }{\insrsid8737846 However}{\insrsid6231436 , }{\insrsid8737846 according}{
\insrsid14097690  to some media coverage, t}{\insrsid6299460\charrsid12860689 he}{\insrsid12011145\charrsid12860689  private secto}{\insrsid15358567\charrsid12860689 r has sought guidance from FDA}{\insrsid7888366  regarding the use of pharmacoge
nomics in its R&D}{\insrsid15358567\charrsid12860689 .  According to a }{\i\insrsid15358567\charrsid9463301 Wall Street Journal}{\insrsid15358567\charrsid12860689  author, }{\insrsid12011145\charrsid12860689 \'93
Major drug companies are likely to welcome a firm signal from the FDA that\~will reduce the questions surrounding the new field. They are al}{\insrsid9463301 so likely to\~applaud the agency\rquote }{\insrsid12011145\charrsid12860689 s promise that volunt
}{\insrsid9463301 arily submitted information won\rquote t be}{\insrsid12011145\charrsid12860689  used in decisions about drug approvals.}{\insrsid13134219\charrsid12860689 \'94}{\cs16\super\insrsid13134219\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Mathews,}{
\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 170.}}}{\insrsid12011145\charrsid12860689  }{\insrsid5258303\charrsid12860689   Stephen Friend, a senior vice\~president at Merck & Co., }{\insrsid3088146\charrsid12860689 explained that }{
\insrsid5258303\charrsid12860689 both patients and pharmaceutical companies need \'93}{\insrsid12011145\charrsid12860689 ground rules because the correct use of this data . . . is going to be\~critical for it to be of benefit}{
\insrsid5258303\charrsid12860689 .}{\insrsid12011145\charrsid12860689 \'94}{\cs16\super\insrsid5258303\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622  }}}{\insrsid1514718\charrsid12860689 
  It is currently unclear what level of proof is required (i.e. }{\insrsid12874126\charrsid12860689 how much evidence and how strong the evidence must be for drugs }{\insrsid2233899\charrsid12860689 that either }{\insrsid1514718\charrsid12860689 are}{
\insrsid12874126\charrsid12860689  efficacious or cause deleterious side effects in a }{\insrsid1514718\charrsid12860689 small portion of the population)}{\insrsid12874126\charrsid12860689 .}{\cs16\super\insrsid12874126\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Greely,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 13 at 2.}{\b\insrsid4156601  }{\insrsid4156601\charrsid11755622  }}}{\insrsid12874126\charrsid12860689   }{\insrsid1013614\charrsid12860689 Lesko}{\insrsid13830419  of the FDA}{
\insrsid1013614\charrsid12860689  }{\insrsid3291963\charrsid12860689 states that the industry was uncertain as to what }{\insrsid10378232 the }{\insrsid3291963\charrsid12860689 FDA would do with pharmacogenomics data once it was submitted.}{
\cs16\super\insrsid3291963\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{\i\insrsid4156601\charrsid11755622 Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{
\insrsid4156601 note 180.  }{\insrsid4156601\charrsid11755622 He states that the industry was \'93concerned that FDA would stop clinical development on the basis of a genomic marker that was not well validated or well understood.\'94}{\insrsid4156601  Id.
}}}{\insrsid3291963\charrsid12860689   }{\insrsid3091070\charrsid12860689 Clarifying this is}{\insrsid12874126\charrsid12860689  one of the purposes of the FDA\rquote s guidance.}{\insrsid7105256\charrsid7105256  }{\insrsid7105256  }{
\insrsid687471\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 A}{\b\insrsid9463301 .  }{\b\insrsid16276297\charrsid12860689 The }{\b\insrsid14307018 G}{
\b\insrsid16276297\charrsid12860689 uidance
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid14101605\charrsid12860689 In May 2002, 
FDA, the preclinical safety committee (DruSafe) of the Pharmaceutical Research and Manufacturers of America (PhRMA)}{\insrsid10773308\charrsid12860689 , and}{\insrsid14101605\charrsid12860689 
 the Pharmacogenetics Working Group (PWG) cosponsored a two-day workshop entitled, \'93Workshop on Pharmacogenetics/Pharmacogenomics in Drug Development and Regulatory Decision-Making.\'94 According to the meeting notice, \'93
it is envisioned that the issues addressed and raised will provide a basis for future regulatory guidance.\'94}{\cs16\super\insrsid14101605\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\cs20\insrsid4156601\charrsid11755622 FDA, Center for Drug Evaluation and Research (CDER), }{\cs20\i\insrsid4156601\charrsid11755622 Meeting Notice, at}{\cs20\insrsid4156601\charrsid11755622  }{\cs20\insrsid4156601\charrsid13786787 
http://www.fda.gov/cder/calendar/meeting/phrma52002/default.htm}{\cs20\insrsid4156601\charrsid11755622 . }}}{\insrsid14101605\charrsid12860689  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid12677297\charrsid12860689 In late 2003, the FDA issued its draft guidance regarding the sub
mission of pharmacogenomic data to the FDA, in order to e}{\cs26\insrsid12677297\charrsid12860689 
ncourage drug companies to conduct pharmacogenomic tests during drug development and to submit resulting data to the FDA, while maintaining an appropriate level of safety and efficacy for consumers.}{\cs16\super\insrsid12677297\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  FDA, }{\i\insrsid4156601\charrsid11755622 Draft Guidance for Industry: P}{\i\insrsid4156601 harmacogenomic Data Submissions, supra }{\insrsid4156601 note 79.}{\insrsid4156601\charrsid11755622   }{
\cs26\i\insrsid4156601\charrsid11755622 See also }{\cs26\insrsid4156601\charrsid11755622 Tracy }{\insrsid4156601\charrsid11755622 Hampton, }{\i\insrsid4156601 supra }{\insrsid4156601 note 39.  }}}{\cs26\insrsid12677297\charrsid12860689   The }{
\cs26\insrsid9573903 draft }{\cs26\insrsid6299460\charrsid12860689 g}{\cs26\insrsid9573903 uidance was considered}{\cs26\insrsid12677297\charrsid12860689  quite \'93pro-pharmacogenomics,\'94 }{\cs26\insrsid12338530 and the FDA stated}{
\cs26\insrsid12214494  that the nonbinding recommendations were}{\cs26\insrsid12677297\charrsid12860689  intended to \'93facilitate,\'94 and \'93not impede, the use of pharmacogenomic tests during drug development.\'94}{
\cs16\super\insrsid12677297\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid9966724 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid9966724 \chftn }{\insrsid4156601\charrsid9966724  }{\insrsid4156601 Id.}{\insrsid4156601\charrsid9966724   }}}{\cs26\insrsid12677297\charrsid12860689   }{\insrsid15736748\charrsid12860689 In discussing the draft gu
idance, }{\insrsid8464831 then-}{\insrsid15736748\charrsid12860689 FDA Commissioner Mark B. McClellan stated that, \'93
Pharmacogenomics holds great promise to shed scientific light on the often risky and costly process of drug development, and to provide greater confidence about the risks and benefits of drugs in specific populations.\'94}{
\cs16\super\insrsid15736748\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15736748 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 FDA Issues Guidance on Pharmacogenomics Data,}{\insrsid4156601\charrsid11755622  FDA, November 3, 2003, }{
\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid11755622 http://www.fda.gov/bbs/topics/NEWS/2003/NEW00969.html.}}}{\insrsid15736748\charrsid12860689   He continued, \'93
By providing practical guidance on how to turn the explosion of pharmacogenomic information into real evidence on new drugs, we are taking an important step toward that goal\'94 of promoting the development of medicine.}{
\cs16\super\insrsid15736748\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15736748 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid15736748\charrsid12860689   McClellan explained that the draft guidance }{\insrsid6782694 wa}{\insrsid15736748\charrsid12860689 s \'93
intended to ensure that evolving regulatory policies and study designs are based on the best science; provide public confidence in this new field where scientifically appropriate; facilitate the use of 
such tests during drug development; and clarify for industry what types of pharmacogenomic data to submit to FDA.\'94}{\cs16\super\insrsid15736748\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15736748 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .}}}{\insrsid15736748\charrsid12860689   }{\insrsid14553620\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid10378232 According to a }{\i\insrsid10378232 JAMA }{\insrsid10378232 author, t}{\insrsid13327727\charrsid12860689 he agency ha}{
\insrsid11418937 d}{\insrsid13327727\charrsid12860689  been frustrated }{\insrsid9511309 with industry\rquote s reluctance }{\insrsid7173957 to}{\cs26\insrsid7173957  provide}{\cs26\insrsid13327727\charrsid12860689  pharmacogenomic data to the }{
\cs26\insrsid8464831 FDA}{\cs26\insrsid13327727\charrsid12860689 .}{\cs16\super\insrsid13327727\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid9966724 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid9966724 \chftn }{\insrsid4156601\charrsid9966724  }{\cs26\insrsid4156601\charrsid11755622 Tracy }{\insrsid4156601\charrsid11755622 Hampton, }{\i\insrsid4156601 
supra }{\insrsid4156601 note 39.  }}}{\insrsid13327727\charrsid12860689   }{\cs26\insrsid7437390 Gualberto Ruano of Genomas LLC}{\cs26\insrsid13327727\charrsid12860689  explained that, \'93The agency is essentially asking for help.\'94}{
\cs16\super\insrsid13327727\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid9966724 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid9966724 \chftn }{\insrsid4156601\charrsid9966724  }{\cs26\insrsid4156601 Id.}}}{\insrsid13327727\charrsid12860689   }{\insrsid4472890\charrsid12860689 FDA provided guidelines in part to walk the thin line between \'93
(a) accepting correlative data on genotype and drug response, which will help them to learn to better assess safety and efficacy, and (b) ensuring that }{\insrsid10378232 t}{\insrsid4472890\charrsid12860689 
he first experiences evaluating this data will not act as a disincentive for drug companies embarking on existing and future drug research and development programs.\'94}{\cs16\super\insrsid4472890\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Jai Shah, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 9 at 3}{\insrsid4156601\charrsid11755622 .}}}{\insrsid4472890\charrsid12860689   }{\insrsid9838791\charrsid12860689 The guidance }{\insrsid4931534\charrsid12860689 seeks}{\insrsid9838791\charrsid12860689  }{
\insrsid4931534\charrsid12860689 to}{\insrsid9838791\charrsid12860689  remedy }{\insrsid4931534\charrsid12860689 pharmaceutical}{\insrsid9838791\charrsid12860689  sponsors\rquote 
 hesitancy in using pharmacogenomic technologies in the drug development phases because of \'93uncertainties in how the data will be used by the FDA in the drug application review process,\'94 by making the agency\rquote s policies clear.}{
\cs16\super\insrsid9838791\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  FDA, }{\i\insrsid4156601\charrsid11755622 Draft Guidance for Industry: P}{\i\insrsid4156601 harmacogenomic Data Submissions, supra }{\insrsid4156601 note 79.}{
\insrsid4156601\charrsid11755622   }}}{\insrsid9838791\charrsid12860689   }{\insrsid10168341 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1326092 {\insrsid10168341 In 2005, the FDA issued its final guidance}{\insrsid9052865 , which d}{\insrsid8878203 oes}{\insrsid9052865  not vary }{
\insrsid7437390 significantly }{\insrsid9052865 from the draft version.}{\insrsid10168341   }{\insrsid1326092\charrsid12860689 The fact that the final guidance h}{\insrsid1326092 ad}{\insrsid1326092\charrsid12860689  been so delayed }{\insrsid1326092 h}{
\insrsid1326092\charrsid12860689 as led to some skepticism among those that it affects.  }{\insrsid1326092 In late}{\insrsid1326092\charrsid12860689  2004, }{\insrsid1326092 Lesko }{\insrsid1326092\charrsid12860689 denied the concern that the wait for 
the final dra}{\insrsid10045214 ft was due to \'93big, big problem,}{\insrsid1326092\charrsid12860689 \'94}{\insrsid10045214  and}{\insrsid1326092\charrsid12860689  predicted that the guidance would be \'93out by January 2005.\'94}{
\cs16\super\insrsid1326092\charrsid12860689 \chftn {\footnote \pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid12202766 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{\i\insrsid4156601\charrsid11755622 Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{
\insrsid4156601 note 180.  (H}{\insrsid4156601\charrsid11755622 e does disclaim this prediction, however, by saying that he \'93hope[s] it\rquote s not videotaped.\'94).}{\insrsid4156601\charrsid16586940  }{\insrsid4156601 
As of early March 2005, the final guidance had not yet been released.}}}{\insrsid1326092\charrsid12860689   He attribute}{\insrsid1790518 d}{\insrsid1326092\charrsid12860689  the delay to }{\insrsid1326092 the 2004}{\insrsid1326092\charrsid12860689 
 political elections, which impeded the cross-center collaboration necessary to issue the final guidance.  He also explain}{\insrsid8142156 ed}{\insrsid1326092\charrsid12860689  that the guidance ha}{\insrsid16137345 d}{\insrsid1326092\charrsid12860689 
 been postponed because it w}{\insrsid16137345 ould}{\insrsid1326092\charrsid12860689  be released with companion documents, including a \'93roadmap for the voluntary submission process.\'94}{\cs16\super\insrsid1326092\charrsid12860689 \chftn {\footnote 
\pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid12202766 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid1326092\charrsid12860689   }{\insrsid1518597 Others have attributed the delay to Mark McClennan\rquote s departure from his position as Commissioner of FDA in March 2004.}{\cs16\super\insrsid1518597 \chftn {\footnote 
\pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid12202766 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid1518597 \chftn }{\insrsid4156601\charrsid1518597  }{
\cs34\insrsid4156601\charrsid1518597 Malorye A. Branca, }{\cs34\i\insrsid4156601\charrsid1518597 L}{\i\insrsid4156601\charrsid1518597 ong-Awaited FDA Pharmacogenomics Guidance Lands, }{\insrsid4156601\charrsid11755622 Bio-It World, (}{\insrsid4156601 
3/24/05}{\insrsid4156601\charrsid11755622 ), a}{\i\insrsid4156601\charrsid11755622 vailable at }{\field\fldedit{\*\fldinst {\insrsid4156601\charrsid11755622  HYPERLINK "http://www.bio-itworld.com/news/062503_report2772.html" }{
\insrsid4156601\charrsid11755622 {\*\datafield 
00d0c9ea79f9bace118c8200aa004ba90b02000000170000003700000068007400740070003a002f002f007700770077002e00620069006f002d006900740077006f0072006c0064002e0063006f006d002f006e006500770073002f003000360032003500300033005f007200650070006f00720074003200370037003200
2e00680074006d006c000000e0c9ea79f9bace118c8200aa004ba90b6e00000068007400740070003a002f002f007700770077002e00620069006f002d006900740077006f0072006c0064002e0063006f006d002f006e006500770073002f003000360032003500300033005f007200650070006f00720074003200370037
0032002e00680074006d006c000000}}}{\fldrslt }}{\insrsid4156601\charrsid1518597 http://www.bio-itworld.com/news/032405_report7911.html}{\insrsid4156601 .}}}{\insrsid1326092\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid1407793 In its guidance, the }{\insrsid15686789\charrsid12860689 FDA provides a number of examples of places in which }{
\insrsid9713164 the field of }{\insrsid15686789\charrsid12860689 pharmacogenomics has yet to be established or generally accepted}{\insrsid13126018  by the scientific community}{\insrsid15686789\charrsid12860689 .}{
\cs16\super\insrsid15686789\charrsid12860689 \chftn {\footnote \pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16675665 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid8158101 \chftn }{\super\insrsid4156601\charrsid8158101  }{\insrsid4156601 FDA, }{\i\insrsid4156601\charrsid11755622 Guidance for Industry: P}{\i\insrsid4156601 harmacogenomic Data Submissions, supra }{\insrsid4156601 
note 65.  }{\cs16\cf1\insrsid4156601\charrsid16675665 These include:
\par }\pard \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16675665 {\cs16\cf1\insrsid4156601\charrsid16675665 \'93\bullet  Laboratory techniques and test procedures may not be well validated. In addition, test}{
\cf1\insrsid4156601  }{\cs16\cf1\insrsid4156601\charrsid16675665 systems may vary so that results may not be consistent or generalizable across different}{\cf1\insrsid4156601  }{\cs16\cf1\insrsid4156601\charrsid16675665 
platforms. A move to standardize assays is underway, and much more information}{\cf1\insrsid4156601  }{\cs16\cf1\insrsid4156601\charrsid16675665 should be available within the next several years.
\par }\pard \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16675665 {\cs16\cf1\insrsid4156601\charrsid16675665 \bullet  The scientific framework for interpreting the physiologic, toxicologic, pharmacologic, or clinical }{
\cf1\insrsid4156601 s}{\cs16\cf1\insrsid4156601\charrsid16675665 ignificance of certain experimental results may not yet be well understood.
\par \bullet  The findings from a specific study often cannot be extrapolated across species or to}{\cf1\insrsid4156601  }{\cs16\cf1\insrsid4156601\charrsid16675665 different study populations (e.g., various human subpopulations with different genetic}{
\cf1\insrsid4156601  }{\cs16\cf1\insrsid4156601\charrsid16675665 backgrounds).
\par \bullet  The standards for transmission, processing, and storage of the large amounts of highly}{\cf1\insrsid4156601  }{\cs16\cf1\insrsid4156601\charrsid16675665 dimensional data generated from microarray technology have neither been well defined}{
\cf1\insrsid4156601  }{\cs16\cf1\insrsid4156601 nor widely tested}{\cs16\cf1\insrsid4156601\charrsid16675665 .\'94}}}{\insrsid15686789\charrsid7036888  }{\insrsid15686789  }{\insrsid10168341\charrsid12860689 The guidance is }{\insrsid1974548 therefore }{
\insrsid10168341\charrsid12860689 intended to motivate the pharmaceutical industry to pursue pharmacogenomic R&D}{\insrsid10168341 , allowing industry and the FDA to become comfortable }{\insrsid9641423 with}{\insrsid10168341 
 novel pharmacogenomic approaches as they develop.}{\cs16\super\insrsid10168341 \chftn {\footnote \pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16675665 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\cf1\super\insrsid4156601\charrsid16675665 \chftn }{\cs16\cf1\insrsid4156601\charrsid16675665  FDA, }{\cs16\i\cf1\insrsid4156601\charrsid3819666 
FDA Works to Speed the Advent of New, More Effective Personalized Medicines}{\cs16\cf1\insrsid4156601  (March 22, 2005)}{\cs16\cf1\insrsid4156601\charrsid16675665  }{\cs16\i\cf1\insrsid4156601\charrsid14825020 at}{
\cs16\cf1\insrsid4156601\charrsid16675665  http://www.fda.gov/bbs/topics/news/2005/NEW01167.html.}}}{\insrsid10168341\charrsid12860689   }{\insrsid1011969 The FDA lists the following as advantages of voluntarily }{\insrsid15417048 submitting pharmacogen
omic data.  Doing so}{\insrsid14502987  allows industry to}{\insrsid15417048 :}{\insrsid1011969 
\par {\listtext\pard\plain\s22 \f3\insrsid5794539 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard\plain \s22\ql \fi-288\li1008\ri720\widctlpar\jclisttab\tx1008\aspalpha\aspnum\faauto\ls18\adjustright\rin720\lin1008\itap0\pararsid1011969 
\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid5794539 Provide[]}{\insrsid1011969  opportunity to have informal meeting with FDA pharmacogenomics experts 
\par {\listtext\pard\plain\s22 \f3\insrsid1011969 \loch\af3\dbch\af0\hich\f3 \'b7\tab}Receive and benefit from informal peer-review feedback on pharmacogenomics issues and/or questions. 
\par {\listtext\pard\plain\s22 \f3\insrsid1011969 \loch\af3\dbch\af0\hich\f3 \'b7\tab}Gain insight into current FDA thinking about pharmacogenomics that may assist in reach strategic decisions. 
\par {\listtext\pard\plain\s22 \f3\insrsid1011969 \loch\af3\dbch\af0\hich\f3 \'b7\tab}Familiarize FDA with pharmacogenomics experiments, data analysis and interpretation approaches. 
\par {\listtext\pard\plain\s22 \f3\insrsid5794539 \loch\af3\dbch\af0\hich\f3 \'b7\tab}}\pard \s22\ql \fi-288\li1008\ri720\widctlpar\jclisttab\tx1008\aspalpha\aspnum\faauto\ls18\adjustright\rin720\lin1008\itap0\pararsid1011969 {\insrsid5794539 Pave[]}{
\insrsid1011969  the way for time- and cost-savings by familiarizing FDA with pharmacogenomics and avoiding future delays in review. Impact FDA thinking and help build consensus around pharmacogenomics standards, policies and guidances.}{
\cs16\super\insrsid1011969 \chftn {\footnote \pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid16675665 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\cf1\super\insrsid4156601\charrsid16675665 \chftn  }{\cs16\cf1\insrsid4156601\charrsid16675665 FDA, Genomics at FDA}{\cs16\i\cf1\insrsid4156601\charrsid3819666 : Frequently Asked Questions}{\cs16\cf1\insrsid4156601\charrsid16675665 
, available at http://www.fda.gov/cder/genomics/FAQ.htm.}}}{\insrsid1011969 
\par }\pard \s22\ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid1011969 {\insrsid1011969 
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid7036888\charrsid12860689 The FDA plans to use }{\insrsid676834 
pharmacogenomic}{\insrsid7036888\charrsid12860689 \~information to gain }{\insrsid7036888 a }{\insrsid7036888\charrsid12860689 better understanding of the field. }{\insrsid15995394  }{\insrsid7036888 Such knowledge is }{\insrsid10635588 \'93important,\~
because there\rquote }{\insrsid7036888\charrsid12860689 s a lot of uncertainty about the significance of data in these\~areas,\'94 according to }{\insrsid524864 the director of regulatory affairs}{\insrsid15933313  of}{\insrsid524864 
 a large pharmaceutical company }{\insrsid7036888\charrsid12860689 which has an aggressive pharmacogenomics program.}{\cs16\super\insrsid7036888\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid7036888 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Mathews,}{
\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 170. (}{\insrsid4156601\charrsid15995394 citing}{\i\insrsid4156601  }{\insrsid4156601\charrsid12860689 Chris Webster, director of regulatory affairs for }{\insrsid4156601 Millennium\~
Pharmaceuticals Inc.).}}}{\insrsid15273867\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8994471 {\insrsid12791996\charrsid12860689 In }{\insrsid12791996\charrsid11418937 most cases, the FDA says, the agency will ask companies to }{
\i\insrsid12791996\charrsid11418937 voluntarily }{\insrsid12791996\charrsid11418937 submit its date related to pharmacogenomics. }{\insrsid13307106\charrsid11418937 The 2005 }{\i\insrsid13307106\charrsid11418937 Manual of Policies and Procedures: }{
\i\insrsid9641423\charrsid11418937 Management}{\i\insrsid13307106\charrsid11418937  of the Interdisciplinary Pharmacogenomics Review Group}{\insrsid1974548  }{\i\insrsid1974548 (}{\i\insrsid13307106\charrsid1974548 IPRG)}{
\insrsid13307106\charrsid11418937 , and other }{\insrsid9641423\charrsid11418937 associated}{\insrsid13307106\charrsid11418937  MAPPs deal only with }{\i\insrsid13307106\charrsid11418937 voluntary }{\insrsid13307106\charrsid11418937 
data submissions, refusing to deal with the designation for genomic data submissions }{\insrsid1647965\charrsid11418937 (GDSs) }{\insrsid13307106\charrsid11418937 that are required (per the relevant regulations) to be}{\insrsid16404252\charrsid11418937  }
{\insrsid13307106\charrsid11418937 submitted to, or as part of, an existing }{\insrsid8994471 application }{\insrsid13307106\charrsid11418937 that}{\insrsid16404252\charrsid11418937  }{\insrsid13307106\charrsid11418937 
will be used during the regulatory decision making process.}{\cs16\super\insrsid9898239\charrsid11418937 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  FDA, }{\insrsid4156601\charrsid15887271 MAPP 4180.2}{\insrsid4156601 ,}{\insrsid4156601\charrsid15887271  }{\i\insrsid4156601\charrsid15887271 
Manual of Policies and Procedures: Management of the Interdisciplinary Pharmacogenomics Review Group}{\insrsid4156601 , (IPRG), }{\i\insrsid4156601 available at }{\insrsid4156601\charrsid15887271 http://www.fda.gov/cder/mapp/4180.2.pdf}{\insrsid4156601 .}
}}{\insrsid13307106\charrsid11418937  }{\insrsid16404252\charrsid11418937  }{\insrsid13307106\charrsid4147655 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8994471 {\insrsid15995394 Thus,}{\insrsid12482763  sometimes pharmacogenomic data submission will not be voluntary. }{\insrsid8994471\charrsid11418937 
Required GDS submissions will continue to be processed according to }{\insrsid8994471\charrsid4147655 standard processing for routine application submissions.}{\insrsid12482763  }{\insrsid8994471  }{\insrsid14574295\charrsid4147655 The }{\insrsid12535012 
FDA }{\insrsid14574295\charrsid4147655 guidance clarifies how submitted data will be utilized in regulating decision-making (i.e.}{\insrsid11159008\charrsid4147655 ,}{\insrsid14574295\charrsid4147655  \'93}{\insrsid15686789\charrsid4147655 
when the data will be considered sufficiently reliable to serve as the basis for regulatory decision making; when it will be considered only supportive to a decision; and when the data will not be used in regulatory decision making}{
\insrsid14574295\charrsid4147655 .\'94).}{\cs16\super\insrsid14574295\charrsid4147655 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 FDA, }{\i\insrsid4156601\charrsid11755622 Guidance for Industry: P}{\i\insrsid4156601 
harmacogenomic Data Submissions, supra }{\insrsid4156601 note 65.}}}{\insrsid14574295\charrsid4147655  }{\insrsid7876367\charrsid4147655  }{\insrsid9456684 For example, if data is submitted to a known valid biomarker}{\insrsid7948622  (defined below)}{
\insrsid9456684 , the }{\insrsid9456684\charrsid11810666 information}{\i\insrsid9456684  }{\i\insrsid9456684\charrsid11810666 must}{\insrsid9456684  be submitted pursuant to CFR 312.23.}{\cs16\super\insrsid852954 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\i\insrsid4156601 See }{\insrsid4156601 FDA, }{\i\insrsid4156601 
Genomic Data Submissions: Quick Reference Guide, available at }{\insrsid4156601\charrsid16253581 http://www.fda.gov/cder/genomics/QuickReference.pdf}{\insrsid4156601 .  }}}{\insrsid9456684   }{\insrsid12674671 Moreover, a}{\insrsid12482763 
 drug company is required to submit pharmacogenomic data}{\insrsid530412  for an IND}{\insrsid12482763  under CFR 312.23 if:
\par }\pard\plain \s22\ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid13650624 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid13650624 1.  }{\insrsid12482763 
The test results are used for making decisions pertaining to a specific clinical trial, or in a animal trial used to support safety (e.g., the results will affect dose selection, entry criteria into a clinical trial safety 
monitoring, or subject stratification). }{\insrsid13650624 
\par }\pard \s22\ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid12674671 {\insrsid13650624 2.  }{\insrsid12482763 
A sponsor is using the test results to support scientific arguments pertaining to, for example, the pharmacologic mechanism of action, the selection of drug dosing, or the safety and effectiveness of a drug.}{\cs16\super\insrsid5709815 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  FDA, }{\i\insrsid4156601 
Genomics at FDA: Submission of Pharmacogenomic Data Decision Tree, available at }{\insrsid4156601\charrsid12482763 http://www.fda.gov/cder/genomics/decisionTree.htm}{\insrsid4156601 .}}}{\insrsid12482763  
\par }\pard \s22\ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid13650624 {\insrsid13650624 
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid13650624 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid2239166 I}{\insrsid2239166\charrsid4147655 
f it is unclear whether a submission is voluntary or required, }{\insrsid2239166 t}{\insrsid7876367\charrsid4147655 he Institu}{\insrsid6116012 tiona}{\insrsid7876367\charrsid4147655 l Pharmacogenomics Review Group (IPRG) }{\insrsid2239166 
(discussed in more detail shortly) }{\insrsid7876367\charrsid4147655 is responsibl}{\insrsid11810666 e for}{\insrsid7876367\charrsid4147655  convening a meeting with the sponsor and representative(s) from the relevant review
 division to help determine the status of the submission in question.}{\cs16\super\insrsid15956291 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  FDA, MAPP 4180.3, }{\i\insrsid4156601 Manual of Policies and Procedures: Processing and Reviewing Voluntary Genomic Data Submissions (VGDSs)}{
\insrsid4156601 , }{\i\insrsid4156601 available at }{\insrsid4156601\charrsid16253581 http://www.fda.gov/cder/mapp/4180.3.pdf}{\insrsid4156601 .}}}{\insrsid14574295\charrsid4147655  }{\insrsid11810666 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid13650624 {\insrsid14574295\charrsid12860689 
The guidance sets out three classifications of biomarkers: exploratory, probable valid, and known valid biomarkers.  What differentiates the categories is \'93their validity or degree of validity,\'94 or \'93their degree of uncertainty.\'94}{
\cs16\super\insrsid14574295\charrsid12860689 \chftn {\footnote \pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10515533 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{\i\insrsid4156601\charrsid11755622 Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{
\insrsid4156601 note 180.  }{\i\insrsid4156601\charrsid10515533 See}{\insrsid4156601\charrsid10515533  }{\insrsid4156601 FDA, }{\i\insrsid4156601\charrsid11755622 Guidance for Industry: P}{\i\insrsid4156601 harmacogenomic Data Submissions, supra }{
\insrsid4156601 note 65.  }{\insrsid4156601\charrsid10515533 The guidance explains that a pharmacogenomic test result may be considered a }{\i\insrsid4156601\charrsid10515533 valid biomarker }{\insrsid4156601\charrsid10515533 if \'93
(1) it is measured in an analytical test system with well-established performance characteristics and (2) there is an established sci
entific framework or body of evidence that elucidates the physiologic, pharmacologic, toxicologic, or clinical significance of the test results.\'94
  It cites the enzyme CYP2D6 as an example, because it is well understood in the scientific community and is reflected in certain approved drug labels. The guidance makes an additional distinction between }{\insrsid4156601 \'93}{
\insrsid4156601\charrsid10515533 known valid biomarkers that have been accepted in the broad scientific community and probable valid biomarkers that appear to have predictive value for clinical outcomes, but may not yet be widely accepted or ha}{
\insrsid4156601 ve been independently verified\'85.\'94}}}{\insrsid14574295\charrsid12860689   Lesko explain}{\insrsid330384 ed}{\insrsid14574295\charrsid12860689  that \'93
the function is driven by the classification, and then the function in turn drives the submission process, }{\insrsid8086754\charrsid12860689 whether}{\insrsid14574295\charrsid12860689 
 it is voluntary or required and whether it is a full report, abbreviated, or synopsis.\'94}{\cs16\super\insrsid14574295\charrsid12860689 \chftn {\footnote \pard\plain 
\s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10515533 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid10515533 \chftn }{\insrsid4156601\charrsid10515533  }{
\insrsid4156601 Id.  }}}{\insrsid5140743  }{\insrsid8157130\charrsid12860689  }{\insrsid14574295\charrsid12860689 The guidance}{\insrsid9838791\charrsid12860689  informs drug sponsors }{\insrsid14162865 on when and }{\insrsid9838791\charrsid12860689 
how to submit pharmacogenomic data during the drug or biological drug product development and review processes, what }{\insrsid12791996 format }{\insrsid14162865 and content}{\insrsid12791996  must be submitted, }{\insrsid14162865 a}{
\insrsid9838791\charrsid12860689 nd how the data will, or will not, be used in regulatory decision making.}{\cs16\super\insrsid9838791\charrsid12860689 \chftn {\footnote \pard\plain 
\s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10515533 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid10515533 \chftn }{\insrsid4156601\charrsid10515533  }{
\insrsid4156601 FDA, }{\i\insrsid4156601\charrsid11755622 Guidance for Industry: P}{\i\insrsid4156601 harmacogenomic Data Submissions, supra }{\insrsid4156601 note 65.}}}{\insrsid9838791\charrsid12860689   }{\insrsid2260467\charrsid12860689 It}{
\insrsid6105110\charrsid12860689  }{\insrsid4931534\charrsid12860689 seeks}{\insrsid6105110\charrsid12860689  to remain consistent with existing FDA policy.  }{\insrsid14553620\charrsid12860689 
Currently, for example, a drug manufacturer must submit a new drug application to FDA.  21 USC \'a7355(b) requires drug sponsors to submit \'93full reports of investigations which have been made to show whether or not\~
such drug is safe for use and whether such drug is effective in use.\'94}{\cs16\super\insrsid14553620\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  21 USC \'a7355(d)(1) (1994).}}}{\insrsid14553620\charrsid12860689   Such reports must \'93
include adequate tests by all methods reasonably applicable\'94 to demonstrate a drug\rquote s safety.   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid6105110\charrsid12860689 Thus, }{\insrsid7415514 b}{\insrsid6105110\charrsid12860689 ecause F
DA regulations establish different requirements for INDs, unapproved NDAs and BLAs}{\insrsid6191652  (}{\insrsid6191652\charrsid12544652 Biologics License Applications}{\insrsid6191652 )}{\insrsid6105110\charrsid12860689 , and approved NDAs and }{
\insrsid12544652 BLAs, }{\insrsid7415514 \'93}{\insrsid6105110\charrsid12544652 this}{\insrsid6105110\charrsid12860689  guidance sets out different submission algorithms for each of these categories.\'94}{\cs16\super\insrsid6105110\charrsid12860689 
\chftn {\footnote \pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10567138 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 FDA, }{\i\insrsid4156601\charrsid11755622 Guidance for Industry: P}{\i\insrsid4156601 harmacogenomic Data Submissions, supra }{\insrsid4156601 note 65.}}}{\insrsid6105110\charrsid12860689   }{
\insrsid6577968\charrsid12860689 The algorithms are }{\insrsid4870230 available on the new FDA pharmacogenomics website}{\insrsid6577968\charrsid12860689 .}{\cs16\super\insrsid12482763 \chftn {\footnote \pard\plain 
\s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10567138 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  FDA, }{\i\insrsid4156601 
Genomics at FDA: Submission of Pharmacogenomic Data Decision Tree, available at }{\insrsid4156601\charrsid12482763 http://www.fda.gov/cder/genomics/decisionTree.htm}{\insrsid4156601 .}}}{\insrsid6577968\charrsid12860689   }{
\insrsid12780379\charrsid12860689 Although}{\insrsid4549414 ,}{\insrsid4081111\charrsid12860689  generally}{\insrsid4549414 ,}{\insrsid4081111\charrsid12860689  submission of pharmacogenomic data is voluntary, t}{\insrsid2260467\charrsid12860689 
he guidance also explains how a drug sponsor could \'93fully integrate pharmacogenomic data into the drug development }{\insrsid1968667 p}{\insrsid2260467\charrsid12860689 rogram.\'94}{\cs16\super\insrsid2260467\charrsid12860689 \chftn {\footnote 
\pard\plain \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10567138 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid3240071 \chftn }{\insrsid4156601\charrsid3240071  }{
\insrsid4156601 FDA, }{\i\insrsid4156601\charrsid11755622 Guidance for Industry: P}{\i\insrsid4156601 harmacogenomic Data Submissions, supra }{\insrsid4156601 note 65.  }{\insrsid4156601\charrsid3240071 The options include \'93
(1) The pharmacogenomic data may be intended to be included in the drug labeling in an informational manner.  For example, such data might be used to describe the potential for dose adjustment by drug metabolism genotype (e.g., CYP2D6*5) or to mention
 the possibility of a side effect of greater severity or frequency in individuals of a certain genotype or gene expression profile. In such cases, the pharmacogenomic test result would be considered a known valid biomarker. However, an FDA-approved pharma
c
ogenomic test may not be available or required to be available, or a commercial pharmacogenomic test may not be widely available. Given this level of complexity, at the current time, sponsors should consult the relevant FDA review division for advice on h
ow to proceed in a specific case. However, whenever a sponsor intends to include pharmacogenomic data in the drug label, complete information on the test and results must be submitted to the Agency as described under \'a7\'a7
 314.50 and 601.2. The pharmacogenomic data and resulting test or tests may be intended to be included in}{\insrsid4156601  }{\insrsid4156601\charrsid3240071 the drug labeling to choose a dose and dose schedule, to identify patients at risk, or to}{
\insrsid4156601  }{\insrsid4156601\charrsid3240071 identify patient responders. Inclusion of a pharmacogenomic test in the labeling would}{\insrsid4156601  }{\insrsid4156601\charrsid3240071 be contingent upon its performance characteristics. For example:

\par }\pard \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3240071 {\insrsid4156601\charrsid3240071 \bullet  Patients will be tested for drug metabolism genotype and dosed according to the test}{\insrsid4156601  }{
\insrsid4156601\charrsid3240071 results.
\par }\pard \s29\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3240071 {\insrsid4156601\charrsid3240071 \bullet  Patients will be selected as potential responders for an efficacy trial (or deselected}{\insrsid4156601  }{
\insrsid4156601\charrsid3240071 because of a high risk) based on genotype (e.g., of either the patient or the patient\rquote s}{\insrsid4156601  }{\insrsid4156601\charrsid3240071 tumor) or gene expression profile.
\par \bullet  Patients will be excluded from a clinical trial based on genotype or gene expression}{\insrsid4156601  }{\insrsid4156601\charrsid3240071 profile (e.g., biomarker for risk of an adverse event).}{\insrsid4156601 \'94  }{
\i\insrsid4156601\charrsid11755622 See also}{\cs26\insrsid4156601\charrsid11755622  Tracy }{\insrsid4156601\charrsid11755622 Hampton, }{\i\insrsid4156601 supra }{\insrsid4156601 note 39.  }}}{\insrsid2260467\charrsid12860689   When doi
ng so, FDA recommends that the tests and drugs be codeveloped, and all }{\insrsid4931534\charrsid12860689 information}{\insrsid2260467\charrsid12860689  submitted to the agency.}{\cs16\super\insrsid2260467\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid2260467\charrsid12860689     }{\insrsid474045\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2177084 {\insrsid12544652\charrsid8675059 Th}{\insrsid4549414 us, th}{\insrsid12544652\charrsid8675059 
e FDA has developed a policy that would allow drug companies to voluntarily share pharmacogenomic results that are not central to their product testing, without fear of the FDA demanding more research}{\insrsid2260467\charrsid8675059 
, since the FDA made clear that it would not use information submitted through the voluntary process for regulatory decision making on INDs or NDAs.}{\cs16\super\insrsid2260467\charrsid8675059 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622   }{\i\insrsid4156601\charrsid11755622 See also }{\insrsid4156601\charrsid11755622 Grant Goss, }{\i\insrsid4156601\charrsid11755622 BIO 2003: Pharmacogenomics: Great Potential, Great Debates}{
\insrsid4156601\charrsid11755622 , Bio-It World, (6/25/03), a}{\i\insrsid4156601\charrsid11755622 vailable at }{\insrsid4156601\charrsid13786787 http://www.bio-itworld.com/news/062503_report2772.html}{\insrsid4156601 .}}}{\insrsid2260467\charrsid8675059  
}{\insrsid2177084  }{\cs26\insrsid6577968\charrsid8675059 The assurance that the FDA will not use the submitted information to make any regulatory decisions was made in reaction to companies\rquote 
 worries that the data will be used against them to keep their products off the market or \'93limit its approval to a small subpopulation of patients.\'94}{\cs16\super\insrsid6577968\charrsid8675059 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\cs26\insrsid4156601\charrsid11755622 Tracy }{\insrsid4156601\charrsid11755622 Hampton, }{\i\insrsid4156601 supra }{\insrsid4156601 note 39.  }}}{\cs26\insrsid6577968\charrsid8675059   }{\cs26\insrsid13307106 
\par }\pard\plain \s22\ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2177084 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid15887271\charrsid8675059 The}{\insrsid4419292\charrsid8675059  }{
\insrsid9854988\charrsid8608984 FDA }{\insrsid15887271\charrsid8608984 set}{\insrsid9854988\charrsid8608984  up }{\insrsid15887271\charrsid8608984 the Interdisciplinary Pharmacogenomics Review Group (IPRG)}{\insrsid9854988\charrsid8608984 
 that will be responsible for \'93look[ing] at the markers that would come in through the process.\'94}{\cs16\super\insrsid9854988\charrsid8608984 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{
\i\insrsid4156601\charrsid11755622 Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 180.  }}}{\insrsid5055925\charrsid8608984   }{\insrsid10767230 
Effective March 16, 2005, t}{\insrsid15887271\charrsid8608984 he IPRG }{\insrsid8086754\charrsid8608984 consist}{\insrsid15887271\charrsid8608984 s}{\insrsid5055925\charrsid8608984  of }{\insrsid8027286\charrsid8608984 approximately seventeen }{
\insrsid8086754\charrsid8608984 representatives}{\insrsid5055925\charrsid8608984  from different FDA centers}{\insrsid13722383\charrsid8608984 ,}{\insrsid8027286\charrsid8608984  including}{\insrsid11760543\charrsid8608984 
 the Center for Drug Evaluation and Research (CDER)}{\insrsid8027286\charrsid8608984 ,}{\insrsid11760543\charrsid8608984  the Center for Biologics Evaluation and }{\insrsid9641423\charrsid8608984 Research}{\insrsid11760543\charrsid8608984  (}{
\insrsid8027286\charrsid8608984 CBER}{\insrsid11760543\charrsid8608984 )}{\insrsid8027286\charrsid8608984 , and}{\insrsid11760543\charrsid8608984  the Center for }{\insrsid9641423\charrsid8608984 Devices}{\insrsid11760543\charrsid8608984 
 and Radiological Health (}{\insrsid8027286\charrsid8608984 CDRH}{\insrsid11760543\charrsid8608984 )}{\insrsid8027286\charrsid8608984 .}{\cs16\super\insrsid14777525\charrsid8608984 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid14777525 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  FDA, }{\insrsid4156601\charrsid15887271 
MAPP 4180.2}{\insrsid4156601 ,}{\insrsid4156601\charrsid15887271  }{\i\insrsid4156601 supra }{\insrsid4156601 note 202. }}}{\insrsid8027286\charrsid8608984   }{\insrsid6191652 The group is}{\insrsid13722383\charrsid8608984 
 responsible for reviewing voluntary genomic submissions (VGDSs) and consulting, on request, }{\insrsid9379466\charrsid8608984 regarding }{\insrsid13722383\charrsid8608984 the }{\insrsid9379466\charrsid8608984 Designation for Genomic Data Submissions (}{
\insrsid13722383\charrsid8608984 GDSs}{\insrsid9379466\charrsid8608984 )}{\insrsid13722383\charrsid8608984 .}{\insrsid9854988\charrsid8608984   }{\insrsid2636799\charrsid8608984 In addition to the IPRG members, e}{\insrsid8195224\charrsid8608984 
xperts also}{\insrsid8675059\charrsid8608984  }{\insrsid8195224\charrsid8608984 serve on a temporary basis and are appointed according to the subject matter of the GDS to be reviewed.}{\insrsid8072911\charrsid8608984   }{\insrsid2177084 
\par }\pard \s22\ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8153775 {\insrsid15349510\charrsid8608984 The IPRG is the primary contact (internal and external) for all VGD}{\insrsid10037210\charrsid8608984 S}{
\insrsid15349510\charrsid8608984 s, \'93coordinating the communication with sponsors and the FDA regarding all VGDS-related}{\insrsid10037210\charrsid8608984  }{\insrsid15349510\charrsid8608984 issues.}{\insrsid8027286\charrsid8608984 \'94}{
\cs16\super\insrsid8027286\charrsid8608984 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{
\insrsid4156601  Id.}}}{\insrsid10037210\charrsid8608984  }{\insrsid15349510\charrsid8608984  }{\insrsid2177084 Drug sponsors can initiate the }{\insrsid1200427 submissions }{\insrsid2177084 process by contacting the IPRG}{\insrsid9049064  to}{
\insrsid2177084  discuss the scope of the proposed VGDS. }{\insrsid5528773\charrsid8608984 Once }{\insrsid12791996\charrsid8608984 drug }{\insrsid2177084 companies }{\insrsid5528773\charrsid8608984 submit their information,}{
\insrsid7364768\charrsid8608984  the IPRG will evaluate the submissions and meet with the sponsors, upon request, to }{\insrsid9641423\charrsid8608984 discuss}{\insrsid1200427  their application }{\insrsid7364768\charrsid8608984 according to}{
\insrsid1200427  the guidelines set out in the accompanying }{\i\insrsid1200427 Manual of Policies and Procedures: Processing and Reviewing Voluntary Genomic Data Submissions (VGDSs)}{\insrsid1200427 .}{\cs16\super\insrsid9068173\charrsid8608984 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}{\i\insrsid4156601   }{\insrsid4156601\charrsid8608984  }{\insrsid4156601 The }{\i\insrsid4156601 
Manual of Policies and Procedures: Processing and Reviewing Voluntary Genomic Data Submissions (VGDSs)}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 206, explains how the IPRG will review all VGDSs and issue VGDS reports. }}}{
\insrsid5528773\charrsid8608984   }{\insrsid9641423\charrsid8608984 Besides advising drug sponsors regarding the voluntary submission of their data, }{\insrsid9641423 t}{\insrsid9641423\charrsid8608984 he purpose of the IPRG is to }{\insrsid9641423 
aid in integrating}{\insrsid9641423\charrsid8608984  pharmacogenomics into the regulatory review process and help develop future guidance and}{\insrsid9641423  }{\insrsid9641423\charrsid8608984 review standards}{\insrsid9641423 .}{
\cs16\super\insrsid9641423 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{
\insrsid9641423   }{\insrsid8608984 T}{\insrsid2758606 he IPRG will be advised by the IPRG Advisory Subcommittee, appointed under the Drug Safety and Risk }{\insrsid9641423 Management}{\insrsid2758606  Advisory Committee.}{\cs16\super\insrsid11558702 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{
\insrsid2758606\charrsid12860689 
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\insrsid7878414 In conjunction with the final guidance, FDA }{\insrsid8088086 
also }{\insrsid7878414 set up its pharmacogenomics website entitled \'93Genomics at FDA.\'94}{\cs16\super\insrsid7878414 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid7878414 \chftn }{\insrsid4156601\charrsid7878414  FDA, }{\i\insrsid4156601\charrsid7878414 
FDA Works to Speed the Advent of New, More Effective Personalized Medicines}{\i\insrsid4156601 , supra }{\insrsid4156601 note 199.  The website is available at }{\insrsid4156601\charrsid1378588 http://www.fda.gov/cder/genomics/default.htm}{
\insrsid4156601 .}}}{\insrsid7878414  }{\insrsid1378588  The site is intended for use by industry, and inc}{\insrsid7878414 ludes }{\insrsid1378588 \'93}{\insrsid7878414 
detailed information on submitting genomic data, including a decision tree to simplify data submissions, relevant regulatory information, and FDA contact information}{\insrsid1378588 .\'94}{\cs16\super\insrsid1980238 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id. }}}{\insrsid7878414 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid8088086 
Although there is little obvious difference between the draft and final guidance, the final version did attempt to respond to public comment, since the}{\insrsid10567138  FDA draft}{\insrsid10567138\charrsid12860689  guidance ha}{\insrsid10567138 d}{
\insrsid10567138\charrsid12860689  some ambiguities.}{\insrsid10567138   I}{\insrsid10567138\charrsid12860689 n its draft form, }{\insrsid10567138 the guidance }{\insrsid10567138\charrsid12860689 d}{\insrsid10567138 id}{\insrsid10567138\charrsid12860689 
 not clarify how pharmacogenomics may affect how drugs will be classified as orphan drugs under the Orphan Drug Act of 1983.}{\cs16\super\insrsid10567138\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10567138 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 NIH Comments on FDA\rquote s Draft Guidance for Industry Pharmacogenomic Data Submission (2}{\insrsid4156601\charrsid11755622 ).}}}{\insrsid10635588   It appears that this problem was not addressed in the guidance
\rquote s final form.}{\insrsid10567138\charrsid12860689   }{\insrsid14039341 On the other hand}{\insrsid10567138 , }{\insrsid10567138\charrsid12860689 Lesko predict}{\insrsid10567138 ed}{\insrsid10567138\charrsid12860689  
that one of the most contentious issues with the guidance is the relation between submission format and which definition }{\insrsid10567138 will apply to biomarkers }{\insrsid10567138\charrsid12860689 within the \'93hierarchy\'94 the guidance provides.}{
\cs16\super\insrsid10567138\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10567138 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{\i\insrsid4156601\charrsid11755622 Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{
\insrsid4156601 note 180.  }}}{\insrsid10567138\charrsid12860689   The definitions the }{\insrsid4724619 draft }{\insrsid10567138\charrsid12860689 guidance provide}{\insrsid4724619 d}{\insrsid10567138\charrsid12860689  }{\insrsid4724619 we}{
\insrsid10567138\charrsid12860689 re unclear, and \'93you need}{\insrsid6840432 [ed]}{\insrsid10567138\charrsid12860689  a lot of specific examples to walk through them, either with a sponsor or with a review division at FDA.\'94}{
\cs16\super\insrsid10567138\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10567138 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid10567138\charrsid12860689   }{\insrsid16013949 Likely}{\insrsid10567138  in response, FDA published a \'93Quick Reference Guide\'94
 and a series of decision trees to make the process as clear as possible}{\insrsid11565916 .}{\cs16\super\insrsid11565916\charrsid11565916  }{\cs16\super\insrsid11565916 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11565916 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\i\insrsid4156601 See }{\insrsid4156601 FDA, }{
\i\insrsid4156601 Genomic Data Submissions: Quick Reference Guide, available at }{\insrsid4156601\charrsid10046675 http://www.fda.gov/cder/genomics/QuickReference.pdf}{\insrsid4156601 .  }{\i\insrsid4156601 See also }{\insrsid4156601 FDA, }{
\i\insrsid4156601 Genomics at FDA: Submission of Pharmacogenomic Data Decision Tree, available at }{\insrsid4156601\charrsid12482763 http://www.fda.gov/cder/genomics/decisionTree.htm}{\insrsid4156601 .}}}{\insrsid11565916   The guide}{\insrsid13717517 
 provides a simple table for determining when data is required to be submitted, and when it may be submitted voluntarily}{\insrsid10567138 .  }{\insrsid11565916 
To clarify further, the FDA also issued an attachment to the guidance, providing prototypical examples of voluntary }{\insrsid6234059 and required }{\insrsid11565916 submissions.}{\cs16\super\insrsid4070837 \chftn {\footnote \pard\plain 
\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid6234059 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\fs20\super\insrsid4156601\charrsid6234059 \chftn }{\fs20\insrsid4156601\charrsid6234059 
 FDA, Attachment to Guidance on Pharmacogenomic Data Submissions: }{\i\fs20\insrsid4156601\charrsid6234059 Examples of Voluntary Submissions or Submissions Required under 21 CFR 312, 314, or 601, }{\fs20\insrsid4156601\charrsid6234059 (March, 2005), }{
\i\fs20\insrsid4156601\charrsid6234059 available at }{\fs20\insrsid4156601\charrsid6234059 http://www.fda.gov/cber/gdlns/pharmdtasub_att.htm}{\insrsid4156601 .}}}{\insrsid9051192 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid6644797 Despite }{\insrsid2447814 some}{\insrsid9729393  }{\insrsid2974098 concerns}{\insrsid474045\charrsid12860689 , t}{
\insrsid478650\charrsid12860689 he FDA guidance has received relatively positive responses thus far.  }{\insrsid944513 According to }{\insrsid10046675 the }{\insrsid944513 FDA, }{\insrsid5318766 many}{\insrsid944513 
 submissions have already been received through both the voluntary and regulatory mechanisms established by the agency.}{\cs16\super\insrsid9051192 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid7878414 FDA, }{
\i\insrsid4156601\charrsid7878414 FDA Works to Speed the Advent of New, More Effective Personalized Medicines}{\i\insrsid4156601 , supra }{\insrsid4156601 note 199.  }}}{\insrsid944513   }{\cs26\insrsid2974098\charrsid12860689 
Brian Spear of Abbott Laboratories,}{\cs26\insrsid2974098  o}{\insrsid478650\charrsid12860689 ne of the members of the steering committee to a workshop attended by both government agency and pharmaceutical industry representatives,}{
\cs26\insrsid478650\charrsid12860689  }{\insrsid478650\charrsid12860689 has called the effort to deal with this new movement in drug development \'93collaborative.\'94  Spear explained, \'93}{\cs26\insrsid478650\charrsid12860689 There}{
\cs26\insrsid2974098 \rquote }{\cs26\insrsid478650\charrsid12860689 
s been a lot of interaction between the FDA and industry groups to come up with a way for industry to use these technologies and for the agency to use the information in drug regulation, but at the same time to avoi
d the concern that we may be getting ahead of ourselves.\'94}{\cs16\super\insrsid478650\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\cs26\insrsid4156601\charrsid11755622 Tracy }{\insrsid4156601\charrsid11755622 Hampton, }{\i\insrsid4156601 
supra }{\insrsid4156601 note 39.  }}}{\insrsid478650\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 B}{\b\insrsid15619348 .  }{\b\insrsid3149194\charrsid12860689 Additional Guidance 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5856396\charrsid12860689 FDA is also }{\insrsid13399720 in the process of }{\insrsid5856396\charrsid12860689 
drafting guidance regarding the codevelopment of pharmacogenomic-based therapeutic drugs and the associated diagnostic tests.}{\cs16\super\insrsid5856396\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{
\i\insrsid4156601\charrsid11755622 Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 180.  }}}{\insrsid5856396\charrsid12860689   }{
\insrsid3290600\charrsid12860689 The guidance will deal directly with drugs that require a genetic test before the drug is administered.  }{\insrsid5856396\charrsid12860689 
In July 2004, it put together a workshop with the Drug Information Association (DIA) entitled }{\insrsid5856396\charrsid12860689 \'93Co-Development of Drug, Biological, and Device Products.\'94  The FDA collaborated with }{
\insrsid5856396\charrsid12860689 
Pharmaceutical Research and Manufacturers of America (PHRMA), Biotechnology Industry Organization (BIO), Advanced Medical Technology Association (ADVAMed), Medical Device Manufacturers Association (MDMA), DIA Biotechnology SIAC, and the Phar
macogenomics Working Group (PWG) to identify the important issues in the codevelopment of pharmacogenomic combination products.}{\cs16\super\insrsid5856396\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 FDA/DIA Pharmacogenomics Workshop: Co-Development of Drug, Biological, and Device Products}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601\charrsid11755622 at }{\insrsid4156601\charrsid13786787 
http://www.diahome.org/docs/events/events_search_detail.cfm?EventID=04040}{\insrsid4156601\charrsid11755622 .  }}}{\insrsid16213495\charrsid12860689   A workshop is }{\insrsid8086754\charrsid12860689 planned}{\insrsid16213495\charrsid12860689  for }{
\insrsid8086754\charrsid12860689 April}{\insrsid16213495\charrsid12860689  2005 in order to }{\insrsid8086754\charrsid12860689 discuss}{\insrsid16213495\charrsid12860689  that draft guidance.}{\cs16\super\insrsid8086754\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Lesko, }{\i\insrsid4156601\charrsid11755622 Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 180.  }}}{\insrsid3149194\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid3149194\charrsid12860689 Moreover, FDA is }{\insrsid2185933\charrsid12860689 collaborating}{\insrsid3149194\charrsid12860689 
 with the }{\insrsid2185933\charrsid12860689 National}{\insrsid3149194\charrsid12860689  }{\insrsid2185933\charrsid12860689 Academy}{\insrsid3149194\charrsid12860689  of }{\insrsid2185933\charrsid12860689 Clinical}{\insrsid3149194\charrsid12860689 
 Biochemistry to develop }{\insrsid2185933\charrsid12860689 guidelines}{\insrsid3149194\charrsid12860689  on pharmacogenomics for laboratory practices, which will ideally be released in June 2006.}{\cs16\super\insrsid3149194\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid8878203   According to one article, }{\cs34\insrsid8878203 the FDA is working on several documents related to pharmacogenomics}{\cs34\insrsid7739747 , including guidances on }{
\cs34\insrsid8878203 genotyping tests for }{\cs34\insrsid8878203\charrsid7739747 drug metabolizing enzymes}{\cs34\b\insrsid7739747 ,}{\cs34\insrsid8878203  instrumentation for }{\cs34\insrsid7739747 clinical multiplex tests,}{\cs34\insrsid8878203 
 and the co-development of drugs and diagnostics.}{\cs16\super\insrsid3239836 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\cs34\insrsid4156601\charrsid1518597 Branca,}{\cs34\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 197.}}}{\insrsid5856396\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 C}{\b\insrsid622334 .  }{\b\insrsid15684490\charrsid12860689 Other }{\b\insrsid14307018 P}{
\b\insrsid15684490\charrsid12860689 ossible FDA }{\b\insrsid14307018 A}{\b\insrsid15684490\charrsid12860689 pproaches to }{\b\insrsid14307018 P}{\b\insrsid15684490\charrsid12860689 harmacogenomics 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid8401074 {\insrsid459053 There }{\insrsid144414 are}{\insrsid459053  a number of }{\insrsid678540 additional ways in which}{\insrsid459053 
 the FDA could get involved in order to deal with the various practical implications of pharmacogenomics.  }{\insrsid8401074\charrsid12860689 The FDA\rquote 
s guidance indicates that that the agency is committed to educating the pharmaceutical industry about how pharmacogenomic data can be submitted in order to help a sponsor\rquote 
s drug through the approval process.  FDA has set up a number of workshops focusing on the integration of genomics and diagnostics into the drug development process.}{\insrsid8401074  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid8401074 {\insrsid8401074\charrsid12860689 Moreover, the agency is concerned that FDA officials may n
ot be prepared to deal with the number of INDs and NDAs that may come in that contain genomic information.  In response, FDA has sponsored a number of \'93internal[ ]\'85
 educational programs for people in the center to raise their awareness level and better prepare them for the applications that they\rquote re going to see.\'94}{\cs16\super\insrsid8401074\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8401074 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Lesko, }{
\i\insrsid4156601\charrsid11755622 Targeted Medicine: From Concept to Clinic}{\insrsid4156601\charrsid11755622 ,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 180.  }}}{\insrsid8401074   FDA has also begun a lecture series entitled 
\'93Pharmacogenomics from the Ground Up,\'94 which was designed for scientists and has}{\cf1\insrsid8401074  created a new training program for genomics for review staff.}{\cs16\cf1\super\insrsid8401074 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8401074 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  FDA, }{\i\insrsid4156601 Genomics at FDA, at }{
\insrsid4156601\charrsid9844915 http://www.fda.gov/cder/genomics/default.htm}{\insrsid4156601 .}}}{\cf1\insrsid8401074   }{\insrsid8401074 Reviewers within CDER are instructed regarding }{\insrsid8401074\charrsid5249095 
Concepts and Tools in Pharmacogenomics}{\insrsid8401074 , }{\insrsid8401074\charrsid5249095 Submissions and Labels in Regulatory Pharmacogenomics, and final training on }{\field\fldedit{\*\fldinst {\insrsid8401074\charrsid5249095 
 HYPERLINK "http://www.fda.gov/nctr/science/centers/toxicoinformatics/ArrayTrack/" }}{\fldrslt {\cs17\insrsid8401074\charrsid5249095 ArrayTrack}}}{\insrsid8401074\charrsid5249095 ,
 an integrated genomics analysis tool developed by the National Center for Toxicology Research (NCTR)}{\insrsid8401074 .}{\cs16\super\insrsid8401074 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8401074 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{\insrsid8401074\charrsid13575038 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid15684490\charrsid12860689 In order to encourage pharmacogenomic developments, the authors of \'93
Creating Incentives for Genomics Research to Improve Targeting of Therapies\'94 recommend, among other options, offering incentives similar to those of the Orphan Drug Act}{\insrsid9133763 , which will be discussed shortly}{
\insrsid15684490\charrsid12860689 .  They suggest \'93bonuses in reimbursement or patent-term extensions for genetically targeted drugs shown to produce low rates of treatment failure in actual clinical practice.\'94}{
\cs16\super\insrsid15684490\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1290.  }}}{
\insrsid15684490\charrsid12860689   }{\insrsid9008365 I}{\insrsid15684490\charrsid12860689 
nstead of granting special drug status due to the small patient group size, they recommend rewarding companies for low rates of adverse events or positive treatment results.  }{\insrsid9008365\charrsid12860689 However, }{\insrsid9008365 
FDA could not pursue this course, as only Congress could do this.   }{\insrsid817885\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid15684490\charrsid12860689 Another possible incentive }{\insrsid678540 the }{\insrsid9179654 FDA could propose }{
\insrsid15684490\charrsid12860689 to }{\insrsid678540 encourage}{\insrsid15684490\charrsid12860689  pharmacogenomic research would be to offer \'93special pathways to expedite drug approvals for promising new targeted therapies.\'94}{
\cs16\super\insrsid15684490\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.  }}}{\insrsid15684490\charrsid12860689   This could be effected through an expansion or changing of the ODA, as we }{\insrsid2192886 
will see below}{\insrsid15684490\charrsid12860689 .  Another recommendation, which does not seem particular to pharmacogenomic products specifically}{\insrsid2192886\charrsid2192886  }{\insrsid2192886 but instead }{\insrsid2192886\charrsid12860689 
pertains to all novel drugs or treatments and insurance decisions generally}{\insrsid2192886 , would be}{\insrsid4805621  for }{\insrsid7220861 the Centers for}{\insrsid622334  Medicare and Medicaid Services}{\insrsid2192886  to}{
\insrsid15684490\charrsid12860689  \'93}{\insrsid2192886 reduce[e] }{\insrsid15684490\charrsid12860689 delays and uncertain}{\insrsid2192886 ties in reimbursement decisions.}{\insrsid15684490\charrsid12860689 \'94}{
\cs16\super\insrsid15684490\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid15684490\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8421295 {\insrsid8421295 In addition, it has been recommended that FDA consider its licensing requirements regarding those compounds that }{
\insrsid8421295\charrsid12860689 would, in the past, not have be}{\insrsid8421295 en}{\insrsid8421295\charrsid12860689  approved without the assoc}{\insrsid8421295 
iated pharmacogenomic targeting.  Because of the ability to market such a drug to a particular subpopulation, the}{\insrsid8421295\charrsid12860689  Nuffield Council on Bioethics advocates, in these instance, that pharmacogenetic tests to be part of th
e license conditions of the drug.}{\cs16\super\insrsid8421295\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8421295 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{
\insrsid4156601\charrsid11755622  .}}}{\insrsid8421295\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11892042\charrsid12860689 Instituting more safeguards thro}{\insrsid2192886 ughout the FDA approval process}{
\insrsid11892042\charrsid12860689  by requiring genetics expert}{\insrsid5185126 s}{\insrsid11892042\charrsid12860689  on institutional review boards (IRBs)}{\insrsid13904591\charrsid12860689  }{\insrsid11892042\charrsid12860689 
may ensure that the increasing use of pharmacogenomics is encouraged while ensuring appropriate protections.}{\cs16\super\insrsid11892042\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Binzak, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 73 at 102.}}}{\insrsid11892042\charrsid12860689   Another }{\insrsid13904591\charrsid12860689 optio}{\insrsid11892042\charrsid12860689 
n is to build in-house regulatory expertise to monitor evolving regulations and to help }{\insrsid5185126 the }{\insrsid11892042\charrsid12860689 FDA }{\insrsid5185126 determine}{\insrsid11892042\charrsid12860689 
 how the regulatory arena will play out in pharmacogenomics.}{\cs16\super\insrsid11892042\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 The Business Case for Pharmacogenomics,}{\insrsid4156601\charrsid11755622 
 }{\i\insrsid4156601 supra }{\insrsid4156601 note 159.  }}}{\insrsid11892042\charrsid12860689   }{\insrsid15684490\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid9375451 Shah}{\insrsid5185126 , t}{\insrsid478650\charrsid12860689 he author of \'93Concept and Putative Applicatio
n of Pharmacogenetics and Pharmacogenomics\'94 notes that pharmacogenomics has impacted the way existing federal agencies are working together, in order to bring together those entities that determine licensing and prescription of ne}{\insrsid8813387 
w drugs and those that regulate}{\insrsid478650\charrsid12860689  and approve linked tests and other medical devices.}{\cs16\super\insrsid478650\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Jai Shah, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 9 at 3}{\insrsid4156601\charrsid11755622 .}}}{\insrsid478650\charrsid12860689   For example, the FDA established the Office of Combination Products in order to \'93
streamline the processing of complex drug-device, drug-biologic, and device-biologic combination products that play an increasingly significant role in health care.\'94}{\cs16\super\insrsid478650\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 FDA Establishes Office of Combination Products}{\insrsid4156601\charrsid11755622 , FDA (12/31/02), }{\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid13786787 
http://www.fda.gov/bbs/topics/NEWS/2002/NEW00862.html}{\insrsid4156601\charrsid11755622 .}}}{\insrsid15279912\charrsid12860689 
\par }\pard \ql \fi720\li720\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0\pararsid14307018 {\b\insrsid14054882 1}{\b\insrsid14157933 .  }{\b\insrsid14307018 Increased Phase IV}{\b\insrsid1844102\charrsid12860689  }{
\b\insrsid14307018 M}{\b\insrsid1844102\charrsid12860689 onitoring
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid1253828\charrsid12860689 Another potential }{\insrsid815200\charrsid12860689 role of the FDA in regulating pharmacogenomics is}{
\insrsid1784636  }{\insrsid815200\charrsid12860689 to require increased monitoring during phase IV trials.}{\insrsid2439493\charrsid12860689   }{\insrsid425301\charrsid12860689 Pharmacogenomics may lead to more of a focus on }{\insrsid1784636 
post-marketing surveillance}{\insrsid425301\charrsid12860689 , because earlier test populations will be so small that adverse events may not be reported until much later.}{\insrsid7941063   }{\insrsid16069307 At}{\insrsid7941063 
 least one critic asserts that }{\insrsid11015870 \'93[b]ecause of the inherent limitations of clinical trials, pharmacogenomic interventions will not alter the existing need for postmarket surveillance.\'94}{\cs16\super\insrsid8655847 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Noah, }{\i\insrsid4156601 supra }{\insrsid4156601 
note 175 at 24.  }}}{\insrsid11015870   However, he does conced}{\insrsid4414768 e}{\insrsid11015870  that \'93these advances could complicate the agency\rquote s effort to process rep}{\insrsid4414768 orts }{\insrsid5578715 of adverse drug reactions\'94
 by ad}{\insrsid16523799 ding extra pressure, straining \'93the agency\rquote s already severely limited resources.\'94}{\cs16\super\insrsid12942001 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{\insrsid425301\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1784636 {\insrsid1784636\charrsid12860689 Critics argue that FDA must be more \'93proactive\'94 in \'93
considering how it is going to regulate the new pharmacogenomic drugs already being developed.\'94}{\cs16\super\insrsid1784636\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1784636 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Binzak, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 73 at 105.}}}{\insrsid1784636\charrsid12860689   As phase IV trials become more and more indispensable for ensuring safety and efficacy, the Office of Post-Marketing Drug Risk Assessment, established by C}{
\insrsid144414 DE}{\insrsid1784636\charrsid12860689 R in 1998, might be the most useful in post}{\insrsid1784636 -}{\insrsid1784636\charrsid12860689 marketing surveillance.  The }{\insrsid1784636 o}{\insrsid1784636\charrsid12860689 
ffice is responsible for conducting epidemiological studies involving possible adverse outcomes.}{\cs16\super\insrsid1784636\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1784636 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Mark Rothstein, }
{\i\insrsid4156601\charrsid11755622 Epilogue to }{\insrsid4156601\charrsid11755622 Pharmacogenomics: Social, Ethical, and Clinical Dimensions 324 (Mark A. Rothstein, ed., Hoboken, NJ: John Wiley & Sons) (2003).}}}{\insrsid1784636\charrsid12860689  
 However, some are concerned that the Office of Post-Marketing Drug Risk Assessment may not be able to do enough.  In 2002, the FDA reported that drug manufacturers had only completed 882 of its 2400 reporting commitments.}{
\cs16\super\insrsid1784636\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1784636 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid1784636\charrsid12860689   }{\insrsid1784636 A}{\insrsid1784636\charrsid12860689 s of 2003, the \'93FDA has never 
pulled a drug from the market for failure to complete a postmarketing study in the absence of reports of adverse events.\'94}{\cs16\super\insrsid1784636\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1784636 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid1784636\charrsid12860689   Perhaps the FDA should be more vigorous in exercising its ability to withdraw drugs from the market post-approval.  One author recom
mends a more formal (and therefore more costly) phase IV system because of the smaller late-stage (Phase II and II) trials that will be a result of pharmacogenomics.}{\cs16\super\insrsid1784636\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1784636 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Jai Shah, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 9 at 3-8}{\insrsid4156601\charrsid11755622 .}}}{\insrsid1784636\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid16069307 Since the premarket trial population will likely be smaller, potential ADRs may not be picked up as easily.  }{
\insrsid1665368\charrsid12860689 Continued monitoring of adverse drug reactions allows a larger trial population than in the clinical trials, although use of the drug }{\insrsid1784636 after FDA approval }{\insrsid1665368\charrsid12860689 
is not as controlled as during the approval process.  }{\insrsid1784636 One possibility for FDA regulation is that if}{\insrsid1665368\charrsid12860689 
, during post-marketing surveillance, a company finds that the number of ADRs is above a certain threshold set by FDA, the drug developer may be required to perform\~pharmacogenomics studies of the drug or submit to withdrawal.}{
\cs16\super\insrsid1784636 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{
\insrsid4156601\charrsid11755622 Wu, }{\i\insrsid4156601 supra }{\insrsid4156601 note 27.  }}}{\insrsid1665368\charrsid12860689   One author claims that this could benefit the dr}{\insrsid12219300 ug manufacturer as well, since
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid12219300 {\insrsid1665368\charrsid12860689 ADR studies could serve as an additional\~
revenue stream in which the manufacturer could secure intellectual property\~rights in any pharmacogenetics test derived from its ADR studies and may avoid a complete withdrawal of its drug from the market by labeling changes that\~
would permit the screening out of }{\insrsid12219300 patients at risk from the drug.}{\cs16\super\insrsid1665368\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid1665368 
\par }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid12219300 {\insrsid12219300\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid1665368\charrsid12860689 Moreover,}{\insrsid2316006\charrsid12860689  one concern with }{\insrsid1852979 greater surveillance only }{
\i\insrsid2316006\charrsid1852979 after}{\insrsid2316006\charrsid12860689  FDA approval is that it might be dangerous to leave adverse event reporting until after }{\insrsid1852979 a drug is already on the market}{\insrsid2316006\charrsid12860689 
.  Doing so might potentially defeat the FDA mandate to ensure safety and efficacy by allowing the product onto the market before it has been fully demonstrated to be safe.}{\insrsid8723362\charrsid12860689 
\par }\pard \ql \fi720\li720\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin720\itap0\pararsid16733115 {\b\insrsid14054882 2}{\b\insrsid9709978 .  }{\b\insrsid478650\charrsid12860689 Off-}{\b\insrsid15622523 L}{
\b\insrsid478650\charrsid12860689 abel }{\b\insrsid15622523 U}{\b\insrsid478650\charrsid12860689 se}{\b\insrsid15215250\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid15298575\charrsid12860689 
An issue of major concern to FDA is the problem of off-label prescription.  Although drug sponsors may be able to demonstrate safety and efficacy in a shorter time frame by using smaller trial samples in their clinical studies, this may have enormous }{
\insrsid5270678 implications }{\insrsid15298575\charrsid12860689 once the drug is on the market}{\insrsid9709978 .  As the drug will only be FDA-}{\insrsid15298575\charrsid12860689 approved for use in the appro}{\insrsid5270678 
ved population, drug companies are prohibited from encouraging}{\insrsid15298575\charrsid12860689  off-label use.  However, doctors are not under the purview of the FDA, }{\insrsid11170861 since}{\insrsid15298575\charrsid12860689  the FDA
 does not regulate the practice of medicine.  Thus, physicians are allowed to prescribe drugs for off-label use.  In fact, some }{\insrsid11170861 observers }{\insrsid15298575\charrsid12860689 might attest that off-label prescription ensures \'93
clinical freedom\'94 and fosters innovation, leading to the development of new treatments.}{\cs16\super\insrsid15298575\charrsid12860689  \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{
\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 51.}}}{\insrsid15298575\charrsid12860689 
  However, since the number of individuals for whom use of the drug would be off-label would increase due to the smaller populations studies in the clinical trials, and off-label use might be more dangerous than for other \'93one size fits all}{
\insrsid14645192 ,}{\insrsid15298575\charrsid12860689 \'94 \'93blockbuster\'94 drugs, it might be necessary to require more safeguards for off-label usage}{\insrsid9709978  in the future}{\insrsid15298575\charrsid12860689 .
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid10439170 {\insrsid1464802\charrsid12860689 Ther}{\insrsid9709978 e are potential solutions}{\insrsid1464802\charrsid12860689  }{\insrsid16069307 to this concern }{
\insrsid1464802\charrsid12860689 which could be implemented alone or together.  }{\insrsid15298575\charrsid12860689 One option}{\insrsid14951739\charrsid12860689  is }{\insrsid9709978 to have}{\insrsid14951739\charrsid12860689  }{\insrsid16069307 the }{
\insrsid14951739\charrsid12860689 FDA}{\insrsid15298575\charrsid12860689  require something akin to phase IV trials (}{\insrsid14645192 e.g., }{\insrsid15298575\charrsid12860689 testing on special populations) before approval because the }{
\insrsid16069307 premarket }{\insrsid15298575\charrsid12860689 small targeted studies will mean that those with dissimilar genomes will not have been tested for adverse events before FDA approval.  Some critics have recommended the \'93
collection of DNA samples as part of drug-related adverse event reporting\'94 to \'93create a resource accessible to the academic community for analysis.\'94}{\cs16\super\insrsid15298575\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id. at 53.}{\insrsid4156601\charrsid11755622   }}}{\insrsid15298575\charrsid12860689  }{\insrsid9709978  Moreover, }{\insrsid7224151 the }{\insrsid9709978\charrsid12860689 FDA could also be more stringent about approval}{\insrsid9709978 
, offering a new class of \'93conditional\'94}{\insrsid9709978\charrsid12860689  approvals}{\insrsid5837623  for drugs targeted to particular subpopulations}{\insrsid9709978\charrsid12860689 .}{\cs16\super\insrsid9709978\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid9709978 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 41. }{\insrsid4156601\charrsid11755622   }}}{
\insrsid1464802\charrsid9709978 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid1464802\charrsid12860689 Another possibility is }{\insrsid5837623 to}{\insrsid1464802\charrsid12860689  requir}{\insrsid5837623 e}{
\insrsid15298575\charrsid12860689  study groups to encompass more varied genotypes (\'93a requirement for a wider safety than the genetic subgroup\'94).}{\cs16\super\insrsid15298575\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .  }}}{\insrsid15298575\charrsid12860689   However, this would }{\insrsid7224151 likely directly counteract the benefit }{\insrsid15298575\charrsid12860689 
that pharmacogenomics offers to clinical trials by increasing the trial populations}{\insrsid5837623 .  This recommendation could }{\insrsid15298575\charrsid12860689 negat}{\insrsid5837623 e}{\insrsid15298575\charrsid12860689 
 the efficiency and safety results pharmacogenomics offered in the first place}{\insrsid5837623 .}{\insrsid1464802\charrsid12860689  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid1464802\charrsid12860689 Alternatively,}{\insrsid15298575\charrsid12860689  FDA could buttress its
 prohibitions against off-label use (i.e.}{\insrsid7224151 ,}{\insrsid15298575\charrsid12860689  by not being as lenient regarding doctors prescribing drugs for purposes other than for which they were approved).  }{\insrsid1464802\charrsid12860689 
However, requiring }{\insrsid15298575\charrsid12860689 \'93}{\insrsid1464802\charrsid12860689 [i]}{\insrsid6250563 ncreased audit of prescribing}{\insrsid1464802\charrsid12860689 ,}{\insrsid15298575\charrsid12860689 \'94}{\insrsid1464802\charrsid12860689 
 might be difficult }{\insrsid12780379\charrsid12860689 because}{\insrsid1464802\charrsid12860689 , as we have seen, }{\insrsid7224151 the }{\insrsid1464802\charrsid12860689 FDA does not have authority over the medical profession.}{
\cs16\super\insrsid15298575\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622   }}}{\insrsid15298575\charrsid12860689  }{\insrsid7224151  }{\insrsid6250563\charrsid12860689 
Another option may be }{\insrsid6250563 to ensure}{\insrsid6250563\charrsid12860689  better educatio}{\insrsid16469959 n of doctors regarding the dangerous}{\insrsid6250563\charrsid12860689  consequ}{\insrsid7224151 
ences of off-label prescription for this class of drug,}{\insrsid6250563\charrsid12860689  while maintaining the legality of }{\insrsid3354919 off-label prescribing}{\insrsid6250563\charrsid12860689 .}{\cs16\super\insrsid7226637 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601 
 The education of physicians will be discussed in more detail in the section on physician liability.  }}}{\insrsid1784969   }{\insrsid6250563 A final }{\insrsid5583725\charrsid12860689 option, which will be }{\insrsid9846994\charrsid12860689 discussed}{
\insrsid5583725\charrsid12860689  in more depth in the liability section, is to impose stricter liability on physicians who prescribe pharmacogenomics products off-label. 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 II}{\b\insrsid1985866 .  }{\b\insrsid8657354 The Orphan Drug Act (}{\b\insrsid5178363\charrsid12860689 ODA}{
\b\insrsid8657354 )}{\b\insrsid3691929 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 \'93We may all soon be orphans!\'94}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Thomas Morrow, }{\i\insrsid4156601\charrsid11755622 Orphan Drug Act Treatments Deserve Full Insurance Coverage}{\insrsid4156601\charrsid11755622 , Managed Care Magazine (2004), }{\i\insrsid4156601\charrsid11755622 available at }{
\insrsid4156601\charrsid11755622 http://}{\insrsid4156601\charrsid13786787 www.managedcaremag.com/archives/0409/0409.biotech.html}{\insrsid4156601\charrsid11755622  (last visited 11/1/04).}}}{\insrsid5178363\charrsid12860689   }{
\b\insrsid5178363\charrsid3691929 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 The often-cited \'93orphan drug problem\'94 can be described as \'93the possibility of focusing on \lquote 
easier to treat\rquote  subsets of the population and excluding from trials those with unfavourable, or simply unusual, genetic constitutions}{\insrsid10634687 .}{\insrsid5178363\charrsid12860689 \'94}{\cs16\super\insrsid5178363\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Goldstein, Tate, and Sisodiya, }{\i\insrsid4156601 supra }{\insrsid4156601 note 1 at 945.}}}{\insrsid5178363\charrsid12860689    }{\insrsid10634687 Pharmacogenomics intens
ifies this problem because of its role in stratifying \'93}{\insrsid5178363\charrsid12860689 patient populations into smaller subgroups, so too might it provide economic disincentives for the development of new drugs\'94 for these groups.}{
\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Pat Buckley and Ross A. McKinnon, }{\i\insrsid4156601\charrsid11755622 Pharmacogenomics, Ethics, and the Community, }{\insrsid4156601\charrsid11755622 
23 Pharmacist 1 (2004).}}}{\insrsid1645567  }{\insrsid5178363\charrsid12860689  Thus, \'93commercial incentives for research may be weakest precisely where improved targeting is most needed.\'94}{\cs16\super\insrsid5178363\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1289.  }}}{\insrsid5178363\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 The }{\insrsid1645567 Orphan Drug }{\insrsid5178363\charrsid12860689 Act}{\insrsid1645567  (ODA)}{
\insrsid5178363\charrsid12860689  was passed by Congress in order to provide incentives for developing drugs for small markets.  It focuses on the more than twenty million Americans with one of six thousand rare diseases, coined as \'93orp}{
\insrsid13044836 han\'94 diseases because }{\insrsid5178363\charrsid12860689 companies}{\insrsid13044836  are reluctant to}{\insrsid5178363\charrsid12860689  develop associated drugs }{\insrsid13044836 due to financial disincentives}{
\insrsid5178363\charrsid12860689 .}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Orphan Drug Act, }{\insrsid4156601\charrsid11755622 21 USC \'a7
360bb(a)(2).  }{\i\insrsid4156601\charrsid11755622 See also }{\insrsid4156601\charrsid11755622 Morrow, }{\i\insrsid4156601 supra }{\insrsid4156601 note 263.  }}}{\insrsid5178363\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 
Currently, orphan drug status applies to drugs that are effective for fewer than 200,000 patients or those that affect a greater number but there is no \'93
reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in}{\insrsid7943187  the United States of such drug.}{\insrsid5178363\charrsid12860689 \'94}{
\cs16\super\insrsid7943187 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{
\insrsid4156601\charrsid11755622 Buckley and McKinnon, }{\i\insrsid4156601 supra }{\insrsid4156601 note 265.  }}}{\insrsid5178363\charrsid12860689  }{\insrsid7943230  P}{\insrsid14616250 atient p}{\insrsid5178363\charrsid12860689 opulation is determi
ned by the total population with clinical symptoms, rather than those who would actually be eligible for use of the drug.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 See }{\insrsid4156601\charrsid11755622 The Orphan Drug Act \'a752 (1983).}}}{\insrsid5178363\charrsid12860689    }{\insrsid13044836 
This definition, as we shall see shortly, has great implications for products developed using pharmacogenomics. }{\insrsid5178363\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 The major provisions of the }{\insrsid6685815 ODA}{\insrsid5178363\charrsid12860689  are as follow}{
\insrsid10692632 s}{\insrsid14616250 : t}{\insrsid10692632 he Act}{\insrsid5178363\charrsid12860689  (1) grants seven-year marketing exclusivity to the sponsoring organization,}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
The Act grants FDA authority to award a drug owner market exclusivity for seven years, rather than the five granted by the Hatch-Waxman Act of 1984.   Rothstein, }{\i\insrsid4156601\charrsid11755622 Epilogue }{\i\insrsid4156601 supra }{\insrsid4156601 
note 251 at 324.  }}}{\insrsid5178363\charrsid12860689  (2) gives a fifty percent tax credit toward the cost of clinical trials in humans, and (3) provides up to $150,000 for phase }{\insrsid7150719 I}{\insrsid5178363\charrsid12860689  studies and up
 to $300,000 for Phase II and II}{\insrsid7150719 I}{\insrsid5178363\charrsid12860689  studies.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Morrow, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 263.  }}}{\insrsid5178363\charrsid12860689   }{\insrsid14616250 The }{\insrsid5178363\charrsid12860689 FDA often grants priority reviews }{\insrsid2233414 for orphan drugs}{\insrsid12610973 ,}{
\insrsid2233414  }{\insrsid5178363\charrsid12860689 and therapies may also be considered for a rapid approval under the special accelerated process.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid5178363\charrsid12860689   In 1997, Congress waived the usual drug application fee charged by the FDA}{\insrsid2233414  for orphan drugs}{\insrsid5178363\charrsid12860689 
, amounting to approximately $500,000 savings to drug developers.}{\cs16\super\insrsid2233414 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{\insrsid5178363\charrsid12860689   The ODA is responsible for the largest single source of clinical grants from the FDA. }{\insrsid869286 
 }{\insrsid5178363\charrsid12860689 In 2004, FDA awarded }{\insrsid869286 a }{\insrsid5178363\charrsid12860689 total }{\insrsid869286 of }{\insrsid5178363\charrsid12860689 $13.3 million in grants}{\insrsid869286  for orphan drugs}{
\insrsid5178363\charrsid12860689 .}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid5178363\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 The Act, sometimes called one of most successful laws Congress has ever written,}{
\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 NIH Comments on FDA\rquote s Draft Guidance for Industry Pharmacogenomic Data Submission (2).}}}{\insrsid5178363\charrsid12860689 
 enabled FDA not only to oversee drug development, but to take an active role in it.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Morrow, }{\i\insrsid4156601 supra }{\insrsid4156601 note 263.  }}}{\insrsid5178363\charrsid12860689   }{
\insrsid14616250 A}{\insrsid10250785 s of October 2002, seventy-four}{\insrsid14616250\charrsid11755622  orphan drugs had achieved market approval status by virtue of the }{\insrsid10250785 ODA.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Sam Tetlow, }{\i\insrsid4156601\charrsid4871421 Successful Pharmacogenomics Business Models}{\insrsid4156601\charrsid11755622 , Cambridge Healthtech Institute (2002) at 2, }{\i\insrsid4156601\charrsid11755622 available at
}{\insrsid4156601\charrsid11755622  http://www.chadvisors.com/services/pharm}{\insrsid4156601 acogenomics_business/sample.pdf.}{\insrsid4156601\charrsid11755622  The author specifies that \'93Sponsor companies include large players (GlaxoSmithKline,}{
\insrsid4156601  }{\insrsid4156601\charrsid11755622 Pharmacia [now Pfizer], Roche, Genentech, Amgen) as well as smaller players (Novartis,}{\insrsid4156601  }{\insrsid4156601\charrsid11755622 Me}{\insrsid4156601 dImmune, Immunex, and others).\'94}}}{
\insrsid5178363\charrsid12860689   }{\insrsid869286 M}{\insrsid5178363\charrsid12860689 ost impressively, approximately fifty percent of the biologics approved for marketing in the U.S. since 1982 have been designated orphan drugs.}{
\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Morrow, }{\i\insrsid4156601 supra }{\insrsid4156601 note 263.  }}}{\insrsid5178363\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid14491262 {\insrsid5178363\charrsid12860689 However, orphan status of pharmacogenomic products is not definite under the current statute.  Although it is \'93
anticipated by industry that subgroups of patients, defined by genotype\'94 would qualify}{\insrsid15928187 , }{\insrsid5178363\charrsid12860689 orphan status may not be certain, \'93
particularly where the target population is only a subgroup of the disease indication.\'94}{\cs16\super\insrsid15928187\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15928187 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{
\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 41.}{\insrsid4156601\charrsid11755622   }}}{\insrsid15928187\charrsid12860689  }{\insrsid15928187  }{\insrsid16130186 
FDA has discretion regarding to which drugs it grants orphan drug status because it can choose to broaden the target drug population so that the drug in question will not qualify.}{\b\insrsid16130186   }{\f285\insrsid12414067 A}{\f285\insrsid8277855  drug
\rquote s patient}{\f285\insrsid14491262  }{\f285\insrsid8277855 population }{\f285\insrsid12414067 is generally defined according to the}{\f285\insrsid8277855  }{\i\f285\insrsid8277855\charrsid12414067 total expected treatment}{\f285\insrsid8277855 
 population, not just those whom the}{\f285\insrsid14491262  }{\f285\insrsid8277855 pharmaceutical company identifies as eligible for clinical trials.}{\f285\insrsid14491262   }{\f285\insrsid12523155 Thus, }{\insrsid5178363\charrsid12860689 
Herceptin, which is often quoted as a rational model for pharmacogenetics, was surprisingly refused orphan status by the FDA}{\insrsid13204515  for}{\insrsid3961156  metastatic}{\insrsid13204515  breast cancer}{\insrsid2897555  because it }{
\insrsid813586 disagreed with the drug sponsor\rquote s }{\insrsid9257870 interpretation of}{\insrsid11340072  the}{\insrsid9257870  size of the}{\insrsid11340072  target population}{\insrsid5178363\charrsid12860689 .}{\cs16\super\insrsid2897555 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601 
 According to the Nuffield Council on Bioethics, Herceptin \'93was not granted the status of orphan medicine in the US. It is estimated that of the more than 1
.5 million women in the US who have been diagnosed with breast cancer, approximately 165,000 have metastatic breast cancer. Up to 30% of these 165,000 women could benefit from Herceptin.  Since the criterion for orphan disease status in the US is that 200
,
000 or fewer patients are affected, both metastatic breast cancer and the subset of metastatic breast cancers that would respond to Herceptin might seem eligible. However, the FDA took the view that the patient population for Herceptin comprises people wi
t
h breast cancer, who number considerably more than 200,000. The FDA was apparently not inclined to define a subset of patients as having a distinct condition based on the genetic characteristics of their tumours. (Interestingly, Herceptin was granted the 
status of orphan medicine for the subset of pancreatic cancers that over-express HER2.)\'94 }{\insrsid4156601\charrsid11755622 Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{
\insrsid4156601\charrsid11755622  }}}{\insrsid5178363\charrsid12860689   }{\insrsid2449724 Michael Dreis, FDA spokesperson, d}{\insrsid12195284 e}{\insrsid2449724 fended the decision}{\insrsid15432783  by the Office of }{\insrsid13453329 Orphan}{
\insrsid15432783  Products Development (OOPD)}{\insrsid2449724  not to grant the drug orphan drug status and explained that ph}{\insrsid11337900 armacogenomic products would not}{\insrsid2449724  be treated differently than other orphan drug submissions.}
{\cs16\super\insrsid15290367 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601 
 Jai Shah, }{\i\insrsid4156601 Economic and Regulatory Considerations in Pharmacogenomics for Drug Licensing and Healthcare, }{\insrsid4156601 21 Nature 747
, 749 (July 2003).  Note that regardless of orphan drug status, Herceptin has become profitable.  However, it is not clear that this will be true for other drugs with smaller patient population.}}}{\insrsid9900160 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid12610973 However, m}{\insrsid5178363\charrsid12860689 
any support the expansion of the ODA to apply to subpopulations identified via pharmacogenomic discoveries.  In order to rectif
y the possibility that stratification of patients by their genetic makeup will lead to a dearth of treatments for those groups, the }{\insrsid10298084 British }{\insrsid5178363\charrsid12860689 
Nuffield Council on Bioethics recommends that regulatory agencies prepare guidance that \'93use existing orphan medicine legislation, or any other policy instrument with equivalent effect, to provide incentives for development.\'94}{
\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622  }}}{
\insrsid5178363\charrsid12860689   The Council continues, explaining, \'93This should include reconsideration of the definition of an orphan medicine, with particular reference to the implications of genetic stratification of both patients and diseases.
\'94}{\insrsid12980370   }{\insrsid5178363\charrsid12860689 It has been suggested that Congress be encouraged to consider making the ODA more flexible and \'93its implementation sufficiently well funded through the FDA to support the development\'94
 of drugs for orphan genotypes.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Rothstein, }{\i\insrsid4156601\charrsid11755622 Epilogue }{\i\insrsid4156601 supra }{\insrsid4156601 
note 251 at 324.  }}}{\b\insrsid5178363\charrsid16130186 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 
Granting orphan drug status to drugs that are only effective or safe in a small subset of the population may be }{\insrsid12980370 desirable because, \'93[a]}{\insrsid5178363\charrsid12860689 
s market size decreases, the total cost of drug development will be spread over a smaller number of users, which will in turn increase the average price of pharmacogenomics-based drugs.\'94}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Reeder and Dickson, }{\i\insrsid4156601 supra }{\insrsid4156601 note 110 at 232.}}}{\insrsid5178363\charrsid12860689   Thus, drug companies, without proper incentives, may be reluctant to put in the resources necessary to develop these drugs.  }{
\insrsid615429 T}{\insrsid5178363\charrsid12860689 he increase}{\insrsid615429 d}{\insrsid5178363\charrsid12860689  price }{\insrsid8286607 of developing a targeted drug for a small population }{\insrsid5178363\charrsid12860689 will}{\insrsid615429 
 ideally}{\insrsid5178363\charrsid12860689  be balanced by the increased number of drug targets.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id. at 233.}}}{\insrsid5178363\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 
Through exclusivity incentives, drug developers could recover the costs of making an investment in expensive orphan genotypes worthwhile.\~ \'93Exclusivity may include barring other drug developers from submitting\~
competing drug applications. Moreover, exclusivity may include extending\~prescription drug benefits to cover drugs for orphan genotypes while denying or limiting coverage for competing drugs.\'94}{\cs16\super\insrsid5178363\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Wu, }{\i\insrsid4156601 supra }{\insrsid4156601 note 27.  }}}{\insrsid5178363\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 Henry Greely, author of \'93Pharmacogenomics: Promise, Prospects, and Potential Problems, Medical Ethics,\'94
 supports the application of legislation such as the ODA to incentivize the development of drugs for small or otherwise overlooked subpopulations.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Greely,}{
\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 13.}{\b\insrsid4156601  }{\insrsid4156601\charrsid11755622  }}}{\insrsid5178363\charrsid12860689   However, Greely\rquote s }{\insrsid11475799 critics }{\insrsid5178363\charrsid12860689 
maintain that those individuals who are denied new pharmacogenomics products are no worse off than they were before these pharmacogenomics discoveries}{\insrsid8286607  because they will still have access to the drugs already on the market}{
\insrsid5178363\charrsid12860689 .}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Jeffrey Kahn, Dialogue}{\i\insrsid4156601\charrsid11755622 : Why Pharmacogenomics is Good for Ethics}{
\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601\charrsid11755622 available at
\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 {\insrsid4156601\charrsid2576039 www.lahey.org/NewsPubs/Publications/Ethics/JournalSpring2002/Journal_Spring_2002_Dialogue.asp}{
\insrsid4156601\charrsid11755622  (last visited 1/04/05).}}}{\insrsid5178363\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 How
ever, application of the ODA, although helping to incentivize pharmacogenomic research by drug companies, will not ameliorate all of the problems.  Because of the increase in the number of orphan groups, distributive justice questions arise related to the
 allocation of scarce research resources between different orphan groups.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  A.K  Rai, }{\i\insrsid4156601\charrsid11755622 
Pharmacogenetic Interventions, Orphan Drugs, and Distributive Justice: The Role of Cost-Benefit Analysis,}{\insrsid4156601\charrsid11755622  19(2) Jour}{\insrsid4156601 .}{\insrsid4156601\charrsid11755622  of Social Phil}{\insrsid4156601 .}{
\insrsid4156601\charrsid11755622  and Policy, 246-70 (2002).}}}{\insrsid5178363\charrsid12860689   One author recommends supplementing moral theory }{\insrsid2901411\charrsid12860689 moral}{\insrsid2901411  debate about access}{
\insrsid2901411\charrsid12860689  }{\insrsid5178363\charrsid12860689 with \'93transparent, well-reasoned political debate\'94 and advocates cost-benefit analysis in order to give preferential treatment to those drugs that are }{
\insrsid3751568\charrsid12860689 considered cost}{\insrsid5178363\charrsid12860689 -beneficial.}{\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid5178363\charrsid12860689    He states that the \'93most promising mechanism for identifying such cost-beneficial drugs, and giving them preference, would be some type of patent term extension.\'94}{
\cs16\super\insrsid5178363\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601  Id.}}}{\b\insrsid5178363\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5178363\charrsid12860689 Managed care org
anizations have been hesitant to cover drugs approved via the orphan drug process, suggesting that the drugs are \'93less \lquote proven\rquote  than those developed through traditional pathways.\'94}{\cs16\super\insrsid5178363\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Morrow, }{\i\insrsid4156601 supra }{\insrsid4156601 note 263.  }}}{\insrsid5178363\charrsid12860689   One reason they cite is that double blind randomized controlled studies are }{\insrsid2637087 often }{
\insrsid5178363\charrsid12860689 not possible because of the dearth of patients.  One alternative to such studies is historic-control trials.  The author of \'93Orphan Drug Act Treatments Deserve Full Insurance Coverage,\'94
 cites the approval of an enzyme which demonstrated efficacy in treating SCID (severe combined immunodeficiency) as a prime example of a historic-control study, which only had six patients enrolled in its pivotal trial.}{\cs16\super\insrsid14755997 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{
\insrsid5178363\charrsid12860689   }{\b\insrsid5178363\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 III}{\b\insrsid4398586 .  }{\b\insrsid15340534 Implications of }{\b\insrsid15622523 Patent}{
\b\insrsid15215223  Law}{\b\insrsid15340534  for Pharmacogenomics }{\b\insrsid15819255\charrsid15557085 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid14776030\charrsid12860689 Congress and regulatory agencies appreciate the ability of }{\insrsid2512868 the }{
\insrsid14776030\charrsid12860689 patent}{\insrsid2512868  regime}{\insrsid14776030\charrsid12860689  to encourage drug }{\insrsid3227732\charrsid12860689 development}{\insrsid14776030\charrsid12860689 .  Thus, the ODA, as we have seen, }{
\insrsid3227732\charrsid12860689 increases}{\insrsid14776030\charrsid12860689  the benefits associated with market exclusivity.}{\insrsid5452912\charrsid12860689   }{\insrsid2637087\charrsid12860689 
The current intellectual property regime allows the drug }{\insrsid1195644 spons}{\insrsid1195644\charrsid12860689 or}{\insrsid2637087\charrsid12860689  to }{\insrsid2637087\charrsid16542566 recover not only the approve
d marketed drug costs, but the enormous R&D costs of all those compounds that did not make it through the approval process due to low efficacy or high rates of adverse events}{\insrsid5452912\charrsid16542566 .}{
\cs16\super\insrsid2447867\charrsid16542566 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nunnally, Brown, and Cohen}{\i\insrsid4156601 , supra }{\insrsid4156601 note 77.}}}{\insrsid5452912\charrsid16542566   However, p}{\insrsid15230251\charrsid16542566 
atents do not always provide adequate private incentives to develop genetic tests.}{\cs16\super\insrsid15230251\charrsid16542566 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Meurer, }{\i\insrsid4156601 supra }{\insrsid4156601 note 7}{\insrsid4156601\charrsid11755622 .}}}{
\insrsid15230251\charrsid16542566 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid11105579 {\insrsid11105579\charrsid16542566 Between 1976 and 2003, approxim}{\insrsid15340534\charrsid16542566 ately four thousand patents were is}{
\insrsid11105579\charrsid16542566 sued relate}{\insrsid16542566\charrsid16542566 d}{\insrsid11105579\charrsid16542566  to pharmacogenomics.}{\cs16\super\insrsid11105579\charrsid16542566 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11105579 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid11755622 Tetlow, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 277 at 13.  }}}{\insrsid11105579\charrsid16542566  According to one study, \'93the percentage of pharmacogenomic-related patents within the pharmaceutical and biotechnology industries has grown
 from virtually zero in 1995 to nearly 6% of all patents issued in the drug, diagnostic, and biotechnology industries in 2003.\'94}{\cs16\super\insrsid11105579\charrsid16542566 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11105579 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id}{\insrsid4156601\charrsid11755622 .}}}{
\insrsid11105579\charrsid16542566   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\outlinelevel0\rin0\lin0\itap0\pararsid16733115 {\insrsid8737116 \tab }{\b\insrsid14054882 A}{\b\insrsid13988542\charrsid13988542 .}{\insrsid13988542   }{\b\insrsid8737116 Criticism of Patent Protection }{
\b\insrsid8737116\charrsid8737116 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid10439170 {\insrsid5660435\charrsid12860689 In order to get a patent}{\insrsid5660435 ,}{\insrsid5660435\charrsid12860689  35 U.S.C. \'a7
101 mandates that the U.S. Patent and Trademark Office (PTO) determine that a product is new, useful, and nonobvious (}{\insrsid16542566 the PTO}{\insrsid5660435  will approve }{\insrsid5660435\charrsid12860689 \'93
any new and useful process, machine, manufacture, or composition of matter\'94).}{\cs16\super\insrsid5660435\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid5660435 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  35 U.S.C. \'a7101.}}}{\insrsid5660435\charrsid12860689 
  The PTO grants exclusivity to the inventor for twenty years, after which the product is in the public domain (and therefore anyone may use or copy the invention).  }{\insrsid14747678\charrsid12860689 It has been }{\insrsid9529228 noted}{
\insrsid14747678\charrsid12860689  that the scope of the patent re}{\insrsid8651790 gime has expanded, as t}{\insrsid5660435\charrsid12860689 he three requirements for obtaining a patent have progressively been loosened, allowing for more patents on }{
\insrsid5660435 \'93}{\insrsid5660435\charrsid12860689 upstream}{\insrsid5660435 \'94}{\insrsid5660435\charrsid12860689  inventions.  }{\insrsid5660435 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid10439170 {\insrsid5660435\charrsid12860689 Gene patents}{\insrsid13988542  }{\insrsid5660435\charrsid12860689 have long been a contentious issue.  }{\insrsid13988542 One}{
\insrsid14747678\charrsid12860689  of the more }{\insrsid11287161 comm}{\insrsid14747678\charrsid12860689 on arguments against allowing individuals to patent genetic code }{\insrsid144414\charrsid12860689 includes}{\insrsid14747678\charrsid12860689  the }
{\insrsid3956810 argument}{\insrsid14747678\charrsid12860689  that genes are }{\insrsid3956810 \'93}{\insrsid14747678\charrsid12860689 found in nature.}{\insrsid3956810 \'94}{\insrsid14747678\charrsid12860689   Intellectual property law prohibits th
e patenting of anything unless it had been modified}{\insrsid3956810  from its \'93natural form\'94}{\insrsid14747678\charrsid12860689  in some significant way}{\insrsid6244539\charrsid12860689 .}{\cs16\super\insrsid6244539\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 See Brothers Seed Co. v. Kalo Inoculant Co.}{\insrsid4156601\charrsid11755622 , Supreme Court, 1948 (S-P35).}}}{\insrsid6244539\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid4027691 More particularly, t}{\insrsid792441\charrsid12860689 
here has been some intense criticism regarding the patenting of SNPs.  Many }{\insrsid14944117 critics }{\insrsid792441\charrsid12860689 contend }{\insrsid10773308\charrsid12860689 that allowing}{\insrsid792441\charrsid12860689  SNPs }{\insrsid70716 
to be patented }{\insrsid792441\charrsid12860689 would prevent others from discovering full-length genes by }{\insrsid10773308\charrsid12860689 granting exclusive}{\insrsid792441\charrsid12860689  rights to the fragment patent holder, thereby making it 
\'93impossible for other researchers to work toward the goal of fully characterizing the gene without incurring licensing fees.\'94}{\cs16\super\insrsid792441\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  
Nunnally, Brown, and Cohen}{\i\insrsid4156601 , supra }{\insrsid4156601 note 77 at 115}{\insrsid4156601\charrsid11755622 .}}}{\insrsid14944117  }{\insrsid792441\charrsid12860689  This essentially limits all downstream \'93essential\'94 research.}{
\insrsid11093221   }{\insrsid5196251 Thus,}{\insrsid656007\charrsid12860689  from a public policy perspective, the expansion of patent law }{\insrsid8210997 could counteract}{\insrsid656007\charrsid12860689  the ideals set forth }{\insrsid656007 
in enumerating the}{\insrsid656007\charrsid12860689  law, resulting in a hindrance, rather than an encouragement, of research and product development.  }{\insrsid1720386\charrsid12860689 
Researchers would be deterred from using the science if patents were granted }{\insrsid2834411 upstream }{\insrsid1720386\charrsid12860689 on gene sequences }{\insrsid9249694 related}{\insrsid1720386 , for example,}{\insrsid1720386\charrsid12860689  }{
\insrsid9249694 to}{\insrsid1720386\charrsid12860689  drug metabolism, because such genes would like}{\insrsid12930142 ly}{\insrsid1720386\charrsid12860689  be implicated for a great number of different drugs to treat a whole array of diseases}{
\insrsid3494168  downstream}{\insrsid1720386\charrsid12860689 .}{\cs16\super\insrsid1720386\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1720386 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 36.}}}{\insrsid1720386   }{\insrsid11093221 As two University of Michigan law professors, Michael A. Heller and Rebecca Eisenberg, stated in 1998, \'93
a proliferation of intellectual property rights upstream may be stifling life-saving innovations further downstream in the course of research and product development.\'94}{\cs16\super\insrsid11093221 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  R. Stephen Crespi, }{\i\insrsid4156601\charrsid11093221 
Genetic Inventions, IRPs and Licensing Practices - A Welcome Report from OECD}{\insrsid4156601  (Sept. 2003), }{\i\insrsid4156601 available at }{\insrsid4156601\charrsid2715263 http://pharmalicensing.com/features/disp/1063797888_3f6844805940a}{
\insrsid4156601 .}}}{\insrsid11287161   }{\insrsid9334126 One response to this fear is that \'93}{\insrsid9334126\charrsid12860689 Gene patent claims that are valid may be read narrowly so that downstream genetic test developers are not infringers.\'94}{
\cs16\super\insrsid9334126\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid9334126 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Meurer, }{\i\insrsid4156601 supra }{\insrsid4156601 note 7 at }{\insrsid4156601\charrsid11755622 20 n. 79}{\insrsid4156601 . }}}{\insrsid9334126\charrsid12860689   }{
\insrsid9334126  }{\insrsid792441\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid16714141 Because it }{\insrsid16714141\charrsid12860689 is unclear what the genes or gene fragments in question }{\insrsid12912828 
code}{\insrsid16714141\charrsid12860689  for, but only that the fragme}{\insrsid16714141 nt is useful in locating }{\insrsid5660897 a }{\insrsid16714141 gene}{\insrsid10773308 , o}{\insrsid792441\charrsid12860689 
ne of the most significant arguments against gene patents is that such patents do not satisf}{\insrsid5660897 y the \'a7101 utility requirement.  }{\insrsid5590632\charrsid12860689 Recently, the Patent Offi
ce has focused specifically on the utility requirement.  }{\insrsid5590632 H}{\insrsid3997902\charrsid12860689 istorically, }{\insrsid5590632 however, }{\insrsid3997902\charrsid12860689 the utility requirem}{\insrsid7425267 
ent has always been quite loose -- g}{\insrsid946586\charrsid12860689 ene fragments were often allowed to be patented regardless of knowledge of their function or utility.}{\cs16\super\insrsid7425267\charrsid7425267  }{
\cs16\super\insrsid7425267\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid7425267 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 The Business Case for Pharmacogenomics,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 159.  }
}}{\insrsid7425267\charrsid12860689  }{\insrsid946586\charrsid12860689   }{\insrsid9334126 There is}{\insrsid946586  therefore}{\insrsid9334126  concern}{\insrsid792441\charrsid12860689  about \'93
the potential to make vague or inaccurate claims as to the utility to ESTs }{\insrsid12930142 (}{\insrsid12930142\charrsid15279068 expressed sequence tags) }{\insrsid792441\charrsid12860689 
and SNPS and the consequences of winning protection on useful research tools to which the patentees do not deserve exclusive rights.\'94}{\cs16\super\insrsid792441\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Nunnally, Brown, and Cohen}{\i\insrsid4156601 , supra }{\insrsid4156601 note 77 at 115.}}}{\insrsid12478582\charrsid12860689   }{\insrsid6707484 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid12218138 {\insrsid9334126 Because of the assertion that}{\insrsid12478582\charrsid12860689 
 allowing gene patenting sets up a major impediment to downstream research, it }{\insrsid1720386 may be}{\insrsid12478582\charrsid12860689  necessary }{\insrsid5975078 to require a patent application t}{\insrsid12478582\charrsid12860689 
o make a strong utility showing in order to gain patent protection.  }{\insrsid12734797\charrsid12860689 Thus, it has been a common suggestion that the PTO strengthen the utility requirement associated with attaining a patent on a genetic fragment.  }{
\insrsid12218138 The PTO has stated, }{\insrsid12218138\charrsid12860689 \'93if an inventor can show how a SNP can be used as a genetic marker to stratify patient populations, then the claim might be patentable.\'94}{
\cs16\super\insrsid12218138\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid12218138 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 The Business Case for Pharmacogenomics,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 159.  }
}}{\insrsid12218138\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid12734797\charrsid12860689 
This seems consistent with the intent of the American patent regime of encouraging product development, even within the expanded scope of patent rights over the last few years.  }{\insrsid12218138 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid14700380 The arguments against patenting gene}{\insrsid6122497  fragments without }{\insrsid13598533 knowing}{\insrsid1138546  }{
\insrsid946586 what trait}{\insrsid6122497 s}{\insrsid946586  a }{\insrsid792441\charrsid12860689 gene codes }{\insrsid6122497 for }{\insrsid946586 a}{\insrsid792441\charrsid12860689 re further }{\insrsid1138546 substantiated }{
\insrsid792441\charrsid12860689 when one considers that a substantial amount of genetic research is publicly funde}{\insrsid946586 d.  It is often argued that the current patent}{\insrsid792441\charrsid12860689 
 system requires the public to pay twice for use of genetic discoveries: once for the }{\insrsid1138546 publicly-funded }{\insrsid792441\charrsid12860689 research and }{\insrsid4989569 again}{\insrsid792441\charrsid12860689 
 for the use of any subsequently patented }{\insrsid946586 inventions}{\insrsid792441\charrsid12860689  (}{\insrsid946586 e.g.}{\insrsid792441\charrsid12860689 , genetic tests utilized in diagnosing and treating illnesses).  }{
\insrsid5666081\charrsid12860689 Others}{\insrsid8861121  have}{\insrsid5666081\charrsid12860689  asserted that gene patents raise difficult moral and intellectual questions that the intellectual property system should not become involved with.}{
\insrsid5666081 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\insrsid8737116 \tab }{\b\insrsid14054882 B}{\b\insrsid1598910\charrsid1598910 .}{\insrsid1598910   }{\b\insrsid8737116 
Arguments }{\b\insrsid1598910\charrsid14378582 F}{\b\insrsid8737116\charrsid14378582 or }{\b\insrsid8737116 Patent Protection}{\b\insrsid4212385  and the PTO\rquote s Stance }{\b\insrsid8737116\charrsid8737116 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid4212385 {\insrsid3932229 Others}{\insrsid792441\charrsid12860689  argue for the ability to patent SNPs}{\insrsid9115790  and ESTs}{
\insrsid792441\charrsid12860689 , asserting that allowing a party to patent a fragment will fuel further innovations by building on already-discovered SNPs (e.g.}{\insrsid3932229 ,}{\insrsid792441\charrsid12860689  the oft-quoted \'93
on the shoulders of giants\'94).  There is no credible evidence, they suggest, \'93that patenting of ESTs and SNPs would cause any more of a chilling effect on identification of whole genes that it has on other technologies.\'94}{
\cs16\super\insrsid792441\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nunnally, Brown, and Cohen}{\i\insrsid4156601 , supra }{\insrsid4156601 note 77.}}}{\insrsid12478582\charrsid12860689  }{\insrsid792441\charrsid12860689  }{
\insrsid12478582\charrsid12860689 PhRMA recommends that }{\insrsid12478582\charrsid12860689 patent incentives are maintained in the U.S.}{\insrsid6308253  }{\insrsid11546468 and}{\insrsid3932229  that they be}{\insrsid12478582\charrsid12860689 
 strengthened worldwide, }{\insrsid12478582\charrsid12860689 establishing the legitimacy of intellectual property protection for medicines in all countries, }{\insrsid12478582\charrsid12860689 in or
der to encourage pharmacogenomic research and development.}{\cs16\super\insrsid12478582\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\super\insrsid4156601\charrsid6053594 307 }{\i\insrsid4156601\charrsid11755622 Pharmaceutical Industry 2004,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 supra }{\insrsid4156601 note 105}{
\insrsid4156601\charrsid11755622 .}}}{\b\insrsid12478582\charrsid12860689   }{\insrsid3105049\charrsid12860689   }{\insrsid16414276\charrsid4212385 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid1976215 {\insrsid14747678\charrsid12860689 
Disregarding some of the more common arguments against the patenting of genes, the Patent Office announced that, if it appeared that something was patentable, they would grant the patent and let other areas of the la}{\insrsid6244539\charrsid12860689 
w deal with other }{\insrsid6308253 political and philosophical }{\insrsid6244539\charrsid12860689 issues}{\insrsid14747678\charrsid12860689 .}{\cs16\super\insrsid6244539\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 Utility Examination Guidelines}{\insrsid4156601\charrsid11755622 , United States Patent and Trademark Office, 66 Fed. Reg. 1092-1104 (2001).}}}{\insrsid14747678\charrsid12860689  }{\insrsid6244539\charrsid12860689  }{
\insrsid1976215 The PTO}{\insrsid1976215\charrsid12860689  found that it was not}{\insrsid1976215  its }{\insrsid1976215\charrsid12860689 role to determine public policy, and held that it was up to Congress to legislate if the results of the PTO\rquote 
s decision }{\insrsid5995389 we}{\insrsid1976215\charrsid12860689 re not desirable.
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid15498688 {\insrsid14747678\charrsid12860689 It 
made it clear that, if certain requirements were met, gene fragments, as well as entire genes, could be patentable.  Their guidelines state that a \'93
purified DNA molecule may meet the statutory utility requirement if, e.g., it can be used to produce a useful protein or if it hybridizes near and serves as a marker for a disease gene.\'94}{\cs16\super\insrsid14747678\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid14747678\charrsid12860689   Thus, a patent is not granted for the gene in its unpurified form, but for the isolated gene.  }{\insrsid3932229 The process of i}{\insrsid14747678\charrsid12860689 
solating the fragment is sufficient to overcome the \'93found in nature\'94 objection.  }{\insrsid14549311 Requiring the fragment to be isolated ensures that critics cannot contend}{\insrsid14747678\charrsid12860689 
 that all individuals who actually carry the gene will infringe}{\insrsid15867721  the patent}{\insrsid14747678\charrsid12860689 .  }{\insrsid15498688 Some}{\insrsid15498688\charrsid12860689  experts predict that \'93
although current policy is subject to judicial review and legislative mandate, the strongest available indications support continuation of the status quo\'94 in relation to patenting of SNPs and other gene fragments.}{
\cs16\super\insrsid15498688\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15498688 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Nunnally, Brown, and Cohen}{\i\insrsid4156601 , supra }{\insrsid4156601 note 77 at 119.}}}{\insrsid15498688\charrsid12860689  }{\insrsid1976215 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\insrsid16414276 \tab }{\b\insrsid14054882 C}{\b\insrsid15867721\charrsid15867721 .}{\insrsid15867721   }{\b\insrsid16414276 
Exceptions to the Patent Law}{\b\insrsid16414276\charrsid16414276 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid1511240 Moreover, pharmacogenomic}{\insrsid792441\charrsid12860689  discoveries will likely not fall within a
ny of the exemptions to patent protection.  }{\insrsid9722050 First, a}{\insrsid792441\charrsid12860689 
lthough there is an exception to patent protection for experimental research when use of the patented product or process is used strictly for research, the exemption is}{\insrsid1511240  very limited.}{\cs16\super\insrsid15867721 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid11755622 Meurer, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 7.}}}{\insrsid1511240   In order to fall within }{\insrsid12520151 it}{\insrsid1511240 , the use can not}{\insrsid792441\charrsid12860689  have any }{\insrsid792441\charrsid12860689 commercial}{
\b\insrsid792441\charrsid12860689  }{\insrsid792441\charrsid12860689 purpose at all.  }{\insrsid1511240 It}{\insrsid792441\charrsid12860689  exists so that }{\insrsid12780379\charrsid12860689 researchers}{\insrsid792441\charrsid12860689 \rquote 
 costs will not be }{\insrsid12780379\charrsid12860689 diminished}{\insrsid792441\charrsid12860689  who must pay royalties to gene patent owners in order to create new products, including chips and tests intended to predict adverse drug reactions.}{
\cs16\super\insrsid792441\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .}}}{\insrsid792441\charrsid12860689   }{\insrsid1511240 Second, }{\insrsid792441\charrsid12860689 
diagnostic products developed via pharmacogenomics most likely do not fall within the restrictions required to get }{\insrsid12520151 a }{\insrsid792441\charrsid12860689 patent on }{\insrsid792441\charrsid12860689 
diagnostic, therapeutic methods, and therefore researchers desiring to develop such products will be required to pay royalties to the patent owner.  }{\insrsid15470738 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid7895255 Michael Meurer, t}{\insrsid7895255 h}{\insrsid7895255\charrsid12860689 e author of }{\insrsid7895255\charrsid12860689 \'93
Pharmacogenomics, Genetic Tests, and Patent-Based Incentives,\'94 }{\insrsid13902737 explains, 
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid13902737 {\insrsid792441\charrsid12860689 Licensing fees required for access to genomic databases could also add significantly to development cost. 
 The high fixed cost of producing a database means that the market is not competitive, but prices are constrained by the existence of nonprofit databases, relatively weak intellectual property protection}{\insrsid13902737 , and the possibility of entry.}{
\cs16\super\insrsid792441\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .}}}{\insrsid792441\charrsid12860689  }{\insrsid13902737 
\par }\pard \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13902737 {\insrsid15470738  }{\insrsid13902737 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid15470738 However, he also suggests that }{\insrsid15470738\charrsid12860689 the licensing and royalty costs }{\insrsid15470738 
discussed by others }{\insrsid15470738\charrsid12860689 might not be as high as they might seem}{\insrsid15470738 , explaining,}{\insrsid15470738\charrsid12860689  \'93many existing gene patents may not survive validity challenges.\'94}{
\cs16\super\insrsid15470738\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15470738 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id. at}{\insrsid4156601\charrsid11755622  20 n.79.}}}{\insrsid15470738\charrsid12860689   }{\insrsid792441\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\insrsid16414276 \tab }{\b\insrsid14054882 D}{\b\insrsid5587973\charrsid5587973 .}{\insrsid5587973   }{\b\insrsid16414276 
Alternatives to Patent Protection}{\b\insrsid16414276\charrsid16414276 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid7544584\charrsid12860689 As an alternative to allowing patenting of SNPs and other gene fragments, it would be possible to prohibit }{
\insrsid5587973 the patenting of genes in a move analogous}{\insrsid7544584\charrsid12860689  to Congress}{\insrsid5587973 \rquote  exception }{\insrsid13703835\charrsid12860689 from patent protection}{\insrsid13703835  }{\insrsid5587973 for }{
\insrsid7544584\charrsid12860689 medical procedures.  Although, in theory,}{\insrsid16341563  it would be legally possible to patent}{\insrsid7544584\charrsid12860689  medical }{\insrsid7342630\charrsid12860689 procedures}{
\insrsid7544584\charrsid12860689 , industry standards}{\insrsid5182223 , as formalized by Congressional action,}{\insrsid16341563  ba}{\insrsid8324195 r}{\insrsid16341563  doing so}{\insrsid9919808 .}{\insrsid7544584\charrsid12860689 
  Congress established this exception to the patent law with a public policy rationale that }{\insrsid13703835 medical }{\insrsid7544584\charrsid12860689 operations }{\insrsid7090434 must be available to benefit humanity}{\insrsid7544584\charrsid12860689 
.}{\cs16\super\insrsid7956400 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{
\insrsid4156601\charrsid11755622 35 U.S.C. \'a7287 (c)(1).}}}{\insrsid7090434  }{\insrsid7544584\charrsid12860689  }{\insrsid15290908 35 U.S.C. }{\insrsid7544584\charrsid12860689 \'a7287, passed in 1996, exempts medical procedures from patent protection.}
{\cs16\super\insrsid2717519\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid7544584\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15022946 {\insrsid15290908 Moreover, regardless of many developers\rquote  push to patent their genetic discoveries, }{\insrsid2491263 
organizations such as the SNP Consortium have placed much of the genome in the public domain, }{\insrsid15022946 thereby making many genes unpatentable.  }{\insrsid12531968 Beyond}{\insrsid13660913\charrsid12860689  the SNP Consortium, }{
\insrsid13660913\charrsid12860689 some pharmaceutical companies are also building public domain genomic databases \'93to ward off potential patents.\'94}{\cs16\super\insrsid12780859\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Meurer, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 7 at }{\insrsid4156601\charrsid11755622 20 n. 79.}}}{\insrsid12780859\charrsid12860689   }{\insrsid15470738 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid14054882 IV}{\b\insrsid3487604 .  }{\b\insrsid7564008 Legal }{\b\insrsid7565182 Liability }{
\b\insrsid9919299\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid9919299\charrsid12860689 As pharmacogenomic discoveries }{\insrsid1854537 are}{\insrsid9919299\charrsid12860689 
 introduced into the market, the higher}{\insrsid1854537  diagnostic and prescription}{\insrsid9919299\charrsid12860689  }{\insrsid3476037\charrsid12860689 precision }{\insrsid9919299\charrsid12860689 will likely lead }{\insrsid9846994\charrsid12860689 to
}{\insrsid9919299\charrsid12860689  }{\insrsid14100597\charrsid12860689 better matching between patients and the appropriate drugs, a reduction or elimination of adverse effects, and more targeted dosaging according to one\rquote 
s particular metabolism.  However, because of these advances, }{\insrsid9178190\charrsid12860689 any adverse events or ineffective treatments will be scrutinized}{\insrsid7369352 , as it would be with any new therapy}{\insrsid9178190\charrsid12860689 
.  Who}{\insrsid9919299\charrsid12860689  will bear the }{\insrsid9178190\charrsid12860689 liability for side effects or unsuccessful therapies?  Both }{\insrsid9846994\charrsid12860689 physicians}{\insrsid9178190\charrsid12860689  and p}{
\insrsid9919299\charrsid12860689 harmaceutical }{\insrsid1854537 manufacturer}{\insrsid9919299\charrsid12860689 s}{\insrsid9178190\charrsid12860689  could be considered for liability}{\insrsid592518\charrsid12860689 , as increased }{
\insrsid9846994\charrsid12860689 liability}{\insrsid592518\charrsid12860689  may encourage more diligence on }{\insrsid1854537 both }{\insrsid592518\charrsid12860689 the}{\insrsid1854537 ir}{\insrsid592518\charrsid12860689  part}{\insrsid1854537 s}{
\insrsid592518\charrsid12860689 .  }{\insrsid9178190\charrsid12860689 Often, the choice of defendant d}{\insrsid9919299\charrsid12860689 epends}{\insrsid9178190\charrsid12860689  on who has the deeper pockets.  }{\insrsid7086171 
In addition, in the pharmacogenomic context, }{\insrsid12409720 the }{\insrsid7086171 choice of defendant may }{\insrsid9919299\charrsid12860689 depend }{\insrsid7086171 on whether}{\insrsid9919299\charrsid12860689  advertising is direct-to-consumer or}{
\insrsid6761832  }{\insrsid12409720 whether }{\insrsid6761832 there is a third party intermediary.}{\insrsid999370 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid13968511\charrsid12860689 
There is currently little liability for mistakes related to drug prescription because of a presumption by law and ethics that medicine is \'93inherently imprecise\'94 }{\insrsid12409720 compared to}{\insrsid13968511\charrsid12860689 
 other types of science.}{\cs16\super\insrsid13968511\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13968511 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1289.}}}{\insrsid12409720 
  This is why }{\insrsid13968511\charrsid12860689 there are no refunds for drugs although we do expect}{\insrsid7369352 , for example, refunds for}{\insrsid13968511\charrsid12860689  faulty refrigerators.}{\cs16\super\insrsid13968511\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13968511 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id. However, o}{\insrsid4156601\charrsid12860689 ne of the authors\rquote  recommendations to incentivize pharmacogenomic research included reversing state statutes and court doctrines \'93
that have long shielded medical product manufacturers from refund obligations.\'94  Like current liability law, the authors recommend that this be done at the state, rather than the federal, level}{\insrsid4156601 
.  Requiring refunds for faulty products can be analogized to a strict liability regime.}}}{\insrsid13968511\charrsid12860689   This presumption may have a deterrent effect on drug companies from developing pharmacogenomic products}{\insrsid349558 .  C}{
\insrsid13968511\charrsid12860689 ompanies may be hesitant to identify }{\insrsid13968511 for }{\insrsid13968511\charrsid12860689 which subpopulations a drug will or will not work }{\insrsid13968511 because if}{\insrsid13968511\charrsid12860689  }{
\insrsid13968511 a}{\insrsid13968511\charrsid12860689  prescribed drug is ineffective, they will not be held liable.}{\cs16\super\insrsid13968511\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13968511 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id. at 290.}}}{\insrsid13968511   Regardless of the reluctance of drug developers to conduct pharmacogenomic research, the}{\insrsid13968511\charrsid12860689  presumption}{\insrsid13968511  that medicine is imprecise}{
\insrsid13968511\charrsid12860689  may change}{\insrsid13968511  nevertheless}{\insrsid13968511\charrsid12860689 .  The authors}{\insrsid13968511  of \'93}{\insrsid13968511\charrsid13968511 
Creating Incentives for Genomics Research to Improve Targeting of Therapies,}{\insrsid13968511 \'94}{\insrsid13968511\charrsid11755622  }{\insrsid13968511\charrsid12860689 argue that the law\rquote s \'93special rules\'94
 regarding medicine are based on, perhaps outdated, presumptions, so the rules can}{\insrsid349558 , and will,}{\insrsid13968511\charrsid12860689  be changed.}{\cs16\super\insrsid13968511\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid13968511 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid13968511\charrsid12860689   
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid3481303 A}{\b\insrsid349558 .  }{\b\insrsid7086171 Liability }{\b\insrsid3366125 Against P}{
\b\insrsid6453500\charrsid12860689 hysicians 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid14897748\charrsid12860689 Pharmacogenomics could be a double-edged sword, where physicians are }{\insrsid8997936 \'93}{
\insrsid14897748\charrsid12860689 damned-if-they-do and damned-if-they-don\rquote t}{\insrsid8997936 \'94}{\insrsid14897748\charrsid12860689  use the technology.  For example, they could be sued fo
r medical malpractice by a patient for refusing to prescribe a drug }{\insrsid8997936\charrsid12860689 (perhaps \'93off-label\'94) }{\insrsid14897748\charrsid12860689 because it was not approved for his or her exact genetic makeup (i.e.}{\insrsid349558 ,}
{\insrsid14897748\charrsid12860689  he or she did not have the genetic predisposition }{\insrsid349558 of}{\insrsid2388386  }{\insrsid14897748\charrsid12860689 those involved in the clinical studies).  
Or, a patient could sue his or her doctor for adverse events associated with a prescription given according to currently accepted standards}{\insrsid7369352 ,}{\insrsid7369352\charrsid7369352  }{\insrsid7369352 
which may not have kept pace with scientific innovations}{\insrsid7369352\charrsid12860689 .}{\insrsid14897748 
\par }\pard \ql \li1440\ri0\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin1440\itap0\pararsid16733115 {\b\insrsid3481303 1}{\b\insrsid349558 .  }{\b\insrsid548638\charrsid12860689 Liability}{\b\insrsid10185250\charrsid12860689  for }{
\b\insrsid3366125 Not Utilizing P}{\b\insrsid10185250\charrsid12860689 harmacogenomic }{\b\insrsid3366125 D}{\b\insrsid10185250\charrsid12860689 iscoveries in the }{\b\insrsid3366125 P}{\b\insrsid10185250\charrsid12860689 ractice of }{\b\insrsid3366125 M}
{\b\insrsid10185250\charrsid12860689 edicine
\par }\pard \ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0\pararsid227349 {\b\insrsid227349\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid4069851 {\insrsid9793 Under the}{\insrsid4066957  current liability regime,}{\insrsid4069851 
 physicians may be sued for malpractice for negligent prescription of drugs, and courts have found doctors liable for failing to test for and prescribe the most appropriate drug for a particular individual.}{\cs16\super\insrsid4069851 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid4069851 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Noah, }{\i\insrsid4156601 supra }{
\insrsid4156601 note 175 at 24 n.112. }}}{\insrsid4069851\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid592518\charrsid12860689 One concern}{\insrsid12679415  with pharmacogenomics}{\insrsid592518\charrsid12860689 
 is whether physicians will have an obligation to utiliz}{\insrsid8997936 e pharmacogenomic}{\insrsid592518\charrsid12860689  diagnostics in order to hone an individual\rquote s prescription to his or her genetic profile}{\insrsid8926083\charrsid12860689 
, or whether the doctor can }{\insrsid592518\charrsid12860689 continue to follow the status quo}{\insrsid8997936  in diagnosing and prescribing medicines}{\insrsid8926083\charrsid12860689 .  It is unclear a}{\insrsid592518\charrsid12860689 
t what point the standard of care }{\insrsid8926083\charrsid12860689 will }{\insrsid592518\charrsid12860689 shift such that physicians are required to conduct genetic tests and prescribe drugs accordingly}{\insrsid8926083\charrsid12860689 . }{
\insrsid592518\charrsid12860689  Will there be liability for NOT testing for genetic predispositions or using }{\insrsid4066957 a }{\insrsid592518\charrsid12860689 particular treatment?}{\insrsid8997936 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid7233874\charrsid12860689 Moreover, even if a physician utilizes pharmacogenomics in their treatment decision, there may still be }{
\insrsid9846994\charrsid12860689 liability}{\insrsid7233874\charrsid12860689  for choosing }{\i\insrsid7233874\charrsid12860689 not }{\insrsid7233874\charrsid12860689 to prescribe a particular drug to an individual.   Because of the 
probabilistic nature of genetics, it is unclear how high a probability of a drug not working or having deleterious effect}{\insrsid10763111 s}{\insrsid7233874\charrsid12860689  would }{\insrsid8997936 be }{\insrsid7233874\charrsid12860689 
necessary to deny treatment.}{\cs16\super\insrsid7233874\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 
{\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Greely,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 13 at 2. }}}{\insrsid7233874\charrsid12860689   If}{\insrsid2388386  there is only one }{
\insrsid7233874\charrsid12860689 treatment available, it may make the threshold for denying it higher.  }{\insrsid2388386\charrsid12860689 It has been explained that, \'93}{\insrsid2388386 [e]}{\insrsid2388386\charrsid12860689 
ven when a group, on average, is unlikely to respond to a given treatment, individual members of the group may still respond.  They could suffer harm if treatment were denied\emdash especially troubling when no other treatment is available.\'94}{
\cs16\super\insrsid2388386\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2388386 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1290.  }}}{
\insrsid2388386\charrsid12860689   }{\insrsid7954998\charrsid12860689 Some critics recommend greater liability for }{\insrsid7954998 negative ou}{\insrsid7954998\charrsid12860689 tcomes or ineffective treatment results}{\insrsid7954998 , worrying that t}{
\insrsid7954998\charrsid12860689 here is the possibility that \'93[p]eople receiving a \lquote negative\rquote  test result will be denied a (more remote) chance of the drug working for them.  Where there are no alternatives this may cause conflict.\'94}{
\cs16\super\insrsid7954998\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid7954998 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 49.}}}{
\insrsid7954998\charrsid12860689   They have called for new standards to limit lawsuits against providers \'93who deny treatments based on careful, evidence-based inferences that the therapy, if administered, would not work.\'94}{
\cs16\super\insrsid7954998\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid7954998 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Evans, Flockhart, }{\insrsid4156601 and }{\insrsid4156601\charrsid11755622 Meslin, }{\i\insrsid4156601 supra }{\insrsid4156601 note 89 at 1290.  }}}{
\insrsid7954998\charrsid12860689   }{\insrsid2388386 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid7233874\charrsid12860689 Because of the complexity of genetic information, and the \'93
perils inherent in broad statistical judgments based on science that will be inexact even in the best scenario,\'94 it will be generally impossible to demonstrate a simple cause and effect relationship between one\rquote 
s genetic profile and the disease or side effects one exhibits.}{\cs16\super\insrsid7233874\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid7233874\charrsid12860689 
  It is clear that not all tests are completely accurate, and the more complicated the gene interactions, the less accurate any pres}{\insrsid7954998 cription}{\insrsid7233874\charrsid12860689  might be.  
\par }\pard \ql \li1440\ri0\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin1440\itap0\pararsid16733115 {\b\insrsid3481303 2}{\b\insrsid7954998 .  }{\b\insrsid10185250\charrsid12860689 Liability for }{\b\insrsid3366125 U}{
\b\insrsid10185250\charrsid12860689 sing }{\b\insrsid3366125 P}{\b\insrsid10185250\charrsid12860689 harmacogenomic }{\b\insrsid3366125 D}{\b\insrsid10185250\charrsid12860689 iscoveries in the }{\b\insrsid3366125 P}{\b\insrsid10185250\charrsid12860689 
ractice of }{\b\insrsid3366125 M}{\b\insrsid10185250\charrsid12860689 edicine}{\b\insrsid10185250 
\par }\pard \ql \li1440\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin1440\itap0\pararsid3366125 {\b\insrsid3366125\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid8926083\charrsid12860689 There are also concerns associated with imposing liability for }{\insrsid7954998 
adverse outcomes resulting from the use of pharmacogenomics i}{\insrsid8926083\charrsid12860689 n diagnosis and }{\insrsid9846994\charrsid12860689 treatment}{\insrsid8926083\charrsid12860689  decisions.}{\insrsid4398378  }{
\insrsid8926083\charrsid12860689  }{\insrsid15955712\charrsid12860689 Greater pressure is expected in coming years for healthcare providers and drug manufacturers to bear a larger share of the costs associated with\~
drug-treatment failures that occur when therapies are not well targeted.}{\cs16\super\insrsid15955712\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 
Pharmacogenomics; Genetically Targeted Therapies Create Opportunities to do Business in New}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Ways, }{\insrsid4156601\charrsid11755622 Genomics & Genetics Wkly 197 (1/14/05) }{
\i\insrsid4156601\charrsid11755622 at}{\insrsid4156601\charrsid11755622  2005 WL 55682494.}}}{\insrsid853400\charrsid12860689   }{\insrsid8997936 Thus, p}{\insrsid853400\charrsid12860689 harmacogenomics may increase the }{\insrsid13573188 doctor\rquote s 
}{\insrsid853400\charrsid12860689 expected standard of }{\insrsid13573188 care}{\insrsid853400\charrsid12860689 , because less}{\insrsid13573188  is}{\insrsid853400\charrsid12860689  left to chance.}{\insrsid15955712\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid14627663 {\insrsid343415\charrsid12860689 This}{\insrsid8997936  anticipated increased standard of care}{\insrsid343415\charrsid12860689  may be}{
\insrsid8997936 , in part,}{\insrsid343415\charrsid12860689  }{\insrsid8997936 a}{\insrsid343415\charrsid12860689  reaction to recent lawsuits that have been filed around the country.  }{\insrsid12208578\charrsid12860689 
For example, there have been a proliferation of}{\insrsid14627663\charrsid12860689  personal liability suits in which, after taking the vaccine LYMErix, individuals claimed severe health problems akin to those associated with Lyme disease.  }{
\insrsid5312938\charrsid12860689 The product was heavily advertised directly to consumers, and \'93[s]ome doctors worried that patients would demand it even if they had a very\~
low chance of getting the disease. Others feared vaccinated people would gain a false sense of security and let their guard down against ticks.\'94}{\cs16\super\insrsid5312938\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Susan Warner, }{
\i\insrsid4156601\charrsid9453935 SmithKline Beecham}{\i\insrsid4156601\charrsid11755622  Faces Lawsuit for Lyme-Disease Vaccines Negative Effects,}{\insrsid4156601\charrsid11755622  The Phil. Inq.}{\i\insrsid4156601\charrsid11755622  at }{
\insrsid4156601\charrsid11755622 (6/13/00) 2000 WL 22621370.}}}{\insrsid1723863\charrsid12860689   In 2002, the drug was taken off the market due to a reduction in sales, }{\insrsid14374629\charrsid12860689 likely}{\insrsid1723863\charrsid12860689 
 resulting from the negative publicity surrounding the }{\insrsid9854029\charrsid12860689 lawsuits.}{\cs16\super\insrsid8997936 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{\insrsid1723863\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid2642389 In 1999, a number of affected individuals brought a class action case}{\insrsid12667650  against the pharmaceutical company}{
\insrsid2642389 .}{\cs16\super\insrsid2642389 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2642389 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 
\chftn }{\insrsid4156601  }{\i\insrsid4156601\charrsid11755622 Cassidy v. SmithKline Beecham Corporation}{\insrsid4156601\charrsid11755622 , (Pa. Ct. of Common Pleas, Chester County, No. 99-
\par 10423, filed December 14, 1999, settled 2003).}}}{\insrsid2642389   The}{\insrsid14627663\charrsid12860689  Pennsylvania suit alleged }{\insrsid548638\charrsid12860689 that}{\insrsid14627663\charrsid12860689  SmithKline Beecham, the }{
\insrsid548638\charrsid12860689 manufacturer}{\insrsid14627663\charrsid12860689  of the product, failed to warn doctors and the public that nearly a third of the general population is genetically predisposed to autoimmune arthritis}{
\insrsid14173816\charrsid12860689 , which is incurable}{\insrsid14627663\charrsid12860689 .}{\cs16\super\insrsid13138034\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid14627663\charrsid12860689   }{\insrsid5312938\charrsid12860689 I}{\insrsid14627663\charrsid12860689 n 2000, a number of the individuals who brought the class action suit filed individually against the manufacturer, a
sking that it expand its vaccine labeling.}{\cs16\super\insrsid14627663\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Holcomb B. Noble, 3 Suits Say Lyme Vaccine Caused Severe Arthritis N.Y. Times at F6 (6/13/00)}}}{
\insrsid14627663\charrsid12860689   }{\insrsid2642389\charrsid12860689 The suits alleged that individuals with a HLA-DR4+ genetic type are susceptible to developing autoimmune\~arthritis if they are exposed to the protein that makes the vaccine work.}{
\cs16\super\insrsid2642389\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2642389 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Warner, }{\i\insrsid4156601 supra }{\insrsid4156601 note 330}{\insrsid4156601\charrsid11755622 . }}}{\insrsid2642389\charrsid12860689  }{\insrsid2642389  }{
\insrsid9128369\charrsid12860689 The plaintiffs}{\insrsid10572521\charrsid12860689 \rquote }{\insrsid9128369\charrsid12860689  allegations included a failure by the drug company to warn consumers of the potential adverse effects of the vaccine.  }{
\insrsid9128369 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid2642389\charrsid12860689 The class action case, }{\i\insrsid2642389\charrsid12860689 Cassidy v. SmithKline Beecham}{
\insrsid2642389\charrsid12860689 , is particularly interesting for a number of }{\insrsid862823 additional }{\insrsid2642389\charrsid12860689 reasons.  }{\insrsid2642389 First, r}{\insrsid2642389\charrsid12860689 ather than seeking comp
ensation for past injuries, as tort law usually mandates, the plaintiffs sought \'93protection against the risks of }{\i\insrsid2642389\charrsid12860689 future}{\insrsid2642389\charrsid12860689  injury.\'94}{\cs16\super\insrsid2642389\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2642389 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  L. Palmer, }{\i\insrsid4156601\charrsid11755622 Medical Liability for Pharmacogenomics}{\i\insrsid4156601 ,}{\i\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid11755622 in Pharmacogenomics: Socia
l, Ethical, and Clinical Dimensions 200 (Mark A. Rothstein, ed., Hoboken, NJ: John Wiley & Sons) (2003).}}}{\insrsid2642389\charrsid12860689   Second, the case is significant because, for maybe the first time, the class is explicitly defined by }{
\i\insrsid2642389\charrsid12860689 genotype.}{\cs16\super\insrsid2642389\charrsid2194861 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2642389 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  However, \'93
[t]The genetic heterogeneity of a putative class of plaintiffs with respect to their susceptibility to a toxic substance may provide defendants with a potent weapon for opposing class
\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid2642389 {\insrsid4156601\charrsid11755622 certification.\'94  Gary E. Marchant}{\i\insrsid4156601\charrsid11755622 , Genomics and Toxic Substances: Part II
\emdash Genetic Susceptibility to Environmental Agents}{\insrsid4156601\charrsid11755622 , Env\rquote t\rquote l Law Reporter, (2003) at 9, available at }{\insrsid4156601\charrsid2576039 http://www.law.asu.edu/files/Programs/Sci
-Tech/Commentaries/toxicogenetics.elr.pdf}{\insrsid4156601\charrsid11755622 . Marchant uses the example of courts using genetic heterogeneity as a factor for denying class certification in cases involving toxic injury.}}}{\insrsid2642389\charrsid12860689 
  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid12287047\charrsid12860689 There}{\insrsid2633606\charrsid12860689  are a number of possible liability theories}{\insrsid5732796 
 for suits such as those involved with LYMErix}{\insrsid2633606\charrsid12860689 , including \'93failure to order genetic testing, improper interpretation of genetic test results, failure to provide necessary genetic counseling, failure to prescribe the p
roper medication and dosage, failure to warn the patient of possible adverse events (and perhaps even failure to warn at-risk relatives), and failure to dispense or administer the medication properly,\'94 as well as, perhaps, failure to }{
\i\insrsid2633606\charrsid12860689 not }{\insrsid2633606\charrsid12860689 prescribe a drug.}{\cs16\super\insrsid2633606\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Rothstein, }{
\i\insrsid4156601\charrsid11755622 Epilogue }{\i\insrsid4156601 supra }{\insrsid4156601 note 251 at 324.  }}}{\insrsid11885793\charrsid12860689  }{\insrsid3414188\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid9916748\charrsid12860689 However,}{\insrsid6056849\charrsid12860689  because}{\insrsid3882467\charrsid12860689  liability is generally
}{\insrsid6056849\charrsid12860689  determined by state, rather than federal law, }{\insrsid9916748\charrsid12860689 some  believed that SmithKline Be}{\insrsid11867222\charrsid12860689 echam would like}{\insrsid11757769 ly}{
\insrsid11867222\charrsid12860689  not be found lia}{\insrsid9916748\charrsid12860689 ble}{\insrsid11867222\charrsid12860689  if the case went to trial}{\insrsid9916748\charrsid12860689 .  They predicted t}{\insrsid6056849\charrsid12860689 hat the \'93
Pennsylvania Supreme Court might take the view that the only warnings a drug manufacturer must give are those required by the Food and Drug Administration.\'94}{\cs16\super\insrsid4022609\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Palmer, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 336.}{\insrsid4156601\charrsid11755622 
  The case was, in fact, settled in 2003.  In its settlement agreement, SmithKline Beecham withdrew LYMErix from the market, paid $975,000 in fees and $147,000 costs to the plaintiffs\rquote 
 lawyers, and the plaintiffs did not relinquish potential personal inj}{\insrsid4156601 ury and economic damage claims.}}}{\insrsid2056480\charrsid12860689   It is interesting to consider, therefore, if}{\insrsid6056849\charrsid12860689 
 these results mandate greater coverage by FDA of the appropriate warnings required for drugs, or, more specifically, for drugs developed using pharmacogenomics.  }{\insrsid16408756\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\insrsid10185250\charrsid12860689 \tab }{\insrsid3366125 \tab }{\b\insrsid3481303\charrsid3481303 3}{
\b\insrsid14171447\charrsid3481303 .}{\b\insrsid14171447   }{\b\insrsid10185250\charrsid12860689 Off-}{\b\insrsid3366125 L}{\b\insrsid10185250\charrsid12860689 abel }{\b\insrsid3366125 P}{\b\insrsid10185250\charrsid12860689 rescription
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11816725\charrsid12860689 Considered in light of the aforementioned L}{\insrsid12264367\charrsid12860689 yme disease liability cases}{
\insrsid11816725\charrsid12860689 ,}{\insrsid12264367\charrsid12860689  if a drug is prescribed to}{\insrsid1057662  an individual in}{\insrsid12264367\charrsid12860689  that part of the population for which it is
 not approved (assuming that the drug was only approved for a very specific subgroup), off-label prescription may make the physician susce}{\insrsid8527606 ptib}{\insrsid12264367\charrsid12860689 l}{\insrsid8527606 e}{\insrsid12264367\charrsid12860689 
 to medical liability}{\insrsid10422782  as well}{\insrsid12264367\charrsid12860689 .  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5523700\charrsid12860689 As we saw}{\insrsid10305054  in the section on }{\insrsid10305054\charrsid10305054 
FDA Approaches to Pharmacogenomics}{\insrsid5523700\charrsid12860689 , there are a number of possible ways to deal wi}{\insrsid1066462 th off-label prescription}{\insrsid8520301 .  One author in Mark Rothstein\rquote s textbook }{\i\insrsid8520301 
Pharmacogenomics: Social, Ethical, and Clinical Dimensions, }{\insrsid8520301 suggests that }{\insrsid1066462 liability may }{\insrsid14171447 be a }{\insrsid12264367\charrsid12860689 preferable}{\insrsid1066462  approach}{
\insrsid12264367\charrsid12860689  because it makes the \'93social and historical challenges that pharmacogenomics must overcome\'94 visible.}{\cs16\super\insrsid12264367\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid9846994\charrsid12860689  }{\insrsid12264367\charrsid12860689 
 Choosing a liability framework rather than a regulatory solution may subject physicians to stricter medical liability for off-label prescription of pharmacogenomics products, }{\insrsid14171447 since}{\insrsid12264367\charrsid12860689  the advers}{
\insrsid11152990 e effects }{\insrsid12208945 may be}{\insrsid11152990  more predictable}{\insrsid12264367\charrsid12860689  than for other drugs.  Howev}{\insrsid12208945 er, this liability approach}{\insrsid12264367\charrsid12860689 
 may not be preferable to regulation because it requires proof of harm}{\insrsid9922114  to hold a physician responsible for off-label prescription}{\insrsid12264367\charrsid12860689 , which regulation may not.  }{\insrsid12208945 If regulation d
oes not require proof of harm}{\insrsid12264367\charrsid12860689 , }{\insrsid12208945 there might be}{\insrsid12264367\charrsid12860689  more of a deterr}{\insrsid2495019 ent effect on both physicians and drug companies}{\insrsid12264367\charrsid12860689 
, thereby encouraging higher safety thresholds in order to avoid FDA investigation.}{\insrsid5512943 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid3553547 \tab \tab }{\b\insrsid3481303 4}{\b\insrsid3553547 .  Education of Physicians 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid3553547 {\insrsid3553547 Although it is likely that adverse events related to prescription may, in many cases, be out of the control of physicians, enhanced genetic education may }
{\insrsid13789525 still }{\insrsid3553547 behoove the profession.  }{\insrsid13960254 If increased education does not }{\insrsid13789525 serve to affect phy}{\insrsid13960254 sic}{\insrsid13789525 i}{\insrsid13960254 ans\rquote 
 prescription behavior, it might deflect some of the litigation that could occur when a patient experiences an adverse reaction because it can be better demonstrated that the physician }{\insrsid13789525 exercised appropriate care and knowle}{
\insrsid13960254 dge in his or her prescription decisions.  }{\insrsid8206158 Moreover, }{\insrsid10816875 providing more information regarding pharmacogenomics to }{\insrsid8737846 physicians}{\insrsid10816875 
 may decrease problems associated with off-label prescription, as well }{\insrsid2954520 as provide physicians with a better understanding of the}{\insrsid10816875  ethical implications of diagnosis and treatment decisions}{\insrsid16262917 
 related to genetics}{\insrsid10816875  (for example, implications for such decisions relating to insurance coverage, discrimination, privacy, etc.}{\insrsid3031702 , all of which will be discussed in more detail later}{\insrsid10816875 ).  }{
\insrsid12273209 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid3553547 {\insrsid13789525 It has been demonstrated that s}{\insrsid3553547 ome}{\insrsid3553547\charrsid12860689  physicians are relatively uneducated about the stochastic natur
e of genetic information.  A 1985 study found that only eighteen percent of U.S. medical schools offered genetic courses.}{\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 B. Childs, CA Huether, and EA Murphy, }{\i\insrsid4156601\charrsid11755622 Human Genetics Teaching in U.S. Medical Schools}{\insrsid4156601\charrsid11755622 , 33 Am. J. Hum. Genet. 1-10 (1981).}}}{\insrsid3553547\charrsid12860689 
  Although this number has surely improved since, many currently-practicing physicians may not be adequately caught up with the science.  }{\insrsid3553547 In 1991, the }{\i\insrsid3553547 New England Journal of Medicine }{\insrsid3553547 
(NEJM) found, in an investigation of New York State hospitals in 1984, that of the }{\f286\fs23\insrsid3553547 2.8 million hospitalizations, 98,609 (3.7%) resulted in adverse events, and of these, 27,179 (27.6%) involved negligence.}{
\cs16\f286\fs23\super\insrsid3553547 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Tetlow, }{\i\insrsid4156601 supra }{\insrsid4156601 note 277 at 6.  }}}{\f286\fs23\insrsid3553547   Thus, the journal\rquote s editors have \'93
publicly stated that physicians need to be educated about pharmacogenomics.\'94}{\cs16\f286\fs23\super\insrsid3553547 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 . (}{\i\insrsid4156601\charrsid11755622 citing}{
\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Doctors Need to be Educated About Pharmacogenomics}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601\charrsid11755622 says NEJM}{\insrsid4156601\charrsid11755622 
. Pharmafocus. 18 Oct 2002, }{\i\insrsid4156601\charrsid11755622 at }{\insrsid4156601\charrsid11755622  http://www.inpharm.com/External/InpH/1,,1-4-0-0-inp_int}{\insrsid4156601 elligence_news-0-10267,00.html.}}}{\f286\fs20\insrsid3553547 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid3553547 {\insrsid3553547\charrsid12860689 
The National Coalition for Health Professional Education in Genetics (NCHPEG) is a group assembled by the American Medical Association (AMA), the American Nurses Association, and the National Human Genome Research Institute}{\insrsid3553547  (NHGRI)}{
\insrsid3553547\charrsid12860689  in order to promote education among health professionals about advances in human genetics.}{\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\i\insrsid4156601\charrsid11755622 National Coalition for Health Professional Education in Genetics}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601\charrsid11755622 at}{\insrsid4156601\charrsid11755622  http://www.nchpeg.org.  }}}{
\insrsid3553547\charrsid12860689   NCHPEG developed and endorsed a list of \'93core competencies}{\insrsid3961354 ,}{\insrsid3553547\charrsid12860689 \'94 or list of minimum knowledge and skills for healthcare providers.}{
\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Core Competencies in Genetics Essential for All Health-Care Professionals}{\insrsid4156601\charrsid11755622 
, National Coalition for Health Professional Education in Genetics }{\i\insrsid4156601\charrsid11755622 at }{\insrsid4156601\charrsid11755622 http://www.nchpeg.org/eduresources/core/coreprinciples.pdf.}}}{\insrsid3553547\charrsid12860689 
  This represents an effort to encourage physicians, nurses, psychologists, social workers, and other healthcare providers to integrate genetic knowledge into routine healthcare in order to accurately edu
cate families and individuals.  NCHPEG stresses the need for these individuals to understand the social and psychological implications of genetic services while being aware of their limitations and knowing when to make a referral to a genetic professional
.}{\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  I}{\insrsid4156601 d}{\insrsid4156601\charrsid11755622 .}}}{\insrsid3553547\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 {\insrsid3553547\charrsid12860689 Besides NCHPEG, others also assert that doctors and other professionals must be able to \'93
incorporate genetic information into their prescribing decisions and also to understand when to test and how to interpret and communicate the results.\'94}{\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{
\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 51.}}}{\insrsid3553547\charrsid12860689   Pharmacogen
omics should be incorporated into both undergraduate and postgraduate healthcare (}{\insrsid3553547 and }{\insrsid3553547\charrsid12860689 both medical and pharmacist) training.}{\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id. at 52.}{\insrsid4156601\charrsid11755622   }}}{\insrsid3553547\charrsid12860689   The authors of \'93Pharmacogenomics, Ethics, and the Community\'94 cite the Nuffield Council on Bioethics report\rquote s recommendation for f
urther education of health professionals.  The authors point to a deficiency in education in the United States, citing a study that gave an account of the \'93
very low number of lecture hours devoted to the science and practice applications of genomics in tertiary US curricula.\'94}{\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Buckley and McKinnon, }{\i\insrsid4156601 supra }{\insrsid4156601 note 265.  }}}{\insrsid3553547\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 {\insrsid3553547\charrsid12860689 
In addition to training future health care workers, continuing education is crucial.  Many professionals do not have training in new diagnostics}{\insrsid3553547  and}{\insrsid3553547\charrsid12860689  therapies not covered by health plans,}{
\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Greely,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 13 at 2.}}}{\insrsid3553547\charrsid12860689  and pharmacogenomics will possibly complicate
 the process of prescribing drugs because it requires an additional diagnostic step.}{\cs16\super\insrsid3553547\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid3553547 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Pharmacogenomics}{\insrsid4156601\charrsid11755622 
, Human Genome Project Information, }{\i\insrsid4156601 supra }{\insrsid4156601 note 25.  }}}{\insrsid3553547\charrsid12860689 
  It is necessary to ensure that health care providers are educated in identifying and reporting adverse events, particularly if a stronger focus is placed on post approval drug surveillance.
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid2382926 B}{\b\insrsid14171447 .  Liability }{\b\insrsid6453500\charrsid12860689 Against }{\b\insrsid1470989 
Pharmaceutical C}{\b\insrsid6453500\charrsid12860689 ompanies
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid6453500\charrsid12860689 Not only is there the }{\insrsid13458818\charrsid12860689 possibility}{\insrsid6453500\charrsid12860689 
 of legal liability}{\insrsid7279172  against }{\insrsid7279172\charrsid12860689 physician}{\insrsid7279172 s}{\insrsid6453500\charrsid12860689  for }{\insrsid13458818\charrsid12860689 adverse}{\insrsid6453500\charrsid12860689 
 events, there is also the possibility for liability }{\insrsid13710853\charrsid12860689 against the pharmaceutical companies who develop drugs.}{\insrsid15800881\charrsid12860689   }{\insrsid13710853\charrsid12860689 In}{\insrsid12931138 
dividuals could bring suit}{\insrsid13710853\charrsid12860689  against }{\insrsid15800881\charrsid12860689 the }{\insrsid16342204\charrsid12860689 industry}{\insrsid13710853\charrsid12860689 
 for faulty products, or for failure to warn consumers directly of the possible adverse reactions associated with their products. }{\insrsid10106589\charrsid12860689  }{\insrsid3288164\charrsid12860689 Once a }{\insrsid14374629\charrsid12860689 patient}{
\insrsid3288164\charrsid12860689  is warned of the possibility of ADRs related to one\rquote s genetic predisposition, however, one author maintains }{\insrsid14374629\charrsid12860689 that}{\insrsid3288164\charrsid12860689  \'93
an individual who nevertheless voluntarily assumes the risk of the product may be precluded from recovery if he or she subsequently gets sick as a result of exposure to the product.\'94}{\cs16\super\insrsid3288164\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Marchant, }{\i\insrsid4156601 supra }{\insrsid4156601 note 337 at 8.  }}}{\insrsid3288164\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid10106589\charrsid12860689 Imposing legal
 liability may obstruct research by deterring pharmaceutical companies from engaging in pharmacogenomic development for fear of being sued.  Thus, the FDA workshop mentioned above discussed the need for a \'93safe harbor\'94
 from liability provision in any federal regulations involving pharmacogenomics in order to facilitate experimentation.}{\cs16\super\insrsid10106589\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Urquhart, Adams and De Santos, }{\i\insrsid4156601 supra }{\insrsid4156601 note 52.  }}}{\insrsid10106589\charrsid12860689   }{\insrsid13710853\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid12931138 {\insrsid15800881\charrsid12860689 Mo}{\insrsid3934149 re}{\insrsid15800881\charrsid12860689  likely}{\insrsid2516698 
 than bringing a failure to warn claim}{\insrsid15800881\charrsid12860689 , a }{\insrsid13710853\charrsid12860689 plaintiff could }{\insrsid13458818\charrsid12860689 allege}{\insrsid13710853\charrsid12860689  marketing or design defect.  }{
\insrsid1003843\charrsid12860689 It has been asserted that }{\insrsid2169419 if }{\insrsid1003843\charrsid12860689 plaintiffs }{\insrsid2169419 sue the pharmaceutical companies that created the drug, they }{\insrsid1003843\charrsid12860689 
should bring product liability claims, as \'93the better-reasoned cases reject \lquote failure to test\rquote  as an independent cause of action.\'94}{\cs16\super\insrsid1003843\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622   (}{\i\insrsid4156601\charrsid11755622 referencing  Akee v. Dow Chem Co.,}{\insrsid4156601\charrsid11755622  2003 WL 21697345 (D.Haw. 2003); }{\i\insrsid4156601\charrsid11755622 
Stitt v. Philip Morris Inc}{\insrsid4156601\charrsid11755622 ., 245 F. Supp. 2d 686 (W.D. Pa. 2002); Cf., }{\i\insrsid4156601\charrsid11755622 American Tobacco Co. v. Grinnell}{\insrsid4156601\charrsid11755622 , 951 S.W.2d 420 (Tex.}{\insrsid4156601  1997
}{\insrsid4156601\charrsid11755622 ).}}}{\insrsid1002189\charrsid12860689   }{\insrsid15298225\charrsid12860689 However, e}{\insrsid13710853\charrsid12860689 xpert testimony is required to support the claims of product defect.  An expert
 must testify that the failure to use pharmacogenomic techniques resulted in a marketing or design defect.}{\cs16\super\insrsid2364376\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid13710853\charrsid12860689   }{\insrsid9983198\charrsid12860689 Because of the state of the technology, it is believed that t}{\insrsid13710853\charrsid12860689 his opinion, regardless of who gives it, should }{
\insrsid9983198\charrsid12860689 not make it past the gatekeeper }{\insrsid3301325 (i.e., the }{\insrsid3934149 standards of expert testimony will }{\insrsid3301325 not }{\insrsid3934149 be met),}{\insrsid3934149\charrsid12860689  }{
\insrsid9983198\charrsid12860689 because it could not}{\insrsid13710853\charrsid12860689  meet the scientific reliability requirements of }{\i\insrsid13710853\charrsid12860689 Daubert v. Merrell Dow. Pharms}{\insrsid13710853\charrsid12860689 .}{
\cs16\super\insrsid9983198\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid11536447\charrsid12860689    }{\insrsid12931138 T}{\insrsid13710853\charrsid12860689 he }{\i\insrsid13710853\charrsid12594726 Dau}{
\i\insrsid12931138\charrsid12594726 bert}{\insrsid12931138  standard weighs a number of factors to determine whether the test or principle is scientifically valid.}{\insrsid543929   }{\insrsid12931138 Thus far,}{\insrsid13710853\charrsid12860689  \'93
the use of pharmacogenetics and pharmacogenomics for this purpose is not generally accepted and seldom used.\'94}{\cs16\super\insrsid11536447\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid13710853\charrsid12860689  }{\insrsid13457052  }{\insrsid11536447\charrsid12860689 As illustration, the authors of \'93Creating Incentives for Genomics Research to Improv}{\insrsid12594726 e Targeting of Therapies,\'94 cite}
{\insrsid11536447\charrsid12860689  }{\insrsid2054073\charrsid12860689 a series of studies}{\insrsid11536447\charrsid12860689  that found that genetic factors make some individuals more susceptible}{\insrsid13457052  to}{\insrsid11536447\charrsid12860689 
 an increased risk of hepatitis from anti-tuberculosis drugs.}{\cs16\super\insrsid11536447\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Huang et al., }{\i\insrsid4156601\charrsid11755622 Polymorphism of the N-acetyltrasfera
se 2 Gene as a Susceptibility Risk Factor for Anti-tuberculosis Drug-Induced Hepatitis}{\insrsid4156601\charrsid11755622 , 35 Hepatology, 883-889 (2002).}}}{\insrsid11536447\charrsid12860689    However, t}{\insrsid2054073\charrsid12860689 
he article states that the}{\insrsid11536447\charrsid12860689  studies do not identify specific markers of liver toxicity, and therefore do not \'93fit\'94 the case in which it would be raised as evidence.}{\cs16\super\insrsid14432672\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  Urquhart, Adams and De Santos, }{\i\insrsid4156601 supra }{\insrsid4156601 note 52.   }}}{\insrsid3288164\charrsid12860689   }{\insrsid13710853\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid2054073 {\insrsid13710853\charrsid12860689 Moreover, plaintiffs could attempt to hold pharmaceutical companies }{\insrsid13458818\charrsid12860689 responsible}{
\insrsid13710853\charrsid12860689  }{\insrsid6453500\charrsid12860689 fo}{\insrsid13710853\charrsid12860689 r n}{\insrsid6453500\charrsid12860689 ot using }{\insrsid543929 pharmacogenomic}{\insrsid6453500\charrsid12860689  technology }{
\insrsid15800881\charrsid12860689 to}{\insrsid13710853\charrsid12860689  }{\insrsid6453500\charrsid12860689 develop drugs}{\insrsid13710853\charrsid12860689  at all}{\insrsid6453500\charrsid12860689 .}{\insrsid687127\charrsid12860689 
  One article discusses the lack of legal duty to use pharmacogenomics to discover potential new drugs that will better target idiosyncratic liver injuries}{\insrsid7633072\charrsid12860689 , which occur}{\insrsid12594726 , on a}{
\insrsid7633072\charrsid12860689  rare}{\insrsid12594726  basis,}{\insrsid7633072\charrsid12860689  with many drugs}{\insrsid687127\charrsid12860689 .}{\cs16\super\insrsid687127\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid7633072\charrsid12860689  }{\insrsid6232525  }{\insrsid13710853\charrsid12860689 The authors }{\insrsid543929 assert}{\insrsid13710853\charrsid12860689  that parties should not be able to sue a drug manufacturer for
 failing to use pharmacogenomics to develop a drug that will reveal an individual\rquote s predisposition to any sort of deleterious side-effect.}{\cs16\super\insrsid13710853\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid13710853\charrsid12860689  }{\insrsid2054073\charrsid12860689  }{\insrsid543929 P}{\insrsid543929\charrsid12860689 erhaps a }{\insrsid543929 convincing }{\insrsid543929\charrsid12860689 argument }{\insrsid543929 
in support of their position }{\insrsid543929\charrsid12860689 is that }{\insrsid10106589\charrsid12860689 \'93prematurely imposing an}{\insrsid3288164\charrsid12860689  }{\insrsid10106589\charrsid12860689 actual or de facto duty
 on drug makers to use these technologies will discourage the cooperative atmosphere needed to overcome the current limitations of pharmacogenetics and pharmacogenomics.\'94}{\cs16\super\insrsid10106589\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid3104513\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\insrsid12925508 \tab \tab }{\b\insrsid2382926 1}{\b\insrsid12594726\charrsid12594726 .}{\insrsid12594726   }{
\b\insrsid12925508 Direct-to-Consumer Advertising }{\b\insrsid12925508\charrsid12925508 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid787616\charrsid12860689 Another possibility for}{\insrsid2054073\charrsid12860689  imposing liability against}{
\insrsid787616\charrsid12860689  }{\insrsid2054073\charrsid12860689 pharmaceutical company}{\insrsid787616\charrsid12860689  relates to direct-to-consumer advertising. }{\insrsid13263370\charrsid12860689 In the 1990\rquote 
s, the FDA issued guidance that allowed drug companies to directly advertise products to the consumer.}{\cs16\super\insrsid13263370\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Rothstein, }{
\i\insrsid4156601\charrsid11755622 Epilogue }{\i\insrsid4156601 supra }{\insrsid4156601 note 251 at 327.  }}}{\insrsid13263370\charrsid12860689   Because of the guidance, direct-to-consumer advertising in the }{\insrsid6232525 U.S.}{
\insrsid13263370\charrsid12860689  increased from $860 million to $2.5 }{\insrsid5702020 b}{\insrsid13263370\charrsid12860689 illion.}{\cs16\super\insrsid13263370\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622  (citing }{\i\insrsid4156601\charrsid11755622 Europe on the Bring of Direct-to-Consumer Drug Advertising, }{\insrsid4156601\charrsid11755622 359 The Lancet, 1709 (2002)).}}}{
\insrsid6516187\charrsid12860689   }{\insrsid733850 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid9723788 Generally, the learned intermediary doctrine maintain}{\insrsid9723788\charrsid12860689 
s that, if a doctor is warned, then the drug manufacturer has fulfilled its obligation to warn the consumer}{\insrsid9723788 , thereby shifting liability to the physician for providing patients with safety warnings.  }{\insrsid9723788\charrsid12860689 
However, a 1999 New Jersey Supreme Court decision found that it is a drug developer\rquote s duty to warn the consumer/patient}{\insrsid9723788  of potential side effect or adverse events}{\insrsid9723788\charrsid12860689 , and the responsibility }{
\insrsid9723788 i}{\insrsid9723788\charrsid12860689 s not satisfied by the}{\insrsid9723788  doctrine.}{\cs16\super\insrsid131793 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  Id.}}}{\insrsid4022609\charrsid12860689   Thus, a warning to physicians when the drug manufacturer advertised directly to consumers}{
\insrsid13263370\charrsid12860689  is not enough.}{\cs16\super\insrsid4022609\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Palmer, }{\i\insrsid4156601 supra }{\insrsid4156601 note 336.}{\insrsid4156601\charrsid11755622   }}}{
\insrsid4022609\charrsid12860689   Manufacturers also have a responsibility, in such cases, to }{\insrsid9057024 directly }{\insrsid4022609\charrsid12860689 warn the consumers as well.}{\insrsid15104910\charrsid12860689  }{
\insrsid9854029\charrsid12860689 
\par }\pard \ql \li720\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin720\itap0\pararsid16733115 {\b\insrsid2382926 C}{\b\insrsid12594726 .  }{\b\insrsid15746163\charrsid12860689 Causation
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid4132263 {\insrsid15746163\charrsid12860689 One hindr}{\insrsid12925508 ance to holding a physician }{\insrsid15746163\charrsid12860689 or }{\insrsid12925508 drug company}{
\insrsid15746163\charrsid12860689  liable for deleterious drug effects or lack of efficacious treatment is the problem of demonstrating }{\insrsid13058669 causation.  As discussed earlier}{\insrsid12861008 , causation}{\insrsid15746163\charrsid12860689  }
{\insrsid12861008 of an adverse event by a particular drug }{\insrsid15746163\charrsid12860689 may be very difficult}{\insrsid12861008  to prove}{\insrsid15746163\charrsid12860689  because of t
he complexities of environmental interactions, coupled with other possible causative factors. }{\insrsid13964257\charrsid12860689  }{\insrsid12861008 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\faauto\rin0\lin0\itap0\pararsid4132263 {\insrsid13964257\charrsid12860689 Moreover, defendants may use genetic discoveries to }{\insrsid2570499\charrsid12860689 establish alternative causes}{\insrsid8547741 
 for the adverse events for which they are being held responsible}{\insrsid2979917\charrsid12860689 , using genetic information to demonstrate that the individual would have developed the illness regardless of the drug\rquote s }{\insrsid2975633 e}{
\insrsid2979917\charrsid12860689 ffect}{\insrsid2570499\charrsid12860689 .  For example, }{\insrsid733850 a }{\insrsid2570499\charrsid12860689 \'93}{\insrsid2570499\charrsid12860689 defendant could also argue that the plaintiff\rquote 
s disease resulted solely from his or }{\insrsid2570499\charrsid12860689 her genetic predisposition, which caused the disease to develop independent of any exposure}{\insrsid2979917\charrsid12860689  }{\insrsid2570499\charrsid12860689 to the defendant
\rquote s product.\'94}{\cs16\super\insrsid2494253\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Marchant, }{\i\insrsid4156601 supra }{\insrsid4156601 note 337 at 8.  }}}{\insrsid9057024   On the other hand}{\insrsid2979917\charrsid12860689 
, a genetic test could demonstrate that a person\rquote s predisposition decreased susceptibility to a disease, thereby providing a useful defense }{\insrsid12258996 against}{\insrsid2979917\charrsid12860689  causation.  }{
\insrsid16413520\charrsid12860689 A defendant could also \'93}{\insrsid15746163\charrsid12860689 seek to test the plaintiff for}{\insrsid16413520\charrsid12860689  }{\insrsid15746163\charrsid12860689 
other genetic variants that provide increased resilience to}{\insrsid867683\charrsid12860689  }{\insrsid15746163\charrsid12860689 the toxic agent at issue, which would make that person less}{\insrsid16413520\charrsid12860689  }{
\insrsid15746163\charrsid12860689 susceptible than the average person}{\insrsid16413520\charrsid12860689 .\'94}{\cs16\super\insrsid16413520\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid658954\charrsid12860689   Even more worrisome is the prospect that defendants could use an }{\insrsid14374629\charrsid12860689 individual\rquote s}{\insrsid658954\charrsid12860689 
 genetic susceptibility to an illness to demonstrate that \'93}{\insrsid658954\charrsid12860689 they have}{\insrsid14374629\charrsid12860689  }{\insrsid658954\charrsid12860689 no duty to protect such hypersensitive individuals.\'94}{
\cs16\super\insrsid658954\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.  }{\insrsid4156601\charrsid11755622 \'93In particular, defendants could assert what has sometimes been described as the \lquote idiosyncr
atic response\rquote 
 defense.   This defense protects from liability a defendant whose product or activity is harmless to the general public but may injure a small number of individuals with a unique and unusual susceptibility.  This defense has generally been a
pplied in cases where a plaintiff developed a rare allergenic response to a cosmetic or similar product, but the defense would presumably also apply to cases where a plaintiff was harmed due to a rare genetic susceptibility to a product that is otherwise}
{\insrsid4156601  }{\insrsid4156601\charrsid11755622 harmless to the general }{\insrsid4156601 p}{\insrsid4156601\charrsid11755622 opulation.\'94}{\insrsid4156601  Id.}}}{\insrsid11697247\charrsid12860689   }{\insrsid13194461\charrsid12860689 
One author explains that, }{\insrsid11697247\charrsid12860689 \'93}{\insrsid6706839 [t]}{\insrsid11697247\charrsid12860689 he formal justification for this defense is that the hypersusceptibility}{\insrsid13194461\charrsid12860689  }{
\insrsid11697247\charrsid12860689 of the plaintiff, rather than some defect in the}{\insrsid13194461\charrsid12860689  }{\insrsid11697247\charrsid12860689 product, is the proximate cause of the plaintiff\rquote s injury.}{\insrsid2896589\charrsid12860689 
\'94}{\cs16\super\insrsid11669740\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid15746163\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\b\insrsid999370\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid5508284 \page }{\b\insrsid2315423\charrsid12860689 ETHICAL ISSUES}{\b\insrsid8079038\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\insrsid8919079 
Besides having implications for various areas of the law, pharmacogenomics is likely to evoke practical, ethical, and o
ther policy-related issues as well.  This section discusses the potential consequences pharmacogenomics may have for insurance decisions, individual privacy, and racial categories and the potential for misuse.}{\insrsid8919079\charrsid8919079 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid2382926 I}{\b\insrsid6706839 .  }{\b\insrsid2315423\charrsid12860689 Insurance}{\b\insrsid2563507\charrsid12860689 

\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid3699889 Pharmacogenomics might impact, and be impacted by, the }{\insrsid9113997 current }{\insrsid3699889 insurance }{
\insrsid9113997 system}{\insrsid3699889 .  }{\insrsid4798412 P}{\insrsid3699889 harmacogenomic discoveries may lead to an increase in the cost of health insurance}{\insrsid3759315 , because of the potentially higher cost of targeted medicines}{
\insrsid3699889 .  }{\insrsid15479093\charrsid12860689 Genetic tests may be costly and time-consuming, thereby increasing }{\insrsid15479093 the time and energy required for the }{\insrsid15479093\charrsid12860689 approval and reimbursement}{
\insrsid15479093  process.  }{\insrsid15479093\charrsid12860689 This increase in cost will be passed on to the consumer, placing payers \'93in a bad squeeze.\'94}{\cs16\super\insrsid15479093\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15479093 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Sherrid,}{\i\insrsid4156601\charrsid10965486  }{\i\insrsid4156601 supra }{\insrsid4156601 note 98. }{\insrsid4156601\charrsid11755622 (quoting George Smith, a healthcare expert at consultant Accenture).  However, \'93
others believe that eventually payers, including government entitlement\~programs, will actually lead the charge. \lquote Personalized medicine definitely has the potential to lower healthcare costs,\rquote  says Jonathan Brown, a senior\~
investigator at the Kaiser Permanente Center for Health Research.\'94 }{\i\insrsid4156601\charrsid11755622 Id. }}}{\insrsid15479093   Thus, i}{\insrsid16342204\charrsid12860689 nsurance companies may have an enormous impact on how and when pharmacog}{
\insrsid10965486 enomic development will occur.}{\insrsid16342204\charrsid12860689   It is predic}{\insrsid2975633 ted by some that insurers will decelerate}{\insrsid16342204\charrsid12860689  the pace of }{\insrsid2975633 
pharmacogenomic research and treatment options}{\insrsid15220834  by restricting coverage, which may lead pharmaceutical companies to find those areas less profitable}{\insrsid16342204\charrsid12860689 .}{\cs16\super\insrsid16342204\charrsid12860689 
\chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}{\insrsid4156601\charrsid11755622  }}}{\insrsid16342204\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid1442800\charrsid12860689 Pharmacogenomics might }{\insrsid747794 also }{\insrsid1442800\charrsid12860689 change }{
\i\insrsid1442800\charrsid747794 who}{\insrsid1442800\charrsid12860689  is c}{\insrsid722671 onsidered insurable.  }{\insrsid15479093\charrsid12860689 It is possible to \'93
imagine a time when insurers would require testing in order for patients to submit reimbursement claims.\'94}{\cs16\super\insrsid15479093\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15479093 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Jai Shah, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 9 at 3}{\insrsid4156601\charrsid11755622 .}}}{\insrsid15479093\charrsid12860689   }{\insrsid722671 For example, }{\insrsid1442800\charrsid12860689 those who, although expected to have a high l}{
\insrsid722671 ikelihood of having a disease,}{\insrsid1442800\charrsid12860689  may also have a high probability that treatment will be effective, thereby putting them in a position \'93
comparable to patients who have the opposite profile; that is, a low risk to develop the disease, but a high likelihood not to respond to medical treatment if the disease does occur.\'94}{\cs16\super\insrsid1442800\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\cs21\insrsid4156601\charrsid11755622 Klaus\~Lindpaintner}{\insrsid4156601\charrsid11755622 , }{\i\insrsid4156601\charrsid11755622 The Impact of Pharmacogenetics and Pharmacogenomics on Drug Discovery}{\insrsid4156601\charrsid11755622 , 1 }{
\insrsid4156601\charrsid11755622 Nature Reviews Drug Discovery}{\insrsid4156601\charrsid11755622  463-469 (2002), }{\i\insrsid4156601\charrsid11755622 available at}{\insrsid4156601\charrsid11755622   }{\insrsid4156601\charrsid15872827 
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrd/journal/v1/n6/full/nrd823_fs.html}{\insrsid4156601\charrsid11755622 .}}}{\insrsid1442800\charrsid12860689   }{\insrsid2563507\charrsid12860689 Thus, }{\insrsid1442800\charrsid12860689 patients}{
\insrsid2563507\charrsid12860689  \'93who are less likely to respond to treatment would be seen as a less favourable insurance risk, particularly if non-responder status is associated with chronic, costly illness rather than w
ith early mortality, the first case having much more far-reaching economic consequences.\'94}{\cs16\super\insrsid2563507\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\cs21\insrsid4156601 Id.}}}{\insrsid722671   Genetic profiling}{\insrsid2563507\charrsid12860689  may become an integral part of determining }{\insrsid1442800\charrsid12860689 insurance}{\insrsid2563507\charrsid12860689  coverage, making it a}{
\insrsid13787476  more}{\insrsid2563507\charrsid12860689  \'93important (financial) risk-assessment parameter than primary disease susceptibility.\'94}{\cs16\super\insrsid2563507\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\cs21\insrsid4156601 Id.}}}{\insrsid2563507\charrsid12860689   However, it is important that insurers remain sensitive to the complexity of genetic information, and resist the desire to fall into genetic determinism.  }{\insrsid12213520 
Of course, with changes in the insurance environment, this will all need to be reconsidered.}{\insrsid2563507\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid11478427 II}{\b\insrsid747794 .  }{\b\insrsid4069952\charrsid12860689 Privacy/Genetic Tests}{
\b\insrsid9584882\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11230449\charrsid12860689 A great number of the }{\insrsid9584882\charrsid12860689 
ethical and legal issues related to pharmacogenomics are entwined with those broader issues }{\insrsid11230449\charrsid12860689 associated with genetic tests}{\insrsid9584882\charrsid12860689  general}{\insrsid11230449\charrsid12860689 
ly, and have been discussed throughout}{\insrsid9584882\charrsid12860689 .}{\cs16\super\insrsid747794 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  As mentioned in the introduction, m}{\insrsid4156601\charrsid12860689 
any of the more general problems related to genetic tests may be better discussed in a different forum.  }}}{\insrsid9584882\charrsid12860689   }{\insrsid10379328 A}{\insrsid5387887 lthough a}{\insrsid722671  number }{\insrsid5328662\charrsid12860689 of 
the }{\insrsid11230449\charrsid12860689 problems}{\insrsid5328662\charrsid12860689  discussed below are not unique to pharmacogenetics}{\insrsid5387887 , they warrant attention in this context}{\insrsid15804314\charrsid12860689 .}{
\insrsid5328662\charrsid12860689  }{\insrsid9584882\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid15804314\charrsid12860689 One of the greatest concerns is that }{\insrsid14700790\charrsid12860689 
information resulting from genetic testing}{\insrsid15804314\charrsid12860689  will be misused}{\insrsid14700790\charrsid12860689 .}{\cs16\super\insrsid14700790\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601  }{
\insrsid4156601\charrsid11755622 Kahn, }{\i\insrsid4156601 supra }{\insrsid4156601 note 288.  }}}{\insrsid15804314\charrsid12860689   }{\insrsid9140985 If genetic information is}{\insrsid6628157  available to employers and insurances companies, }{
\insrsid12457497 there is the potential that it will}{\insrsid6628157  be used inappropriately. }{\insrsid13907156  }{\insrsid6628157 H}{\insrsid9376660 owever, not all share this worry.  }{\insrsid553264\charrsid12860689 Jeffrey Kahn, author of \'93
Dialogue: Why Pharmacogenomics is Good for Ethics,\'94 says that the tests utilized to prescribe drugs developed according to one\rquote s genetic makeup are particular to that specific disease or one\rquote s metabolic range, }{\insrsid13907156 
rather than }{\insrsid553264\charrsid12860689 one\rquote s}{\insrsid5055007  non-drug-related information, and therefore}{\insrsid553264\charrsid12860689  many of the issues generally related to privacy may not be as significant as }{\insrsid12650185 
others}{\insrsid553264\charrsid12860689  }{\insrsid15628330 contend}{\insrsid553264\charrsid12860689 .}{\cs16\super\insrsid553264\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id}{\insrsid4156601\charrsid11755622 .}}}{\insrsid5387887\charrsid5387887  }{\insrsid8737861  }{\insrsid9376660 Likewise, i}{\insrsid14891062\charrsid12860689 
n its recent report, the Nuffield Council on Bioethics determined that some of the issues generally related to genetic tests, including the impact on family members, }{\insrsid12939507\charrsid12860689 are}{\insrsid14891062\charrsid12860689 
 unlikely to be}{\insrsid14309326  as}{\insrsid14891062\charrsid12860689  relevant to the area of pharmacogenomics}{\insrsid14309326  as they are to other domains where genetic information may be useful}{\insrsid14891062\charrsid12860689 .  }{
\insrsid3750687 The report}{\insrsid14309326  emphasized, }{\insrsid14891062\charrsid12860689 \'93}{\insrsid14309326 [i]}{\insrsid14891062\charrsid12860689 
n general it is likely that if a test is clinically indicated, it will be carried out on the individual in question, regardless of the results of tests taken by family members.\'94}{\cs16\super\insrsid14891062\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Nuffield Council on Bioethics}{\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622    }}}{\insrsid14891062\charrsid12860689   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid14891062\charrsid12860689 Although }{\insrsid1532125\charrsid12860689 
it has been asserted that genetic information gleaned from pharmacogenomics treatments is easily kept private, some still worry that \'93the revelation of possible secondary information about disease predisposition or progression may have ad
verse employment or insurance effects, and also implications for relatives.\'94}{\cs16\super\insrsid1532125\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\super\insrsid4156601 381 }{\insrsid4156601\charrsid11755622 Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{
\insrsid4156601 note 36 at 48.}}}{\insrsid1532125\charrsid12860689   }{\insrsid883411\charrsid12860689 The Nuffield Council state}{\insrsid3750687 d}{\insrsid883411\charrsid12860689 , \'93
There may be circumstances in which the obligation of health professionals to their individual patients comes into conflict with their obligations 
to others, and when they may therefore wish to encourage patients to share pharmacogenetic information with family members.\'94}{\cs16\super\insrsid15416897 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid11755622 Nuffield Council on Bioethics}{
\insrsid4156601 , }{\i\insrsid4156601 supra }{\insrsid4156601 note 34.  }{\insrsid4156601\charrsid11755622  }}}{\insrsid883411\charrsid12860689   However, the Council }{\insrsid3750687 asserted}{\insrsid883411\charrsid12860689 
 that, at least in Great Britain, there are already mechan}{\insrsid265315 isms in place for dealing with }{\insrsid883411\charrsid12860689 conflicts}{\insrsid265315  related to the sharing of medical information.  }{\insrsid14700790\charrsid12860689 

\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11607422\charrsid12860689 Moreover, testing an individual}{\insrsid3750687 \rquote s entire genome}{\insrsid11607422\charrsid12860689 
 once and }{\insrsid3750687 maintainin}{\insrsid11607422\charrsid12860689 g all }{\insrsid2966843 genetic }{\insrsid11607422\charrsid12860689 information on file, rather than destroying }{\insrsid2966843 the}{\insrsid11607422\charrsid12860689 
 information after }{\insrsid8141067 it is }{\insrsid11607422\charrsid12860689 no longer useable in a particular test, may seem much }{\insrsid12939507\charrsid12860689 simpler}{\insrsid11607422\charrsid12860689  }{\insrsid8141067 and more cost-effective 
}{\insrsid11607422\charrsid12860689 for patients to ensure they get appropriate dosage and effective treatments.  However, }{\insrsid8141067 keep}{\insrsid206091\charrsid12860689 ing an }{\insrsid12939507\charrsid12860689 individual\rquote s}{
\insrsid206091\charrsid12860689  genetic profile on file may mean that more stringent protective measures must be taken to guard }{\insrsid5926699\charrsid12860689 the information from misuse.}{\insrsid11607422\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid5451095\charrsid12860689 The 1996 Health }{\insrsid7808596\charrsid12860689 Insurance}{\insrsid5451095\charrsid12860689 
 Portability and Accountability Act (HIPAA), which has been }{\insrsid8157130\charrsid12860689 in effect }{\insrsid5451095\charrsid12860689 since 2001, is the first federal protection for genetic information in health insurance.}{
\cs16\super\insrsid5451095\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Insurance Portability and Accountability Act of 1996.  Public law 104-191. }{\i\insrsid4156601\charrsid11755622 Available at }{\insrsid4156601\charrsid15872827 
http://aspe.hhs.gov/admnsimp/pl104191.htm}{\insrsid4156601\charrsid11755622  (last visited 1/21/05).}}}{\insrsid5451095\charrsid12860689  }{\insrsid7355270  }{\insrsid5451095\charrsid12860689 It is intended to protect patients from discrimination by i
nsurers and employers based on their genetic information.  However, it does not focus particularly on genetic information and perhaps is not comprehensive enough to deal with all of the privacy and confidentiality issues that arise from genetic tests in g
eneral.  }{\insrsid1114195 Besides, enforceability of HIPAA is an area of continuing concern.}{\insrsid9380708\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11691278\charrsid12860689 As }{\insrsid2966843 has been}{\insrsid9650803  discussed elsewhere in this paper}{
\insrsid11691278\charrsid12860689 , }{\insrsid10829247\charrsid12860689 healthcare professionals}{\insrsid11691278\charrsid12860689  and the public}{\insrsid10829247\charrsid12860689  need to be educated in the complexities of genomic}{
\insrsid3950368\charrsid12860689 s.  Although genetic experts are necessary on ethics committees and IRBs in pharmacogenomic studies, all members should be informed in issues related to }{\insrsid10829247\charrsid12860689 consent, identifi}{
\insrsid3950368\charrsid12860689 cation and }{\insrsid8141067 genetic }{\insrsid3950368\charrsid12860689 sample storage.}{\cs16\super\insrsid11210869\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  D}{
\insrsid4156601\charrsid14093851  }{\insrsid4156601\charrsid11755622 Melzer, Raven}{\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 35.}}}{
\insrsid10829247\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid11478427 III}{\b\insrsid15548651 .  }{\b\insrsid1062030\charrsid12860689 Race/Ethnicity}{
\b\insrsid11096387\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid17136\charrsid12860689 Pharmacogenomics has been heralded }{\insrsid3539051 and decried }{\insrsid17136\charrsid12860689 
for both the potential destruction of the notion of race }{\i\insrsid17136\charrsid12860689 and}{\insrsid17136\charrsid12860689  the reinforcement of }{\insrsid3284043\charrsid12860689 racial and ethnic classifications}{\insrsid17136\charrsid12860689 .}{
\cs16\super\insrsid17136\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Greely,}{\insrsid4156601  }{\i\insrsid4156601 supra }{\insrsid4156601 note 13 at 2.}}}{\insrsid17136\charrsid12860689 
  Concern has been expressed that certain ethnic minorities may be excluded from both research and treatment in a socially unacceptable manner. An alternative view i
s that pharmacogenetics may provide a more satisfactory and accurate predictor of response to treatment that will not be simply based on racial phenotype.}{\cs16\super\insrsid17136\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Melzer, Raven}{
\insrsid4156601 ,}{\insrsid4156601\charrsid11755622  Detmer, Ling, and Zimmern, }{\i\insrsid4156601 supra }{\insrsid4156601 note 36 at 45.}}}{\insrsid17136\charrsid12860689 
  Awareness and sensitivity will be integral to avoiding apparent or real discrimination in research and prescribing practice.
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid9782816\charrsid12860689 The neglect of racial and ethnic minorities }{\insrsid12939507\charrsid12860689 has}{
\insrsid9782816\charrsid12860689  always been }{\insrsid12591431 of }{\insrsid9782816\charrsid12860689 
concern.  In response, FDA requires drug manufacturers to disclose effectiveness and safety data for specific gender, racial, and age subgroups, but it does not require that members of such subgroups participate in drug safety and efficacy studies.}{
\cs16\super\insrsid11280793 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid14617132 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{
\insrsid4156601  }{\insrsid4156601\charrsid11755622 Phyllis Griffin Epps, }{\i\insrsid4156601\charrsid11755622 White Pill, Yellow Pill, Red Pill, Brown Pill: Pharmacogenomics and the Changing Face of Medicine,}{\insrsid4156601\charrsid11755622  (5/30/00)
, }{\i\insrsid4156601\charrsid11755622 available at 
\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid14617132 {\insrsid4156601\charrsid15872827 www.law.uh.edu/healthlawperspectives/Genetics/20000530WhitePill.html}{\insrsid4156601\charrsid11755622 
 (last visited 01/06/05)..}}}{\insrsid15943161\charrsid12860689   }{\insrsid17136\charrsid12860689 In March 1994, the National Institutes of Health published guidelines implementing a new statutory requirement that women and minorities be adeq}{
\insrsid8737861 uately represented in federally-}{\insrsid17136\charrsid12860689 funded research.}{\cs16\super\insrsid17136\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\cs23\insrsid4156601\charrsid11755622 Richard C. Thompson,}{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601 Protecting \'93Human Guinea Pigs, }{\cs18\insrsid4156601\charrsid11755622 FDA Consumer special report, (1995), }{
\cs18\i\insrsid4156601\charrsid11755622 available at }{\insrsid4156601\charrsid11755622  }{\insrsid4156601\charrsid15872827 http://www.fda.gov/fdac/special/newdrug/guinea.html}{\insrsid4156601\charrsid11755622 .}}}{\insrsid17136\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15091075 {\insrsid144154\charrsid12860689 The field of pharmacogenetics}{\insrsid4469571 , prior to the availability of genomic information,}{
\insrsid15091075  used proxies}{\insrsid144154\charrsid12860689  such as ethnicity, geography, language, and race, for actual genetic information in order to determine the presence of inherite}{\insrsid12794889\charrsid12860689 d factors in 
reaction to drugs.  }{\insrsid15091075\charrsid12860689 A }{\i\insrsid15091075\charrsid3539051 New York Times}{\insrsid15091075\charrsid12860689 
 author explains that geneticists cannot currently sequence individual genomes cost-effectively.  She explains, 
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid15091075 {\insrsid15091075\charrsid12860689 Until they can, they may view race as a handy shortcut, a way to make some useful generalizations about how
 an individual patient will\~fare with a particular drug. But while using race this way might increase the odds of finding the right medication, it is an imprecise method, a kind of\~
roulette in which the physician is making educated guesses based on probabilities.}{\cs16\super\insrsid15091075\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15091075 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Robin Marantz Henig, }{\i\insrsid4156601\charrsid11755622 The Genome in Black and White (and Gray),}{
\insrsid4156601\charrsid11755622  New York Times at 6 (Oct. 10, 2004).}}}{\insrsid15091075 
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid15091075 {\insrsid15091075 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid6044649 {\insrsid12794889\charrsid12860689 Pharmacogenomics promises to do away }{\insrsid1403258\charrsid12860689 with}{
\insrsid12794889\charrsid12860689  these proxies, and replace them with actual genetic profiles.  }{\insrsid11368408\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid11478427 A}{\b\insrsid984344 .  }{\b\insrsid5908163\charrsid12860689 Dispel}{\b\insrsid2119501\charrsid12860689 
ling Historical Categories}{\b\insrsid5908163\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid611424\charrsid12860689 It is commonly }{\insrsid984344 believed}{\insrsid611424\charrsid12860689 
 that genetic discoveries will lead to the destruction of classic racial and ethnic classifications.   }{\insrsid9857270\charrsid12860689 The completion of a rough draft of the human genome has demonstrated that }{\insrsid9857270\charrsid12860689 
all human beings share 99.9% of their DNA with everyone else, }{\insrsid9857270\charrsid12860689 and that \'93}{\insrsid5908163\charrsid12860689 there is no basis in the genetic code for race: it has also been demonstrated that ther
e is as much within-race genetic variation as there is between-race variation.\'94}{\cs16\super\insrsid5908163\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Buckley and McKinnon, }{\i\insrsid4156601 supra }{\insrsid4156601 note 265.  }}}{
\insrsid5908163\charrsid12860689  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid476054\charrsid12860689 Craig Venter,}{\insrsid6687143\charrsid12860689  one of the key players in the race to complete the genome,}{
\insrsid476054\charrsid12860689  in a press conference in June 2000 with }{\insrsid12939507\charrsid12860689 President}{\insrsid6687143\charrsid12860689  Clinton}{\insrsid984344 , stated, \'93}{\insrsid476054\charrsid12860689 
The concept of race has no genetic or scientific basis.\'94}{\cs16\super\insrsid6949484\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Henig, }{\i\insrsid4156601 supra }{\insrsid4156601 note 389.}}}{\insrsid2303560\charrsid12860689   The promise 
}{\insrsid2758147 of such assertions}{\insrsid7103477  is}{\insrsid2303560\charrsid12860689  that }{\insrsid8787353\charrsid12860689 pharmacogenomics will lead to more equity and accuracy }{\insrsid2303560\charrsid12860689 in health care.}{
\insrsid13526652\charrsid12860689 
\par }{\insrsid3879645\charrsid12860689 The concept of race could be dispelled and reconceived according to one\rquote s genetic makeup, simil}{\insrsid3879645 ar to }{\insrsid3879645\charrsid12860689 the way in which cancer diagnoses }{\insrsid3879645 might}{
\insrsid3879645\charrsid12860689  also be recategorized.  }{\insrsid13526652\charrsid12860689 Since pharmacogenomics may help dispel traditional notions of race while also creating new minority groups, it is important to be sensitive to this possibility.}
{\cs16\super\insrsid13526652\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11755622 Ethical, Legal and Social Implications (ELSI) of Human Genomics: Pharmacogenomics,}{\insrsid4156601\charrsid11755622 
 World Health Organization, }{\i\insrsid4156601\charrsid11755622 available at 
\par }\pard \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 {\insrsid4156601\charrsid15872827 http://www.who.int/genomics/elsi/pharmacogenomics/en/}{\insrsid4156601\charrsid11755622  (last visited 1/11/05).}}}{
\insrsid8787353\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid11478427 B}{\b\insrsid11814530 .  }{\b\insrsid1062030\charrsid12860689 R}{\b\insrsid2119501\charrsid12860689 
einforcing R}{\b\insrsid5251244\charrsid12860689 acial and Ethnic Categorizations}{\b\insrsid7306973\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid11814530 On the other hand, t}{\insrsid7085827\charrsid12860689 
here is major concern that phenotype-genotype associations will parallel already-existing racial lines, which will only encourage society\rquote s predetermined notions of racial differences}{\insrsid3870234\charrsid12860689 .}{
\cs16\super\insrsid3870234\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Jai Shah, }{\i\insrsid4156601 supra }{\insrsid4156601 note 9 at 3}{\insrsid4156601\charrsid11755622 .}}}{\insrsid7085827\charrsid12860689  }{\insrsid14760930  }{
\insrsid9928673\charrsid12860689 Some worry that pharmacogenomic discoveries could potentially \'93reify rac}{\insrsid10311342\charrsid12860689 e as a pseudoscientific measure}{\insrsid9928673\charrsid12860689 \'94}{\insrsid14760930 
 and that these new classifications}{\insrsid10311342\charrsid12860689  \'93will be introduced into a culture that continues to have a difficult time dealing with the issue of race}{\insrsid14760930 .}{\insrsid10311342\charrsid12860689 \'94}{
\cs16\super\insrsid10311342\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Rothstein, }{\i\insrsid4156601\charrsid11755622 Epilogue }{\i\insrsid4156601 supra }{\insrsid4156601 note 251 at 330.  }}}{\insrsid3167996\charrsid12860689  }{
\insrsid14177199\charrsid12860689  }{\insrsid3167996\charrsid12860689 The World Health Organization (WHO) is concerned that \'93
pharmacogenomic knowledge could be linked with specific racial or ethnic indicators, making it tempting to assume a biological linkage between race and responsiveness to particular medications, which could lead to inappropriate decisions about treatment.
\'94}{\cs16\super\insrsid3167996\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\i\insrsid4156601\charrsid11104287 Ethical, Legal and Social Implications (ELSI) of Human Genomics:}{\insrsid4156601  }{\i\insrsid4156601\charrsid11104287 
Pharmacogenomics}{\i\insrsid4156601 ,}{\i\insrsid4156601\charrsid11104287  }{\i\insrsid4156601 supra }{\insrsid4156601 note 392.  }}}{\insrsid3167996\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid16066567 Particular}{\insrsid6757518 ly within our society}{\insrsid12085276 , with its checkered history of }{
\insrsid12085276\charrsid12860689 discrimination and marginalization}{\insrsid6757518 , the possibility that racial classifications could be reinforced, rather than dispelled, is a major concern, as the public may interpret such information in
 destructive and prejudiced ways.  }{\insrsid9254043\charrsid12860689 S}{\insrsid13526652\charrsid12860689 ome critics }{\insrsid14484898 question}{\insrsid13526652\charrsid12860689 , \'93
In a country with such strong traditions of racial and ethnic discrimination, what forces, if any, will ensure that all segments of the population are included in the drug development strategies of drug manufacturers?\'94}{
\cs16\super\insrsid13526652\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Epps, }{\i\insrsid4156601 supra }{\insrsid4156601 note 387.}}}{\insrsid3881289\charrsid12860689   The use of \'93scientific\'94 information to segment and tear }{
\insrsid12939507\charrsid12860689 apart}{\insrsid2633588  society is not unique}{\insrsid3881289\charrsid12860689  to the U.S.  A disturbing}{\insrsid9050967\charrsid12860689  analogy has been made to the }{\insrsid14484898 German }{
\insrsid9050967\charrsid12860689 eugenic movement of the 1940s.  }{\insrsid12939507\charrsid12860689 However, many also caution against slippery-slope arguments.  A }{\i\insrsid12939507\charrsid2633588 New York Times }{\insrsid12939507\charrsid12860689 
author encourages us to \'93let scientists hunt down the facts \endash  facts that will no doubt affirm, one way or another, that the human genome is indeed our common thread.\'94}{\cs16\super\insrsid12085276 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601 \chftn }{\insrsid4156601  }{\insrsid4156601\charrsid11755622 Henig, }{\i\insrsid4156601 
supra }{\insrsid4156601 note 389.}}}{\insrsid3881289\charrsid12860689  }{\insrsid13526652\charrsid12860689   }{\insrsid656508\charrsid12860689 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid11478427 C}{\b\insrsid7173408 .  }{\b\insrsid819117\charrsid12860689 Usefulness of }{\b\insrsid1470989 R}{
\b\insrsid819117\charrsid12860689 ace/}{\b\insrsid1470989 E}{\b\insrsid819117\charrsid12860689 thnicity in }{\b\insrsid1470989 P}{\b\insrsid819117\charrsid12860689 harmacogenomic }{\b\insrsid1470989 R}{\b\insrsid819117\charrsid12860689 esearch
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8982766 {\insrsid1383102\charrsid12860689 It is likely that }{\insrsid819117\charrsid12860689 
pharmacogenetic polymorphisms vary in frequency among ethnic and racial groups.  }{\insrsid6058008\charrsid12860689 Thus, \'93
[f]or any given malady, drug manufacturers may find themselves dedicated to the task of developing a drug for use by a specific racial or ethnic group.\'94}{\cs16\super\insrsid6058008\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Epps, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 387.}}}{\insrsid6058008\charrsid12860689   R}{\insrsid819117\charrsid12860689 ace cannot be ignored when conducting }{\insrsid15096796\charrsid12860689 comprehensive }{\insrsid819117\charrsid12860689 
pharmacogenomic research.  The case has been made that}{\insrsid8982766  \'93}{\insrsid14769177 r}{\insrsid819117\charrsid12860689 
acial and ethnic categories are useful for generating and exploring hypotheses about environmental and genetic race factors, as well as the interaction between risk factors that most lik}{\insrsid11556307 ely underlie complex diseases.}{\insrsid8982766 
\'94}{\cs16\super\insrsid819117\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Buckley and McKinnon, }{\i\insrsid4156601 supra }{\insrsid4156601 note 265.  }}}{\insrsid819117\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid819117 {\insrsid819117\charrsid12860689 The usefulness of race in pharmacogenomics is evident in the attempts to \'93
make a dent in health disparities: the frustrating gap in the health status of different racial groups that stubbornly refuses to close or even to be adequately explained.\'94}{\cs16\super\insrsid819117\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Henig, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 389.}}}{\insrsid819117\charrsid12860689  }{\insrsid10117327  }{\insrsid14434618\charrsid12860689 Robin Marantz Henig, author of }{\insrsid13505226\charrsid12860689 a }{\insrsid8546890\charrsid12860689 2004 }{
\i\insrsid13505226\charrsid2256572 New York Times}{\insrsid13505226\charrsid12860689  article entitled}{\insrsid14434618\charrsid12860689  }{\insrsid8546890\charrsid12860689 \'93The Genome in Black and White (and Gray),\'94 }{
\insrsid819117\charrsid12860689 continues,
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid819117 {\insrsid819117\charrsid12860689 In terms of national measures of physical well-being -- lif
e expectancy, infant mortality, some chronic diseases -- blacks tend to do worse than whites. Many factors account for this health gap, including the fact that minorities suffer disproportionately the effects of low income, lack of health insurance, poor 
diet, exposure to environmental toxins, discrimination and stress. But some\~
geneticists think that at least some part of health disparities can be explained by genes. Social scientists think genetic explanations might obscure the all-too-real social and economic causes.}{\cs16\super\insrsid819117\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid819117\charrsid12860689 
\par }\pard \ql \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0\pararsid819117 {\insrsid819117\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid819117 {\insrsid6058008\charrsid12860689 Similarly, }{\insrsid819117\charrsid12860689 Phyllis Griffin Epps declares that \'93
society must confront the reality that immutable genetic differences among individuals of various racial and ethnic backgrounds may require separate treatment for the same conditions.\'94}{\cs16\super\insrsid819117\charrsid12860689 \chftn {\footnote 
\pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622 
 Epps, }{\i\insrsid4156601 supra }{\insrsid4156601 note 387.}}}{\insrsid819117\charrsid12860689   She stresses the need to pursue equality in the availability of drugs, and to avoid a \'93
pharmaceutical apartheid, in which the price and availability of a needed drug are a function of genetics and race.\'94}{\cs16\super\insrsid819117\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid819117\charrsid12860689   }{\insrsid10117327 Epps}{\insrsid819117\charrsid12860689  is concerned that the application of pharmacogenomi
cs and the stratification of the patient population could lead to a scarcity of drugs for those small subpopulations that are n}{\insrsid3479850 ot considered profitable by }{\insrsid819117\charrsid12860689 pharmaceutical companies.}{
\insrsid7299068\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid819117 {\insrsid7867764 On the other hand, some drugs are being developed for typically underserved populations.  T}{\insrsid819117\charrsid12860689 
he drug BiDil}{\insrsid8402828 , which has proven effective in reducing heart failure in the black community,}{\insrsid819117\charrsid12860689  may be the first drug in America that is being niche-marketed to people of a particular race}{\insrsid7299068 
, and is }{\insrsid7299068\charrsid12860689 expected to be approved early in 2005}{\insrsid819117\charrsid12860689 .  }{\insrsid2256572 Henig }{\insrsid819117\charrsid12860689 calls it \'93our first ethnic medicine.\'94}{
\cs16\super\insrsid819117\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Henig, }{\i\insrsid4156601 supra }{\insrsid4156601 note 389.}}}{\insrsid819117\charrsid12860689   }{\insrsid7299068 I}{\insrsid819117\charrsid12860689 
nvestigators ended the}{\insrsid14769177  clinical studies}{\insrsid819117\charrsid12860689  early because they\~thought BiDil was so effective that \'93it would be unethical to continue to deny it to people in the control group.\'94}{
\cs16\super\insrsid819117\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid15991375   However, }{\insrsid819117\charrsid12860689 although this drug is promising
 in its ability to reduce heart failure, it also concerns ethicists and the public alike}{\insrsid3479850  who worry that a}{\insrsid819117\charrsid12860689  focus on biological difference between ethnicities and races could }{\insrsid3479850 
serve to further racial divides}{\insrsid819117\charrsid12860689 .
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0\pararsid16733115 {\b\insrsid11478427 D}{\b\insrsid14769177 .  }{\b\insrsid15482563\charrsid12860689 Access}{
\b\insrsid819117\charrsid12860689  to Pharmacogenomic Discoveries}{\b\insrsid15482563\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid15482563\charrsid12860689 Pharmaco
genomics may, by only being approved for certain subpopulations or groups, preclude individuals from access to a drug who are not within that population.  Phyllis Griffin Epps worries, \'93
how will the health insurance industry respond to a scenario in which different ethnic minorities require more expensive care than their white counterparts?\'94}{\cs16\super\insrsid15482563\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Epps, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 387.}}}{\insrsid15482563\charrsid12860689   She states,
\par }\pard \ql \li720\ri547\widctlpar\aspalpha\aspnum\faauto\adjustright\rin547\lin720\itap0\pararsid11368408 {\insrsid15482563\charrsid12860689 
Individuals could find themselves precluded from using a drug that has been proven effective for one or several racial or ethnic groups, but ineffective a
nd even dangerous for another.  Such exclusion, while medically justified, may cause negative social repercussions unless addressed in}{\insrsid11368408\charrsid12860689  a timely and sensitive manner.}{\cs16\super\insrsid15482563\charrsid12860689 \chftn 
{\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{
\insrsid4156601\charrsid11755622  }{\insrsid4156601 Id.}}}{\insrsid15482563\charrsid12860689   
\par }\pard \ql \li720\ri547\widctlpar\aspalpha\aspnum\faauto\adjustright\rin547\lin720\itap0\pararsid11368408 {\insrsid11368408\charrsid12860689 
\par }\pard \ql \li0\ri540\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin540\lin0\itap0\pararsid10439170 {\insrsid15482563\charrsid12860689 Epps fears, \'93Given finite resources available for research and development, the questi
ons for drug manufacturers are \lquote who will they have in mind\rquote  and \lquote who will be left behind\rquote  in new drug development.\'94}{\cs16\super\insrsid15482563\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  }{
\insrsid4156601 Id.}}}{\insrsid15482563\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid10439170 {\insrsid15482563\charrsid12860689 The \'93orphan drug problem\'94 discussed }{\insrsid13854110 earlier}{\insrsid15482563\charrsid12860689 
 is implicated for minorities in particular because it is a distinct possibility that certain illnesses will be neglected in order to maximize profits by focusing on those traits or illnesses that will yield the greatest return.  }{
\insrsid5968782\charrsid12860689 It is }{\insrsid3627562 necessary}{\insrsid5968782\charrsid12860689  to find treatments for both those with \'93majority and minority\'94 genomes.}{\cs16\super\insrsid5968782\charrsid12860689 \chftn {\footnote \pard\plain 
\s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Kahn, }{
\i\insrsid4156601 supra }{\insrsid4156601 note 288.  }}}{\insrsid5968782\charrsid12860689   }{\insrsid15482563\charrsid12860689 Expansion of orphan drug laws ha
s been suggested as a solution to inequalities in the future development of a drug candidate due to ability}{\insrsid6839849  of that targeted subgroup}{\insrsid15482563\charrsid12860689 
 to pay, because of socio-economic status which is often associated with race.}{\cs16\super\insrsid15482563\charrsid12860689 \chftn {\footnote \pard\plain \s15\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid11755622 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs16\super\insrsid4156601\charrsid11755622 \chftn }{\insrsid4156601\charrsid11755622  Jai Shah, }{\i\insrsid4156601 supra }{\insrsid4156601 note 9 at 3}{\insrsid4156601\charrsid11755622 .}}}{
\insrsid15482563 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid8285153 {\insrsid2309146 \page }{\b\insrsid15805436 CONCLUSION}{\b\insrsid2309146 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid14842821 {\insrsid7694547 Pharmacogenomics has implications for }{\insrsid6648512 individuals, extending to }{\insrsid7694547 topics as significant as l
}{\insrsid4217442 ife and death, pain and suffering, }{\insrsid358378 privacy}{\insrsid11829035 ,}{\insrsid358378  }{\insrsid10292516 racial discrimination }{\insrsid358378 and equality}{\insrsid5863533 .  Pharmacogenomics will }{\insrsid15611576 have}{
\insrsid5863533  far-}{\insrsid15611576 reaching and diverse effects on drug research and development}{\insrsid3094354 , and promises to reduce
 adverse drug reactions and allow physicians to make more accurate diagnoses and prescription and dosage decisions.  Along with such innovations, pharmacogenomics will likely have consequences for }{\insrsid15611576 
various areas of law, such as patent law, medical liability, and i}{\insrsid14825705 nsurance and discrimination law.}{\insrsid15611576  }{\insrsid14825705  The field of pharmacogenomics and associated genetic discoveries also shape, and are shaped by, }{
\insrsid15611576 the}{\insrsid15611576\charrsid12860689  current regulatory and }{\insrsid15611576 regime}{\insrsid14825705  under the guidance of the FDA.  }{\insrsid12479219 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15817138 {\insrsid2063649 We}{\insrsid15817138  as a society must choose the most appropriate alt
ernatives in the effort to establish an adequate and protective system, both for individuals seeking new and effective drugs and society at large.  Legal and policy decision-makers, as well as insurance companies and the pharmaceutical industry, are entru
sted with the responsibility of making proper resource allocation decisions.  }{\insrsid991706 By properly d}{\insrsid12667908 istributing}{\insrsid991706  resource}{\insrsid12667908 s}{\insrsid991706 
 through, for example, the ODA, we can ensure that certain historically underserved groups are given access to therapeutic advancements.}{\insrsid15817138 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15236380 {\insrsid9194020 The various }{\insrsid14842821 players}{\insrsid7231138  }{\insrsid14842821 all have decisions}{\insrsid14576910  to make}{
\insrsid7231138 , which could positively or adversely affect the role that pharmacogenomics can and will}{\insrsid3094354  play in providing therapeutic}{\insrsid7231138  innovations to the public}{\insrsid14576910 .  }{\insrsid13462438 For example, t}{
\insrsid14842821 he}{\insrsid4470005  pharmaceutical}{\insrsid14842821  }{\insrsid3156726 industry}{\insrsid14842821  must choose whether to pur}{\insrsid4470005 su}{\insrsid14842821 e }{\insrsid4470005 pharmacogenomic}{\insrsid14842821 
 R&D at all, depending on financial and other incentives.  }{\insrsid15817138 Congress and the regulatory agencies}{\insrsid14842821  must choose whether, and how, to encourage pharmacogenomic innovations }{\insrsid3156726 while}{\insrsid9184765 
 providing equal and fair access t}{\insrsid4470005 o targeted therapies and drugs.}{\insrsid9184765   }{\insrsid5067596 Policy-}{\insrsid6495515 makers must also determine}{\insrsid10496741 , through the patent system,}{\insrsid6495515 
 how to balance the promotion of downstream pharmacogenomic research while protecting the rights of innovators.  Likewise, they must consider the appropriate }{\insrsid14576910 liability regime }{\insrsid10496741 for both physi}{\insrsid11078652 c}{
\insrsid10496741 i}{\insrsid11078652 ans and the industry}{\insrsid15086657 .  }{\insrsid5064181 An a}{\insrsid15086657 ppropriate liability}{\insrsid5064181  regime}{\insrsid15086657  for drug sponsors }{\insrsid9192373 must}{\insrsid15086657  }{
\insrsid11078652 avoid discouraging }{\insrsid9192373 the pharmaceutical industry}{\insrsid11078652  from pursuing valuable therapeutic advancements}{\insrsid15086657 .  Liability against physicians must continue to }{\insrsid14576910 allow }{
\insrsid3156726 physician}{\insrsid8484877  }{\insrsid15301321 independence}{\insrsid8484877  }{\insrsid14576910 while still protectin}{\insrsid8484877 g the interests of the patient}{\insrsid15817138 
, striking a balance between the conflicting standards of paternalism and }{\insrsid15301321 patient autonomy}{\insrsid15817138 .}{\insrsid8484877   }{\insrsid15236380 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15236380 {\insrsid15236380 In light of t}{\insrsid10234727 hese choices}{\insrsid15236380 , e}{\insrsid15236380\charrsid12860689 ducation}{
\insrsid8804437  regarding the promises and consequences of pharmacogenomics}{\insrsid15236380\charrsid12860689  is }{\insrsid1714035 a}{\insrsid15236380\charrsid12860689  basic, but significant, }{\insrsid1714035 necessity}{\insrsid10234727 .}{
\insrsid15236380\charrsid12860689   It is fundamental to different aspects of society,}{\insrsid15236380  including the public at large}{\insrsid13518711 , the regulatory bodies making policy choices,}{\insrsid15236380  }{\insrsid4206448 and}{
\insrsid15236380  }{\insrsid15236380\charrsid12860689 physicians and health workers. }{\insrsid15236380  Focused education will enable policy-makers and the public to further the goal of allowing people to understand the framework within which they }{
\insrsid7424189 are making}{\insrsid15236380  decisions.}{\insrsid15236380\charrsid12860689 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0\pararsid15236380 {\insrsid15605316 We are only at the threshold of pharmacogen}{\insrsid549800 omic discoveries, which promise}{\insrsid15605316 
 tailor-made drugs with fewer side effects.  The implications}{\insrsid7738831  that}{\insrsid15605316  the current legal regime has for pharmacogenomics, and vice versa, }{\insrsid2063649 have only begun to be explored.  However, it is imperative that }{
\insrsid5863533 society}{\insrsid2063649  proactively anticipate}{\insrsid5863533 s}{\insrsid2063649  the potential dilemmas and issues associated with scientific advancement in order to keep legal and ethical consideratio
ns current with technological innovations.}{\insrsid549800   Only }{\insrsid8804437 in }{\insrsid549800 this way can we hope to effectively advance, rather than hinder, appropriate technological progress while protecting the rights of individuals}{
\insrsid5863533  and ensuring that they receive the best medical treatment available}{\insrsid549800 .}{\insrsid2063649   }{\insrsid12325676\charrsid12860689 
\par }}