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\b\scaps\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\fs28 Accutane:  Post-Approval Drug Regulation in a Risk Management Framework 
\par }{
\par 
\par }{\b0\scaps0 Gina M. Petrocelli
\par Harvard Law School
\par Class of 2002
\par Combined Third Year / Food & Drug Law Paper
\par }\pard\plain \qc \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\scaps\f0\fs24 April 30, 2002}{\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }{
\par 
\par 
\par 
\par 
\par 
\par 
\par 
\par 
\par 
\par 
\par 
\par 
\par 
\par 
\par }\pard\plain \s2\qc \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel1\adjustright\rin0\lin0\itap0 \b\scaps\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {Abstract}{\cs20\super {\field{\*\fldinst SYMBOL 42 \\f 
"Symbol" \\s 12}{\fldrslt\f3\fs24}}{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\f0\super {\field{\*\fldinst SYMBOL 42 \\f 
"Symbol" \\s 10}{\fldrslt\f3\fs20}}}{\f0  }{I would like to thank Mr. Peter Barton Hutt for his encouragement and advice during the preparation of this paper.}}}{
\par }\pard\plain \s3\ql \li0\ri0\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel2\adjustright\rin0\lin0\itap0 \i\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {The acne drug Accutane lies at the center of
 a movement to expand post-approval controls on drug regulation in an effort to effectively manage drug risks.  Accutane\rquote 
s regulatory history tracks a trend towards the increasing emphasis in drug regulatory policy on post-marketing risk management.  The A
ccutane experience illustrates the fundamental regulatory problems of drug safety, drug availability and individual autonomy driving this shift.  Recent reform of Accutane regulation through the S.M.A.R.T. program both exemplifies the trend and suggests i
ts limitations.
\par }\pard\plain \qc \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par }{\b\f0\fs24 
\par I.  }{\b\scaps\f0\fs24 Introduction}{\scaps\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par \tab 
\par }\pard\plain \s18\ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\'93
As an individual practitioner, it was my decision that this patient be treated with Accutane, and it should remain my decision and not that of the manufacturer the pharmacist, or anyone else.\'94}{\cs20\super {\*\bkmkstart _Ref7839298}\chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i Meeting of the}{ }{\i Dermatologic and Opthalmic Drug
s Advisory Committee }{183 (September 18, 2000) (statement of Dr. John Strauss, Professor Emeritus, Department of Dermatology, University of Iowa and former President of the American Academy of dermatology), available at }{\field\flddirty{\*\fldinst {
\cf17  HYPERLINK "http://www.fda.gov" }{\cf17 {\*\datafield 00d0c9ea79f9bace118c8200aa004ba90b0200000003000000e0c9ea79f9bace118c8200aa004ba90b2800000068007400740070003a002f002f007700770077002e006600640061002e0067006f0076002f000000}}}{\fldrslt {\cs22\cf17 
http://www.fda.gov}}}{\cf17 /cder}{/drug/infopage/accutane/default.htm [hereinafter }{\i 2000 Pregnancy Prevention Hearings}{].
\par }}}{{\*\bkmkend _Ref7839298}
\par }\pard\plain \ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par }\pard\plain \s18\ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\'93The FDA has to regulate drugs in the real world.  In this world doctors are imperfect\'85
People are not always straightforward about their sexual activity.  Women with acne come into offices demanding treatment\'85One of the world\rquote s most potent teratogens cannot be left to ride on all these waves of chance.\'94}{\cs20\super 
{\*\bkmkstart _Ref7795153}\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i 
Dermatologic Drugs Advisory Committee Open Public Hearing, Accutane (isotretinoin}{) Capsules 148 (April 26, 1988) }{\i available at}{ }{\field\flddirty{\*\fldinst {\cf17  HYPERLINK "http://www.fda.gov" }{\cf17 {\*\datafield 
00d0c9ea79f9bace118c8200aa004ba90b0200000003000000e0c9ea79f9bace118c8200aa004ba90b2800000068007400740070003a002f002f007700770077002e006600640061002e0067006f0076002f000000}}}{\fldrslt {\cs22\cf17 http://www.fda.gov}}}{\cf17  /cder}{
/drug/infopage/accutane/default.htm [hereinafter 1988 Hearing]}}}{{\*\bkmkend _Ref7795153}  
\par }\pard\plain \ql \li720\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 This paper explores the story of Accutane, or Isotretinoin, a drug approved in 1982 for the treatment of severe recalcitrant cystic acne.}{
\cs20\f0\fs24\super {\*\bkmkstart _Ref7763554}\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{
 Joan H. Krause, }{\i Accutane: Has Drug Regulation in he United States Reached its Limits?, }{6 }{\scaps J.L. and Health}{ 7 (1991-92)}}}{\f0\fs24 {\*\bkmkend _Ref7763554}
  Its regulatory history, and the debate captured by the quotations above, tracks the larger story of American drug regulatory policy and its increasing emphasis on post-approval drug regulation.
\par Accutane\rquote s story is inextricably intertwined with that of another drug-- thalidomide.  Thalidomide was widely used in Europe in the 1960s as a morning sickness remedy and a sleeping pill.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i Id}{. at 4}}}{\f0\fs24 
  However, much like Accutane, the drug also caused severe deformities in thousands of babies.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i Id.}}}{\f0\fs24   In the United States, Thalidomide was distributed to doctors for purposes of investigation, but it was never mass marke
ted.  A Food and Drug Administration (\'93FDA\'94) medical officer, Dr. Frances O. Kelsey, had rejected the drug for non-compliance with the safety requirements of the Federal, Food Drug and Cosmetic Act of 1938 (\'931938 Act\'94).}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   
\par The 1938 Act was passed in the wake of an earlier drug-related tragedy; In 1937, \'93Elixir Sulfonilamide\'94 killed at least 70 people when it was widely marketed with neither animal not human safety testing.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\scaps Hutt, Peter Barton & Richard A. Merrill, Food and Drug Law}{
 476 (1991)}}}{\f0\fs24 .  The tragedy placed into sharp relief the inadequacies of the then prevailing regulatory system structured by the Food and Drug Act of 1906 (\'931906 Act\'94).}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Krause, }{\i supra}{ note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 4.}}}{\f0\fs24   The 1906 Act required that drugs purity and strength standards to prevent misbranding and adulteration.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  Yet it provided no safety or efficacy standards and prosecution under the Act was virtually impossible.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   The Act offered no preventive remedies, but provided manufacturers numerous loopholes.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  In addition, its interpretation in the courts substantially limited its effectiveness.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id. }}}{\f0\fs24   
\par To remedy the situation, Congress passed the 1938 Act.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i Id. }{at 4-5}}}{\f0\fs24   In accordance with its provisions, manufacturers must provide evidence of their drug\rquote s safety.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  The 1938 Act also made prosecution more feasible by eliminating the 1906 Act\rquote s intent requirement in misbranding cases.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Factory inspections were aut
horized as a preventative measure under the Act, injunctive relief became available and cosmetics and food were brought under federal regulation.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Nevertheless, proof of a drug\rquote 
s effectiveness was still not required under the 1938 Act.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   
\par The Thalidomide tragedy prompted Congressional amendments.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   In 1962, Congress required by a unanimous vote that products meet both safety and efficacy standards.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  The Amendments established detailed drug approval procedures, including the animal and human clinical trials performed today.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   
\par }\pard\plain \s17\ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
Twenty years later, with this system largely intact, the United States became the first country to approve Accutane for the treatment of severe recalcitrant acne.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id}{. at 7}}}{  Like Thalidomide, Accutane causes debilitating birth defects.}{
\cs20\super {\*\bkmkstart _Ref7766421}\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{
  Gina Kolata, Europeans Place Stiffer Curbs on Acne Drugs, }{\scaps N.Y. Times}{, Apr. 28, 1988, at A1.}}}{{\*\bkmkend _Ref7766421}  Even 
minimal exposure to during pregnancy produces at least a 25 percent chance of having a baby with severe birth defects.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{  Such problems include mental retardation, lethal heart defects, and malformed faces lacking ears or featuring ears below the chins.}{\cs20\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{  A
n additional 40 percent of fetuses are spontaneously aborted.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i Id.}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
The severity of these teratogenic risks are frequently compared to those of Thalidomide, which often produced babies of normal intelligence, but with flipper like limbs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Yet in Accutane\rquote s cas
e, it was the U.S. rather than Europe that first approved the drug for mass marketing.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Once approved in Europe, Accutane was usually subjected to far stricter restrictions on its distribution.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  England and Spain carefully monitored Accutane patients and limited prescribing power to selected specialists.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   In Britain, a woman needed to first visit her own doctor and receive a referral to one of these dermatologists.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  She would only receive the drug after receiving warnings, signing an informed consent form, and agree to abort any pregnancy conceived during therapy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  The United States generally rejected strict post-marketing regulation while emphasizing pre-approval safety testing.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7794649}\chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Harvey Teff, }{\i Drug Approval in England and the United States}{, }{\scaps 
Am. J. Comp. L}{. 567, 579 (1985).}}}{\f0\fs24 {\*\bkmkend _Ref7794649}
\par Yet during the 1980s, critics of FDA often portrayed American drug regulatory policy as overly cautious; exacting pre-approval investigation seemed to deprive Americans of valuable drugs available overseas.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Kolata, supra note }{\field{\*\fldinst { NOTEREF _Ref7766421 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360036003400320031000000}}}{\fldrslt {22}}}}}{\f0\fs24   Accutane\rquote 
s relatively rapid approval and unrestricted post-marketing distribution conflicted with the critics\rquote  image of FDA\rquote s \'93drug lag.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   However, Accutane\rquote 
s prompt release was perhaps a harbinger of the speedier drug approval schemes produced by subsequent revisions of regulatory policy in the 1990s; the Prescription Drug User Fee Act of 1992 (\'93PDUFA\'94) and the Food and D
rug Modernization Act of 1997 have since accelerated access to new drugs.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7782337}\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Barbara A. Noah, }{\i Adverse Drug Reactions: Harnessing Experiential Data to Promote Patient Welfare}{, }{\scaps Cath. U. L. Rev}{. 449, 462 (2000)}}}{
\f0\fs24 {\*\bkmkend _Ref7782337}
\par Today Accutane lies at the center of a backlash against this accelerated process.  Recent revisions of Accutane regulation through the System to Manage Accutane Related Teratogenicity, (\'93S.M.A.R.T\'94
),  reflect worries that faster review and relatively lax post-marketing controls endanger society.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Diane Knich, }{\i New Restrictions on Acne Drug Aim to Curb Birth Defects}{, }{\scaps Bos. Globe}{, Apr. 11, 2002}}}{\f0\fs24 
  Allegations that Accutane may also cause depression and suicide have only intensified these concerns.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7834885}\chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See generally Accutane\emdash 
Is this Acne Drug Treatment Linked to Depression and Suicide?}{: }{\i Before the House Committee on Government Reform}{, 106}{\super th}{ Congress (2000) [hereinafter }{\i House Hearings}{]; }{\i See}{ also Katherine Hobson, }{\i Mind versus Face}{, }{
\scaps U.S. News & World Report}{, Apr. 1, 2002.}}}{\f0\fs24 {\*\bkmkend _Ref7834885}
\par }\pard\plain \s21\ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {In Part II of this paper, I examine
 the recent debate over FDA risk management strategies and analyze a general shift in American drug regulatory policy towards post-marketing controls.  In Part III, I trace the regulatory history of Accutane, from its rapid approval in 1982 to the S.M.A.R
.T program\rquote 
s imposition of stricter post-marketing regulation in 2002.  Although Accutane did not instantly prompt the sudden sweeping reform sparked by Thalidomide, its unique regulatory history departs dramatically from traditional drug regulation.  
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 Reas
ons for this departure lie in the core tensions at work in American drug regulation policy.  Part IV explores the role that fundamental regulatory dilemmas have played in Accutane\rquote 
s story.  A tradeoff between safety and availability often underlie regulatory decisions.  For Accutane, post-marketing controls may ensure fewer pregnancy exposures and adverse psychiatric events.  Yet they also threaten to limit the drug\rquote 
s availability and to fuel a dangerously unregulated underground market.  Also shaping the A
ccutane debate have been competing conceptions of acne and birth defects.  At one extreme, the debate risks trivializing acne as a uniformly superficial annoyance, rather than recognizing its potentially devastating social and emotional consequences.  At 
the other extreme, it risks minimizing the suffering of those born with Accutane\endash related birth defects.  Ironically, the very severity of their disabilities may make Accutane\rquote s victims \'93too easily hidden from public view\'94
 and their problems too easily overlooked.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super 
\chftn }{ }{\i See}{ Krause supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{ at 28.}}}{\f0\fs24 
  Unlike Thalidomide victims, Accutane victims are usually so disabled that they cannot testify to the hardships they face.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Issues of individual choice, maternal responsibility and physician autonomy further complicate the debate as Accutane regul
ation struggles to balance the welfare of the unborn fetus with the freedom of patients and doctors.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{., at 28.}}}{\f0\fs24   
\par The Accutane experience reflects broader risk management dilemmas.  In Part I, I explore a significant shift in American drug regulatory philosophy exemplified by the Accutane experience.  
\par }{\b\f0\fs24 
\par }\pard \qc \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\b\scaps\f0\fs24 II.  Overview of FDA Risk Management Policy}{\scaps\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\b\f0\fs24 A. Introduction to the Task Force on Risk Management
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 By May 1999, growing criticism of FDA prompted FDA Commissioner Dr. Jane Henney to commission a Task Force on Risk Management.}{
\cs20\f0\fs24\super {\*\bkmkstart _Ref7779381}\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{
 Managing the Risks From Medical Product Use\emdash Creating a Risk Management Framework: Report to the FDA Commissioner from the Task Force on Risk Management 17 (May 1999), }{\i available at}{ http://}{\field\flddirty{\*\fldinst {\cf17 
 HYPERLINK "http://www.fda.gov/oc/tfrm/riskmanagment.pdf" }{\cf17 {\*\datafield 
00d0c9ea79f9bace118c8200aa004ba90b0200000003000000e0c9ea79f9bace118c8200aa004ba90b5a00000068007400740070003a002f002f007700770077002e006600640061002e0067006f0076002f006f0063002f007400660072006d002f007200690073006b006d0061006e00610067006d0065006e0074002e00
7000640066000000}}}{\fldrslt {\cs22\ul\cf17 www.fda.gov/oc/tfrm/riskmanagment.pdf}}}{ (last visited Apr. 28, 2002) [herinafter }{\i Report}{]}}}{\f0\fs24 {\*\bkmkend _Ref7779381}  The Task Force responded to critics with a report entitled }{\i\f0\fs24 
Managing the Risks from Medical Product Use--Creating}{\f0\fs24  }{\i\f0\fs24 a Risks Management Framework}{\f0\fs24 .}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i Id.}}}{\f0\fs24   Critics had alleged that speedier review of New Drug Applications (\'93NDAs\'94) had resulted in more unexpected adverse drug reactions (\'93
ADRs\'94).}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  They also suggested that FDA\rquote s post-approval surveillance mechanisms inadequately monitored these ADRs.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7779519}\chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Denise Grady, }{\i Need is Seen for a Drug Safety Board}{, }{\scaps 
N.Y. Times}{, Dec. 29, 1998, at F7; Gina Kolata, }{\i The F.D.A. Approves a Drug. Then What?}{, }{\scaps N.Y. Times}{, Oct. 7, 1997 at F1.  }}}{\f0\fs24 {\*\bkmkend _Ref7779519}  These charges contrasted sharply with critics\rquote 
 a longstanding concerns about FDA alleged \'93drug lag.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 
{\cs20\super \chftn }{  }{\i See}{ Report, supra note }{\field{\*\fldinst { NOTEREF _Ref7779381 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 16.}}}{
\f0\fs24   In the 1980s and early 1990s, critics considered the approval process too lengthy and the delay with which AIDS and cancer patients received new therapies too extensive.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  Yet by the late 1990s there were calls for the retrenchment of expedited review procedures.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ Grady, supra note }{\field{\*\fldinst { NOTEREF _Ref7779519 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003500310039000000}}}{\fldrslt {44}}}{ }}}{\f0\fs24   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\b\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {B. Overview of Traditional Drug Approval Process
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par Traditionally, FDA has required that manufacturers seeking new drug approval test their product in laboratory animals.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 5.}}}{\f0\fs24   Animal testing reveals information on the drug\rquote s toxicity, its absorption in the
 body and safe dosage.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{   }{\i Id.}}}{
\f0\fs24   After completion of animal testing, the drug\rquote s sponsor submits its research to FDA and proposes testing on human subjects.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{   }{\i Id.}}}{\f0\fs24 
  This proposal describes the contemplated research in the form of an \'93investigational new drug application\'94 or IND.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Controlled testing in humans can only begin once FDA determines that such testing can safely be conducted with human volunteers.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   
\par If FDA makes such a determination, then the drug\rquote s sponsor may commence human trials.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   These tests usually contain three phases.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Phase I focuses on the drug\rquote s safety.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  Over several months, fewer than 100 healthy, paid volunteers usually take the drug to determine its safety.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Phase II trials begin if the drug passes the Phase I tests.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   In Phase II, researchers examine the drug\rquote 
s effectiveness in treating the ailments it is designed to combat.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Several hundred patients with the particular disease that the drug targets are usually involved.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  Phase II studies usually last for several months to two years and are randomized control trials; a \'93treatment\'94 group receives the drug while a control group receiving either a placebo or the standard treatment is established for comparison.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   In \'93blinded
\'94 Phase II studies, the patient\rquote s group is concealed from both the patient and the  doctor delivering the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  Finally, Phase III approximates normal medical usage of the drug; several thousand patients with the particular condition may take the drug in an attempt to reveal a drug\rquote s rarer side affects.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
\par Phase III may last for four years or more.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super 
\chftn }{  }{\i Id.}}}{\f0\fs24   The sponsor files a \'93New Drug Application,\'94 or NDA, with FDA upon completion of Phase III.  FDA\rquote s approval of the drug hinges on proof of its safety and the development of appropriate labeling for the drug.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  Labels must state the drug\rquote s approved indications, its recommended dosage, contraindications, side effects and warnings.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   This information usually appears on \'93package inserts\'94
 accompanying the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{
\f0\fs24   Sometimes, however, patients and doctors receive labels developed especially for their respective needs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
\par In particular cases, patients had received investigational new drugs, (\'93INDs) after FDA had issued ad hoc \'93Treatment INDs\'94 or \'93Compassionate INDs.\'94  In 1987, the FDA\rquote s official IND policy was revised so that patients with immed
iately life-threatening illnesses could receive experimental drugs without enrolling in a research trial.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Under the revised policy, drugs for immediately life-threatening diseases could receive approval after Phase II trials.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Similarly, drugs for serio
us illnesses could receive approval during Phase III.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   In 1988 FDA, further increased the availability of new drugs by proposing a \'93fast-track\'94 approval program for drugs treating life-threatening or severely debilitating illnesses.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i Id.}}}{\f0\fs24   This program provide
d for more lenient FDA risk-benefit analysis of the drugs and entailed greater collaboration between FDA and the sponsor in developing Phase II clinical trials.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}{ at 6}}}{\f0\fs24 
\par In 1992, steps to accelerate access to new drugs continued.  FDA regulations relaxed scientific evidence requirements for drugs used to treat serious or life-threatening illnesses \'93
that provide meaningful therapeutic benefit patients over existing treatment.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Noah, supra note }{\field{\*\fldinst { NOTEREF _Ref7782337 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700380032003300330037000000}}}{\fldrslt {35}}}{, at 462-463}}}{\f0\fs24   To qualify for expedited review under this regulation, sponsors must conduct post-approv
al studies of the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}
{ }}}{\f0\fs24   Congressional passage of the Prescription Drug User Fee Act of 1992 (PDUFA) also accelerated the process.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Report, supra note }{\field{\*\fldinst { NOTEREF _Ref7779381 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 17.}}}{\f0\fs24 
  Pursuant to PDUFA the sponsors of new drug and biological products provide FDA with user fees to support the review of new pharmacological products.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24 
  The Food and Drug Modernization Act of 1997 (FDAMA) reauthorized PDUFA and relaxed the \'93substantial evidence\'94 standard so that NDA sponsors need only submit one rather two controlled clinical trials.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 16}}}{\f0\fs24   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {C.  Criticism of Expedited Review
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 Critics of FDA questioned the wisdom of the resulting expedited review.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Denise Grady, }{\i 
In a Survey, the F.D.A. is Accused of Hasty Approval of Drugs}{, }{\scaps N.Y. Times}{, Dec. 3, 1998, at A1.}}}{\f0\fs24   A prominent opponent of the reforms was Public Citizen\rquote 
s Health Research Group, directed by Dr. Sidney Wolfe and founded by consumer advocate Ralph Nader in 1971.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24   In a 
press conference, the advocacy group reported the results of its anonymous survey of FDA medical officers, agency employees assigned to oversee drug evaluations.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Nineteen medical officers stated that 27 drugs were approved over their objections, seventeen considered FDA\rquote 
s safety and efficiency standards lower than they had been in the past and nineteen reported feeling more pressured by Congress, the pharmaceutical industry and FDA to approve drugs for mass marketing.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Public Citizen alleged that pressur
es to accelerate dug approval had threatened public safety.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See}{ Report, supra note }{\field{\*\fldinst { NOTEREF _Ref7779381 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 17.}}}{
\f0\fs24   
\par Complaints had intensified as several FDA approved drugs were withdrawn from the market upon discovery of previously unforeseen side affects or dangerous interaction with other drugs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Noah, supra note }{\field{\*\fldinst { NOTEREF _Ref7782337 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700380032003300330037000000}}}{\fldrslt {35}}}{, at 491}}}{\f0\fs24   Among t
hese drugs were the diet drug Redux, the high blood pressure medication Posicor, and the allergy drug Seldane.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ id, at 491; }{\i See}{ Grady; supra note }{\field{\*\fldinst { NOTEREF _Ref7779519 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003500310039000000}}}{\fldrslt {44}}}{.}}}{\f0\fs24 
\par Drs. Raymond Woosley, Alastair J.J. Wood and Michael Stein have likened these drug recalls to airplane crashes.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Grady, supra note }{\field{\*\fldinst { NOTEREF _Ref7779519 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003500310039000000}}}{\fldrslt {44}}}{.}}}{\f0\fs24   Writing in the }{\i\f0\fs24 New England Journal of Medicine}{\f0\fs24 
, they called for the establishment of an independent safety review board to investigate drug \lquote crashes\rquote  much as the transportation board investigates plane crashes.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The Doctors contended that if the same organization that approves plane m
anufacturers and airlines should not investigate disasters involving those planes and manufacturers, then the same entity that approves drugs should not be the sole investigator of the drug\rquote s post-approval reactions.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The doctors noted that since accelera
ting its approval process FDA had approved drugs at almost twice its previous rate.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  For them, this acceleration strains an inherently limited drug regulatory system; pre-approval clinical investigators, of relatively short duration and involving a relati
vely small number of subjects from a relatively narrow sample of subjects, may not reveal all drug risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{; }{\i see}{ }{\i also}{ Noah, supra note }{\field{\*\fldinst { NOTEREF _Ref7782337 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700380032003300330037000000}}}{\fldrslt {35}}}{, at 458-462.}}}{\f0\fs24   The doctors also deemed FDA\rquote 
s post-approval surveillance mechanisms too informal to promptly detect these risks and are feared that the already impaired system would suffer further strain as more drugs enter the market annually.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Grady, supra note }{\field{\*\fldinst { NOTEREF _Ref7779519 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003500310039000000}}}{\fldrslt {44}}}{.}}}{\f0\fs24 
  Post-marketing, drugs become widely available to a diverse set of patients who may take the drug in combination with other prescriptions.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Thus, some adverse reactions may 
first surface outside of this controlled environment.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Dr. Woosley characterized these post-approval patients as unwitting subjects in a massive experiment and argued that such an experiment needs more careful monitoring.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Holders of an NDA are required by the Food Drug and Cosmetic Act to report any data relating to clinical experiences with drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Noah, supra note }{\field{\*\fldinst { NOTEREF _Ref7782337 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700380032003300330037000000}}}{\fldrslt {35}}}{, at 466.}}}{\f0\fs24 
  However, FDA regulations do not require holders of an approved NDA to actively seek such information.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24   When a health care professional or consumer spontane
ously reports an adverse reaction, the manufacturer must submit an adverse experience report.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 469.}}}{\f0\fs24   Noah argues that this \'93 \lquote mandatory\rquote 
 system is only as effective as the degree of voluntary participation permit.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Although health care providers are not legally mandated to report adverse drug reactions, they are ethically obliged to do so.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 477.}}}{\f0\fs24 
  In its first concerted effort to formally involve physicians in post-marketing surveillance, FDA established the MedWatch system in 1993.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 478.}}}{\f0\fs24   Physicians receive one page form
s and are asked to complete them in order to report all serious adverse reactions.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Included in the events physicians are asked to report are death, disability, birth defects and miscarriage.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24   
\par Barbara A. Noah considers the quality and effectiveness of physician participation in the program \'93moderately favorable.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24 
  Nevertheless, she notes that while the quality of the reports has improved, the overall number of reports has declined since the MedWatch launch.  Spontaneous reporting of ADRs peaks at the end of a second year of the drug\rquote 
s marketing, but declines dramatically thereafter, regardless of presumably constant rates of prescriptions and ADRs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Noah suggests, that increasingly common managed care organizations may foster the routine collection and reporting of ADRs because they can gather and analyze masses of data.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 480.}}}{\f0\fs24 
  Yet other features of managed care plans may offset this advantage.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 479}}}{\f0\fs24   Patients change physicians far more often under managed care, impeding communication with doctors.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 479-480.}}}{\f0\fs24   Communication 
is also hampered by pressure to reduce the duration of each patient visit.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 479.}}}{\f0\fs24 
  As lines of communication erode, the risks to monitor multiply; under managed care doctors prescribe more pharmaceuticals to manage chronic disease.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 479.}}}{\f0\fs24 
\par Indeed, by one 1998 report, only a fraction of doctors can even recognize the forms FDA provides to report adverse events.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Kolata, supra note }{\field{\*\fldinst { NOTEREF _Ref7779519 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003500310039000000}}}{\fldrslt {44}}}{.}}}{\f0\fs24 
  Doctors and other health care workers may often be unaware that they are expected to detect and report serious medication  side affects.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Thus some doctors and
 scientists have called for more formal, possibly mandatory, involvement of health care workers in the surveillance process.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {D.  The Task Force Defense of Pre-Approval Procedures
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par The Task Force\rquote s Report acknowledged the growing complexity of the health care environment and proposed changes to meet its demands.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i generally}{, Report, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7779381 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 20.}}}{\f0\fs24   Healthcare is no longer \'93
provided by a family practitioner who treated patients from cradle to grave,\'94 the Report notes.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The Report reflects a growing emphasis on post-marketing risk manageme
nt strategies, a trend away from disproportionate reliance on pre-approval testing.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i generally}{ Report, supra note }{\field{\*\fldinst { NOTEREF _Ref7779381 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 63-70.}}}{\f0\fs24 
\par Nevertheless. the Task Force defended the quality of FDA\rquote s pre-market approval process.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 35-42.}}}{\f0\fs24   FDA\rquote s data showed no increase in the rate of drug withdrawals since PDUFA.  It al
so found no evidence that drugs approved since PDUFA caused higher rates of serious adverse events on the market.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 35.}}}{\f0\fs24   Rates of serious adverse events identified post-marketing were lower for drugs approved under PDUFA.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The Task Force also criticized Public
 Citizen\rquote s survey method; the group failed to collect information on how frequently or when medical officers\rquote 
 recommendations to disapprove a product were not followed--facts relevant in assessing the true extent of the problems they alleged.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 18.}}}{\f0\fs24 
\par Yet the Task Force recommended improvements to FDA\rquote 
s quality control system, including periodic review of a sample of product approval administrative records, procedures for the continuation of review despite administrative disruptions and evaluation of whether scient
ific disputes among reviewers predicts post-marketing problems.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at  49-50.}}}{\f0\fs24 
  The Task Force also recommended ongoing professional education and core competency training for reviewers, the completion and updating of Good Review Practice (\'93GRP\'94) documents and the analy
sis of and incorporation into GRP documents of post-marketing events.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24 
  Additionally, the task force proposed possible expansion of community based trial centers and the concentration of early post-approval use in certain populations for whom new product would be especially advantageous.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Overall however, the task force found that the key elements of FDA\rquote s quality control system were intact.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {E.  Post-Marketing Surveillance Reform
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par The Report acknowledged the need for greater reform of FDA\rquote s post-marketing surveillance}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 52.}}}{\f0\fs24 
.  The Task Force noted the increasingly challenging environment in which post-marketing monitoring occurs, painting a portrait of the current health care climate similar to that of FDA\rquote s critics.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 51.}}}{\f0\fs24   This account included frequent doctor ch
anges, shorter patient visits and the pressure to prescribe items approved by managed care plans.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 53.}}}{\f0\fs24   Yet unlike its critics, the Report shifted emphasis from the post-market monitoring of }{\i\f0\fs24 unexpected}{\f0\fs24 
 adverse reactions, to surveillance of }{\i\f0\fs24 expected}{\f0\fs24  adverse reactions.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 51}}}{\f0\fs24   Many of the most highly publicized drug withdrawals involved the product\rquote s unanticipated side effects.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Noah, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7782337 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700380032003300330037000000}}}{\fldrslt {35}}}{, at 486, 492.}}}{\f0\fs24 
  Seldane and Redux, for example, were withdrawn from the market upon discovery of unforeseen drug interactions and side affects respectively.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par FDA, however, reported that its post-marketing monitoring system was performing to accomplish the purposes for which it was designed\emdash \'93to detect adverse events not previously observed.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Report, supra note }{\field{\*\fldinst { NOTEREF _Ref7779381 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 52}}}{\f0\fs24   Nevertheless Dr. Jane Henney has stressed that most injuries and dea
ths caused by medical products result from their }{\i\f0\fs24 expected}{\f0\fs24  results.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7896420}\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Jane E. Henney, M.D., Remarks of the Commissioner of Food and Drugs, 55 }{\scaps Food Drug L.J.}{ 1, 1 (2000); }{\i See}{ Report, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7779381 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 12}}}{\f0\fs24 {\*\bkmkend _Ref7896420}  For example, Accutane\rquote 
s risk of birth defects are well known; post-marketing monitoring of Accutane would monitor the extent of a known problem.
\par The Report suggests that FDA could assume a more proactive risk management role post-marketing, departing from its traditionally passive post-marketing activity.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Report, supra note }{\field{\*\fldinst { NOTEREF _Ref7779381 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 92}}}{\f0\fs24   It reports, \'93
[t]he management of risks associated with using medical products, known as the practice of medicine, has traditionally been left in the hands of health professionals.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{.}}}{\f0\fs24 
  Although the Report acknowledges that the medical community has resisted FDA\rquote s restrictions on its practices, it argues that the medical community has increasingly accepted post-approval FDA regulation.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{.}}}{\f0\fs24   Am
ong the possible reforms, the Report suggests that FDA could impose restrictions on product distributions, impose safety programs for risky products\emdash 
including mandatory education programs for prescribers and patients, mandatory re-labeling or re-approval of products\emdash and restrict drugs to certain uses or prescriber categories.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i generally}{ }{\i Id.}{ at 92-94.}}}{\f0\fs24 
  The Report noted that such efforts would be particularly appropriate for drugs with especially high risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ id at 92.}}}{\f0\fs24 
\par The Report also suggested improvement to FDA\rquote s risk communication strategies.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 93-96.}}}{\f0\fs24 
  Although FDA is already actively engaged in the risk communication process, the Report  suggests that these activities would be more successful within a systematic strategy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 93.}}}{\f0\fs24 
  For example, FDA could categorize the types and severity of risks and base their communication strategy on these classifications.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The Report proposed a Government sponsored database that health care professionals could access.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24   As an example of the information suitable for such a database, the Report lists \'93registry informati
on on the outcomes of the use of drugs during pregnancy.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 
{\cs20\super \chftn }{  }{\i See id.}{ at 94.}}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {F.  A Comparative Perspective
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 \tab 
These proposals reflect a shift in U.S. regulatory philosophy towards the British model.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Teff, supra note }{\field{\*\fldinst { NOTEREF _Ref7794649 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390034003600340039000000}}}{\fldrslt {32}}}{, at 579.}}}{\f0\fs24   Harvey Teff, in his comparative study of drug approval in England and in t
he United States, characterizes U.S. and British regulatory philosophy as fundamentally different.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24   According to Teff, the U.S. drug approval process places more emphasis on ensuring drug safety prior to the product\rquote 
s marketing than does its British counterpart.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super 
\chftn }{  }{\i See id.}}}{\f0\fs24   By contrast, the British system has traditionally stressed post-marketing risk management strategies.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 In part, Teff attributes this difference to British regulators\rquote  more explicit acknowledgement \'93
of the unpalatable truth that the research process continues even after a licenses drug has been made available for general prescription.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Even with demanding pre-marketing testing, rare side effects will often only appear once a far greater portion of the population uses the drug post-approval.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In 
the U.K., it is far more common for certain drugs only to be prescribed by hospitals or by certain medical specialists}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 .  Accutane is subject to such limitations in the U.K.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Kolata, supra note }{\field{\*\fldinst { NOTEREF _Ref7766421 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360036003400320031000000}}}{\fldrslt {22}}}{; }{\i See}{ also 1988 Hearing, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 139 (testimony of Dr. Lynn Silver)}}}{\f0\fs24 
  There has also been far more attention paid to the post-marketing monitoring of adverse events in the U.K. than in the U.S.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Teff, supra note }{\field{\*\fldinst { NOTEREF _Ref7794649 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390034003600340039000000}}}{\fldrslt {32}}}{, at 579.}}}{\f0\fs24   By contrast, FDA begins its supervision of the drug\rquote s testing earlier in the regulatory process.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\tx1348\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{\tab }}}{
\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 \tab Underlying these different approaches are the political and social climates in which American and British regulators work.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Britain is relatively small, has a more homogenous population and has a national health care system equipped to gather and study masses of data.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{.}}}{\f0\fs24 
  These factors make more feasible post-marketing controls and monitoring.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In addition, Teff ar
gues that the American political system demands more formal accountability of its regulators; Congressional oversight, media scrutiny and an active consumer lobby pressure FDA to achieve maximum safety prior to mass marketing.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 579-580}}}{\f0\fs24 
  In the U.K., a tradition of administrative secrecy has relieved some of this pressure.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {G.  FDA Sub-Committee on Drug Safety and Management
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 \tab 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 The Task Force Report suggests a departure from tradition.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Report, supra note }{\field{\*\fldinst { NOTEREF _Ref7779381 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 92.}}}{\f0\fs24   The Report\rquote s call for enhanced post-marketing surveillance, proposals of patien
t registries and limitations on prescribing power echo the British post-marketing approach.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The same Congressional scrutiny, media attention and consumer lobbying that had pressured FDA to perform extensive pre-approval investigation now demands strengthening of post-marketing supervision.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i See}{ }{\i id.}}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 \tab This shift is reflected institutionally in the establishment of FDA\rquote 
s new Subcommittee on Drug Safety and Risk Management, a group expected to gain full committee status.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Francesca Lunzer Kritz, }{\i FDA to Weigh New Controls on Problematic Drugs; Lotronex Will Be First for Consideration by New Panel,}{ }{\scaps Wash. Post}{
., Apr. 16, 2002 at F01.}}}{\f0\fs24   The group will focus on the safety issues of approved drugs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  In discussing the sub-committee, reporter Francesca Lunzer Kritz asks a question steeped in the traditional philosophy demanding exacting pre-approval scrutiny, \'93Why not just get all the kinks out before approving a drug?\'94}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   She answers 
her own question with acknowledgement of the reality of drug regulation, \'93Often all the kinks aren\rquote t known then\'85often rare side effects don\rquote t show up until a drug is being used in hundreds of thousands of people.\'94}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Among the sub-committee\rquote s concerns will be demands that already approved drugs be banned from the market.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Other risk management missions of the group are suggested by the experiences of its members.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Members include the Director for the Institute for Safe Medication Practices, a nonprofit organization concentrating on medication errors,  and a psychologist who has studied risk communication via patient package inserts.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ id}}}{\f0\fs24 
  At its most recent meeting, the sub-committee considered re-introducing the irritable bowel syndrome drug, Lotronex, despite its side affect of ischemic colitis.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Two more meetings are scheduled for this year.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{  }}}{\f0\fs24 
\par \tab Accutane regulation illustrates the ideological shift underlying the sub-committee\rquote s establishment.  Part III traces the drug\rquote s regulatory history with its increasing emphasis on strengthening post-marketing Accutane controls.
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard \qc \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\b\f0\fs24 III.  }{\b\scaps\f0\fs24 History of Accutane Regulation}{\b\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {A.  Acne
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 Accutane is prescribed to combat acne.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{
, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{
, (statement of Dr. David Pariser, Chief of Dermatology and Professor of Dermatology at the Eastern Virginia Medical School at Norfolk.)}}}{\f0\fs24   The basic cause of acne is unknown, but scientists know that it is a disease of the pilosebaceous units.
}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   T
hese consist of oil glands connected to hair follicles.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In acne patients, the lining of the hair follicle changes to prevent sebum, the oily substance produced by the sebaceous gland, from passing through the follicle to the skin\rquote s surface.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In normal p
atients, the sebum empties onto the skin\rquote s surface through the follicle.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   By contrast, the cells lining the acne patient\rquote s follicle shed too quickly and clump together to block the follicle\rquote 
s opening.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  As the sebum remains trapped in the skin, bacteria that normally live harmlessly on the skin grows in the hair follicle and produce inflammation causing chemicals.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The pilosebaceous units are most common on the areas of the body on which acne is most likely to appear\emdash the face, scalp upper back and chest.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Acne is generally classified by the kinds of lesions on the patient\rquote s body.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24   Often, however, doctors can debate the appropriate classification of a condition.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\
h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 112.}}}{\f0\fs24   Patients may suffer from different kind of lesions simultaneously.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }
{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{, (statement of Dr. David M. Pariser)}}}{\f0\fs24 
  Accutane was originally indicated for severe cystic acne, a disease that results in large, painful and scarring lesions.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 24. (statement of Dr. David Graham, Group Leader, Epidemiology Branch, Office of Epidemiology and Biostatistics.)}}}{
\f0\fs24   Defining cystic acne has been an important issue in determining the appropriate use of Accutane.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {B.  Acne Treatments
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 The first step doctors usually recomm
end for acne treatment is gentle cleansing of the skin.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  Drs. Jonathan Fielding and Valerie Ulene, }{\i Our Health: Many Therapies Hit the Spot for Relief of Acne,}{ }{\scaps L.A. Times}{, March 25, 2002, at S7}}}{\f0\fs24 
  According to the American Academy of Dermatology, the skin should be washed twice daily with water and a mild cleanser.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   This reduces excess oils on the skin\rquote s surface.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Yet washing is rarely a su
fficient remedy and medication is normally required.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Most patients start by applying an over-the-counter gel, cream or lotions several times a day.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Topical treatments often contain either benzoyl peroxide, salicylic acid, sulfur or resorcinol.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i id}}}{\f0\fs24   These popular treatments prevent follicles from plugging.  Benzoyl peroxide-containing}{ }{\f0\fs24 
products can also inhibit bacterial overgrowth.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super 
\chftn }{  }{\i See id.}}}{\f0\fs24   Yet many patients also require prescription medications.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Doctors prescribe antibiotics in either pill or topical form to stop or slow the growth of  bacteria.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  In addition, drugs called retinoids, of which Accutane is an example, combat acne by unplugging blocked follicles or reducing the amount of sebum produced.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {C.  Accutane 
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
Accutane is an oral retinoid, also known as isotretinoin.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}
{, (statement of Dr. James O\rquote Donnell, Assistant Professor of Pharmacology at the Rush Medical College.)}}}{\f0\fs24   The drug is a Vitamin A derivative.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  By reducing gland size and differentiation, it lowers sebum production.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   With less sebum in the skin, fewer pores clog and less nutrition becomes available for organisms such as  Proprionibacterium acnes
, which lives in the follicle and causes the body\rquote s inflammatory response.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  In addition, Accutane itself is an anti-inflammatory; it soothes pre-existing lesions to minimize scarring.  In short, Accutane is a uniquely effective acne treatment.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Many pati
ents who undergo a complete course of Accutane treatment for 15 to 20 weeks enjoy a complete and prolonged remission of the disease.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 
\\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{, (statement of Dr. David Pariser)}}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {D. Accutane\rquote s Invention
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
Accutane was first developed in Switzerland in 1955.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}
{, (statement of Dr. James O\rquote Donnell)}}}{\f0\fs24   At the time, its inventors recognized its teratogenicity, or ability to cause birth defects.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 7.}}}{\f0\fs24   The drug\rquote 
s inventor has suggested that after the thalidomide tragedy, the use of a teratogenic drug for as seemingly benign an ailment as acne was likely to meet much opposition.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {E.  FDA Approval of Accutane
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
In the late 1970s, however, Roche began testing Accutane as a treatment for severe recalcitrant acne.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The definition of this condition has been debated amongst doctors and regulators.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7839309}\chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{
  Joint Meeting of the Dermatologic Drugs and the Fertility and Maternal Health Drugs Advisory Committees, (May 20, 1991), available }{\cf0 at }{\field\flddirty{\*\fldinst {\cf0  HYPERLINK "http://www.fda.gov" }{\cf0 {\*\datafield 
00d0c9ea79f9bace118c8200aa004ba90b0200000003000000e0c9ea79f9bace118c8200aa004ba90b2800000068007400740070003a002f002f007700770077002e006600640061002e0067006f0076002f000000}}}{\fldrslt {\cs22\ul\cf0 www.fda.gov}}}{. [herinafter }{\i 1991 Hearings}{]}}}{
\f0\fs24 {\*\bkmkend _Ref7839309}  Some try to classify the condition by the number and type of lesions on the patient\rquote s body.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\
h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 24 (statement of Dr. David Graham).}}}{\f0\fs24 
  Others object to quantifying the classification and argue that individual doctors must diagnose the condition patient by patient rather than through a rigid general formula.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1991 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7839309 \\
h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, at 134 (statement of Dr. Jerome Shupack Professor of Dermatology at New York University)}}}{\f0\fs24 
  Some argue that the original definition of severity has changed over time.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 184.}}}{\f0\fs24 
\par FDA approved the drug in May 1982, making the U.S. the first country to approve Accutane as a severe recalcitrant cystic acne treatment.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Kolata, supra note }{\field{\*\fldinst { NOTEREF _Ref7766421 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360036003400320031000000}}}{\fldrslt {22}}}{. }}}{\f0\fs24   Roche had conducted clinical trials including 550 subject and tested the drug at four uni
versities and the National Cancer Institute.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super 
\chftn }{ }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 7.}}}{\f0\fs24 
  FDA approval came nine months after the NDA submission, causing some critics to question the speed with which the drug was approved\emdash an unusual criticism of FDA at a time when most critics considered the agency overly cautious.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Kolata, supra note }
{\field{\*\fldinst { NOTEREF _Ref7766421 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360036003400320031000000}}}{\fldrslt {22}}}{.}}}{\f0\fs24 
  Widespread media coverage of the drug as a miraculous cure and relatively little media attention devoted to its risks worried some.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 7, 21.}}}{\f0\fs24   Indeed, the drug\rquote 
s original package insert warned that pregnant women should not take the drug, but it explicitly stated only that Accutane caused birth defects in animals.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 7.}}}{\f0\fs24   
\par }\pard\plain \s1\ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {F.  Education and Communication
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 Following Accutane\rquote 
s marketing, FDA and Roche made education the cornerstone of the drug\rquote s risk management program.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 8-9; }{\i See}{ also }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{ (statement of Dr. Jonca Bull, Deputy Director of the Office of Drug Evaluation, C
enter for Drug Evaluation and Research, Food and Drug Administration.)}}}{\f0\fs24   One commentator Joan H. Krause, contrasts this incremental risk communication strategy with the \'93sweeping changes of regulatory policy\'94
 prompted by the Thalidomide tragedy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{
  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 3.}}}{\f0\fs24   Yet Krause
\rquote s characterization of the publicity efforts undertaken by FDA and Roche as \'93minor\'94 conflicts with many commentators characterization of the regulatory attention devoted to the drug as unprecedented.\'94}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1991 Hearings}{, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7839309 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, at 156}}}{\f0\fs24 
  Dr. Mary Spraker, in her statement at the 1991 Advisory Committee Meetings on Accutane, argues, \'93Never in the history of drug prescribing has more been done to educate physicians and patients about the teratogenicity of a medication.\'94}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Krause herself acknowledges that FDA demonstrated laudable creativity and flexibility in the Accutane regulation and education efforts undertaken during this period.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 21.}}}{\f0\fs24   
\par Roche notified doctors of several cases Accutane related birth defects in \'93Dear Doctors\'94 letters.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 17.}}}{\f0\fs24   Similarly, in August 1983, FDA reported 12  cases of  Accutane related \'93adverse pregnancy outcomes.\'94}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
  Soon thereafter Public Citizen charged that Accutane\rquote s warnings against pregnancy exposure were inadequate and that the drug was over-prescribed.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7899821}\chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Philip J. Hilts, }{\i Acne Drug is Oversold, Group Says}{, }{\scaps 
Wash. Post}{ (Sept. 9, 1983), at A4.}}}{\f0\fs24 {\*\bkmkend _Ref7899821}  Roche soon changed Accutane\rquote s labeling to make clear the risk of human birth defects.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 8.}}}{\f0\fs24 
\par In 1984, after reports of 21 Accutane related birth defects and 24 spontaneous abortions, Dr. Paul J. Benke identified an \'93isotretinoin teratogen syndrome.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i id}{.; }{\i see also}{ Dr. Paul J. Benke, }{\i The Iso
tretinoin Teratogen Syndrome}{, 251 JAMA 3267 (1984).}}}{\f0\fs24   Benke had studied two children born to Accutane users.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See }{Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 8.}}}{\f0\fs24   Based on this study, he detailed  a syndrome characterized by ear, face and central nervous system problems.
}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Frequentl
y infants exposed to the drug during pregnancy suffered from mental retardation.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Benke reported that Accutane could even cause birth defects if taken by a pregnant women only briefly during the first trimester of pregnancy, when many women are unaware of their pregnancy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par The same year, Roche and FDA intensified warnings about Accutane\rquote s teratogenicity.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 8.}}}{\f0\fs24 
  Patients were advised to use contraception for a month before and after Accutane treatment, and blood banks were asked to reject donations from those exposed to the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Roche developed an Accutane education program targeted at physicians; in a \'93Medical Director\rquote s Page\'94 printed in }{\i\f0\fs24 the Journal of the American Medical Association}{\f0\fs24 , Roche emphasized Accutane\rquote 
s dangers in pregnant women.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i 
See id.}{ }}}{\f0\fs24   In her testimony to the U.S. House of Representatives Committee on Government Reform, Dr. Jonca Bull, Deputy Office Director of the FDA Office of Drug Evaluation outlined the education efforts made during these years including:

\par }\pard\plain \s18\ql \li720\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {1) physician labeling changes; 2) repeated ma
iling of special letters to doctors and pharmacists detailing proper use and emphasizing the risks; 3) two articles in FDA\rquote 
s Drug Bulletin, which reached more than a million health professionals, emphasizing proper prescribing of Accutane; 4) distribution 
to patients through doctors of a patient information leaflet highlighting the risks; 5) distribution to pharmacists of red warning stickers to be placed on each prescription bottle; and 6) issuance of press releases and background papers to the general ne
ws media for use in warning the public about the risks associated with Accutane.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{ (statement of Dr. Jonca Bull).}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 \~
\par Yet by 1988 there was evidence that many women were still using the drug despite having relatively mild acne.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 9.}}}{\f0\fs24   The Center for Disease Control  published a report of four ca
ses of serious birth defects resulting from Accutane between 1983 and1987.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{ (statement of Dr. Jonca Bull)}}}{\f0\fs24   The CDC article also noted additional cases of birth defects.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Thus, FDA convened a Dermatologic Drugs Advisory Committee (the \'93Committee\'94) meeting to address the problem.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Experts from several medical specialties and scientists from the CDC, FDA, Hoffman-La Roche, Public Citizen\rquote 
s Health Research Group, the American Academy of Pediatrics and the American Academy of Dermatology participated in day-long proceedings.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In a unanimou
s vote, the Committee recommended the continued sale of Accutane with revised labeling and increased restrictions on the drug\rquote s distribution}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The Committee called for new packaging featuring stronger warnings and more explicit information about Accutane\rquote s risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  It also recommended that the drug only be used in women who have had a negative pregnancy test.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Finally, it recommended written acknowledgement from patients that they had been informed of Accutane\rquote s risk of birth defects.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par In a split vote, the committee also proposed the adoption of several other measures.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Some committee members suggested that the government empower only certain types of physicians to dispense the drug.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Others called for the imposition of special restrictions for high risk patients, including a requirement that high risk female patients obtain a second opinion.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Other suggestions focused on physician awareness of Accutane
\rquote s risks and proposed doctor certification for Accutane distribution though an education program.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Finally, the Committee recommended that the use and adverse events associated with Accutane be continually monitored.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par In May 1988, FDA issued a letter to Hoffman-La Roche discussing effective risk communication.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   While drug warnings usually appear in a packa
ge insert accompanying a drug, FDA asked that Accutane warnings appear on the blister pack containing the drug itself.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   These warnings included pictures depicting the severe physical abnormalities of those with Accutane-related birth defects.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In additio
n, to facilitate the monitoring of Accutane\rquote s risks, the blister pack was to include a tear-off for mailing patient contact information to the company.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   FDA also called for research on patient behavior.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  For example, it wanted further exploration of why patients become pregnant while using Accutane.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  FDA then asked that both physicians and female patients signed a form acknowledging that they understood the serious likelihood that severe birth defects could result from pregnancy exposure to Accutane}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 .  
\par FDA also focused on health care professional\rquote s education.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  It demanded more detailed physician and patient labeling, further educational campaigns for physicians, pharmacists as well as patients and advertisements discussing Accutane\rquote s risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Finally FD
A asked that Roche run further clinical trials investigating the effectiveness of Accutane when taken at different doses for different period of time; shortening the length of Accutane therapy or the dosage of the drug could affect the risk of pregnancy e
xposure.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 

\par }\pard \ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {G. Roche Pregnancy Prevention Program

\par }\pard\plain \s18\ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {By mid-1989, Roche used this risk management framework to develop a \'93
Pregnancy Prevention Program for Women on Accutane\'94.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super 
\chftn }{  }{\i See id.}}}{  In May 1990, the Committee again evaluated the program\rquote s effectiveness and determined that the company had made a strong education effort.  }{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
  Nevertheless the data on its effectiveness were limited.  In 1990, one case of Accutane related birth defects was reported.  In 1989, there were four reports and in 1988 there were three.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{  Ten such reports were made in 1987 and twelve were made in 1986.}{
\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
\par However, the Committee made several additional recommendations.  It suggested that educational materials place greater emphasis on pregnancy testing prior to the commencement of Accutane therapy.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{ 
 It also suggested that physicians emphasize the importance of the informed consent forms to their patients and that the forms be presented in several languages.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
  Pregnancy prevention counseling was deemed an important component of the risk management scheme; physicians were asked to emphasize it.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
  Finally the Committee proposed that Roche address the danger that patients will take Accutane without medical supervision by saving leftover medication.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{  The Committee recommended that Roche arrange for the re
turn of all leftover medication.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.
}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
In September 2000 the Committee re-visited its discussion of fetal exposures.  It decided that three principles should guide an Accutane risk management strategy on this topic.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   First, no pregnant woman should begin Accut
ane treatment.  Second, no one should become pregnant while using Accutane.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Finally, to evaluate the program\rquote s effectiveness in meeting these goals, a monitoring program should assess results.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The Committee considered the five designs FDA proposed for 
upholding the principles and by a majority, chose a program including education and informed consent, the registration of both patients and physicians who would fully participate in the program, the monitoring of fetal exposures using a program involving 
a pregnancy registry, and surveys.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{
\i See id.}}}{\f0\fs24   The Committee rejected some proposals for the restricted distribution of the drug however.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par On October 31 2001, FDA released a Talk Paper outlining a new program designed to achieve the pregnancy prevention goals established at the September 2000 meeting.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7917742}\chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Press Office, FDA, }{\i 
FDA Announces Change to the Risk Management Program to Prevent Birth Defects Caused by Accutane }{ (2001).}}}{\f0\fs24 {\*\bkmkend _Ref7917742}
  The program is called S.M.A.R.T., System to Manage Accutane Related Teratogenicity.  Pursuant to its provisions, prescribers must study the S.M.A.R.T. \'93Guide to Best Practices,\'94 developed by Roche and then sign and ret
urn to the company a Letter of Understanding certifying their understanding.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Prescribers are also urged to take a half-day Continuing Medical Education course also developed by Roche in which specific pregnancy prevention tactics are discussed.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Roche t
hen sends to prescribers special self-adhesive Accutane Qualification Stickers.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The prescriber must attach this yellow sicker to their regular prescription form to permit pharmacists to dispense the drug.  Female patient\rquote s \'93qualification\'94 for Accutane en
tails a negative pregnancy test and education and counseling about pregnancy prevention.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   No prescriptions are to be given for more than a one month supply so that pregnancy tests can be given monthly.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Female patients take two urine and serum pregnancy tests prior to receiving an Accutane prescription.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   If the tests are negative they receive a prescription for a one month supply of Accutane.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  They must have another negative pregnancy test each month before receiving another prescription.  Sexually activ
e patients, or patients who might become sexually active with a male partner must also use two forms of effective contraception simultaneously.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Contraception use must begin at least one month before the start of Accutane treatment, continue throughout treatment and for at least one month after the completion of treatment.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ id}}}{\f0\fs24   Female patients must sign a \'93Patients Information/Consent
\'94 form discussing Accutane\rquote s teratogenicity.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   They are also asked to participate in the Accutane Survey, a confidential survey conducted by the Slone Epidemiology Unit of the Boston University School of Public Health studying S.M.A.R.T.\rquote 
s effectiveness in minimizing fetal exposures.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super 
\chftn }{  }{\i See id.}}}{\f0\fs24 
\par Pharmacists will only dispense Accutane if the patient presents a prescription with an Accutane Qualification Sticker.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The maximum quantity pharmacists may provide is a one month supply.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  They will also only fill prescriptions within seven days of the \'93qualification\'94 date}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   All patients will receive with the drug a Medication Guide detailing the drug\rquote 
s risks, and pharmacists will refuse requests for more Accutane without a new prescription or with only a phoned-in prescription.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   An independent audit of pharmacies will assess prescriber
\rquote s use of Accutane Qualification Stickers.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\b\f0\fs24 H.  Depression and Suicide
\par }{\f0\fs24 \tab While controversy over Accutane related birth defects has intensified, the alleged psychiatric risks of the drug have also garnered increasing attention.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ generally }{\i House Hearings}{, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{.}}}{\f0\fs24   Some suggest that Accutane causes depression and suicide.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par }\pard \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 No reports of either problem appeared in Accutane\rquote s original NDA safety database.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{,  (statement of Dr. Jonca Bull.)}}}{
\f0\fs24   Post-marketing, however, there were reports of depression in Accutane users.  Again education became the center of an Accutane risk management strategy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In the mid-1980s the drug\rquote s labeling was changed
 to provide, \'93Depression has been reported in some patients on Accutane therapy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In some of these patients, this has subsided with discontinuation of therapy and recurred with reinstitution of therapy.\'94}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24 
  The adverse reaction section of the labeling was also changed to explain, \'93
The following CNS reactions have been reported and may bear no relation to therapy: seizures, emotional instability, dizziness, nervousness, drowsiness, malaise, weakness, insomnia, lethargy and paresthias.\'94}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 \tab In 1996, an FDA physician noted two cases of suicide in a listing of recent adverse events associated with Accutane.}
{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ id}}}{\f0\fs24 
  FDA began a re-evaluation of the drug\rquote s potential link to suicide.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Dr. Bull noted that reports such as those noted in 1996 do not necessarily indicate a ca
usal relationship between depression and Accutane use.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Nevertheless, FDA epidemiology specialists investigated the potential link.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par \tab Although these investigators did not scientifically establish a causal relationship, they did make findings suggestive of a causal link.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   FDA compared the number of reports to the \'93
background rate,\'94 the rate of depression and suicide expected to be seen in the population likely to receive Accutane, teens and young adults.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   There were not many reports relative to the expe
cted incidence of these problems in the teen and young adult population.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Yet details of some of the reports warranted further attention.  Some of the patients had apparently never experienced psychiatric symptoms prior to their Accutane treatment; there was no other apparent reason for their symptoms.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Other patients experienced depression upon beginning Accutane therapy and reported that the symptoms ended soon after the treatment ended.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Some reported that the symptoms reappeared when Accutane therapy resumed.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par \tab On March 3, 1997, French officials required that suicide be listed as a possible side affect of the drug.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7846004}\chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Meeting of the Dermatologic and Opthalmic Drugs Advisory Comm
ittee 154 (September 19, 2000) (statement of Liam Grant, Chairperson of the Roaccutane Litigation Group) 154 available at }{\field\flddirty{\*\fldinst {\cf0  HYPERLINK "http://www.fda.gov" }{\cf0 {\*\datafield 
00d0c9ea79f9bace118c8200aa004ba90b0200000003000000e0c9ea79f9bace118c8200aa004ba90b2800000068007400740070003a002f002f007700770077002e006600640061002e0067006f0076002f000000}}}{\fldrslt {\cs22\ul\cf0 http://www.fda.gov}}}{
. [hereinafter 2000 Psychiatric Hearings].}}}{\f0\fs24 {\*\bkmkend _Ref7846004}  FDA began working with Roche in May 1997 to address the possibility of Accutane related depression.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 
\\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{, (statement of Dr.. Jonca Bull)}}}{\f0\fs24   In February 1998, Accutane\rquote s profe
ssional label in the U.S. was again changed to explicitly highlight the risk of suicide.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The label provided, \'93
Psychiatric Disorders: Accutane may cause depression, psychosis, and rarely suicidal ideation, suicide attempts and suicide.  Discontinuation of
 Accutane therapy may be insufficient; further evaluation may be necessary.  No mechanism of action has been established for these events. (see Adverse reactions: Psychiatric).\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The adverse reactions section listed, \'93
 psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis (see warnings: Psychiatric Disorders), emotional instability.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par }\pard \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
Doctors who might prescribe Accutane and those likely to see patients with psychiatric disturbances also received a letter about the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   A sp
ecial notice on the FDA website and a Talk Paper released to the press were also made available.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Yet Roche was also running media advertisements touting Accutane\rquote s pycho-social benefits; the company implied that by treating acne the drug improves the patient\rquote s state of mind, increasing confidence and social skills.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  On March 8, 1998, FDA requested that these advertisements end.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   FDA deemed the advertisements false and misleading.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par The patient information regarding Accutane had included mood changes as a \'93sign\'94 of potentially serious problem even before the 1998 professional labeling changes.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Patients were advised to stop taking Accutane and to contact their doctors if they experienced mood changes.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In 1998, FDA revised the patient information to provi
de specific information about the possible outcomes of a broader range of serious adverse events.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  An interim version of this re-designed information appeared in the summer of 2000 and described the possibility that suicide can result from the mood disorders.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  FDA critiqued this version and found that the risks were not fully described.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Roche agreed to explore further revisions.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Soon after the 1998 labeling change FDA and Roche embarked on further study of the possible connection between Accutane and psychiatric disorders.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Roche conducted several studies and participated in frequent working meetings with FDA.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Yet the studies provided no definitive evidence of a causal link between Accutane use and psychiatric disorders.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par In October 2000 Accutane\rquote s potential psychiatric risks received widespread attention when five-term Congressman and member of the House Committee with FDA oversight, Bart Stupak (D., Mich), and his wife Jamie appeared on }{\i\f0\fs24 NBC-TV\rquote 
s Today Show }{\f0\fs24 to discuss the May 2000 suicide of their 17-year-old son B.J. Stupak.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Interview by Matt Lauer with Congressman Bart Stupak and Mrs. Jamie Stupak, NBC Today Show (Oct. 5, 2000).}}}{\f0\fs24 
  The teenager shot himself in the head after a post-prom party thrown for his high school friends.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   B.J. Stupak had undergone Accutane therapy for seven months prior to his suicide and the Stupaks accused Accutane of causing his death.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Congressman Stupak criticized FDA\rquote s management of Accutane risks saying:
\par }\pard \ql \li720\ri0\sb100\sa100\sbauto1\saauto1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 {\f0\fs24 
All these people are dying, suicide thoughts, depressed, being hospitalized. The reports are coming into the FDA and they don't do anything? It takes you two and a half y
ears to put a warning on a package. Where are they? Who's watching out? If the watchdog, the FDA, is not watching out for our children, and the consumers and the parents, who's watching out for us?}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 Yet defenders of the drug and of FDA\rquote s risk management ef
forts argue that instead of being objective investigators of Accutane\rquote s risks, the Stupaks were grieving parents desperately seeking a reason for their son\rquote s death.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24 
  Indeed some suggest that their criticism of Accutane merely deflects attention from more likely contributors to their son\rquote s suicide\emdash their absence during his party and his access to alcohol and to a gun.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Connie Giovanni, }{\i 
Letters to the Editor: Acne Drugs and Suicide}{, }{\scaps Wash Post}{. (Jan. 15, 2001), at A20.}}}{\f0\fs24 
\par Nevertheless, the Dermatologic and Opthalmic Drugs Advisory Committee met again in September 2000.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ 2000 Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7846004 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800340036003000300034000000}}}{\fldrslt {300}}}{.}}}{\f0\fs24   It discussed these studies of Accutane\rquote s
 link to depression and noted that a controlled masked clinical study was unlikely due to ethical and technical reasons.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The Committee tried to explore other research strategies with the expert participants in the 2000 Committee hearings.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   After examini
ng the issue of psychiatric events, the Committee agreed that the risk remained uncertain.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Nevertheless, it considered the exploration of additional risk management strategies necessary because of the degree of concern about the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Specifically, it 
called for the addition of information about psychiatric adverse events to the consent form patients and physicians sign upon beginning Accutane therapy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The Committee also recommended that Roche provide an enhanced prescriber education program on psychiatric events and a Medication Guide for Accutane.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  These MedGuides, patient information books, are generally only required by FDA for the few drugs that it believes pose serious risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Further testimony on Accutane\rquote 
s possible association with psychiatric disorders took place before the House Committee on Government Reform in December 2000
\par The issue has also reached the courts.  On April 11, 2002, however, one jury rejected an Oklahoma\rquote s woman\rquote s claim for $3 million in compensatory damages for her psychia
tric problems; the plaintiff, 39-year-old Carla Gray, accused Roche of negligence, but Roche\rquote s expert witnesses testified that no study demonstrates a causal link between Accutane use and depression.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i Daily Briefing}{, }{\scaps Atlanta Jrnl & Const}{
. (Apr. 17, 2002), at 2D.}}}{\f0\fs24 
\par Nevertheless, another high profile law suit is now underway.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 
{\cs20\super \chftn }{  }{\i See}{ Richard Jerome and Don Sider, }{\i The Lost Boy: Grieving Mom Julie Bishop Blames and Acne Drug for her Son\rquote s Bizarre, Tragic Suicide}{, }{\scaps People}{ (Apr. 29, 2002), at 107.}}}{\f0\fs24 
  It was brought on April 15}{\f0\fs24\super th}{\f0\fs24  by Julie Bishop and Karen Johnson, the mother and grandmother respectively of 15-year old Charles Bishop , a St. Petersburg Florida teen who committed suicide by flying a stolen plane into the 28}
{\f0\fs24\super th}{\f0\fs24  floor of a Tampa building.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Karen Johnson has reported that her grandson had been taking Accutane twice daily for 10 months prior to his suicide and that the drug must have made him severely psychotic.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  She and her daughter now seek $70 million in a wrongful death action.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard\plain \s18\ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {Others are skeptical of Accutane\rquote 
s role in the suicide and even called concerns about Accutane and mental health risks \'93hysteria.\'94}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Phillip W. DeVous, }{\i Think Tank Wrap-up}{, }{\scaps United Press International}{, Jan 24, 2002. (arguing that no biological evidence supports the drug
\rquote s link with suicide and no trace of the drug was found in Charles Bishop\rquote s bloodstream following the suicide.)}}}{  One commentator views the allegations of Accutane\rquote s role in the suicide as symptomatic of society\rquote 
s misguided demand for definitive explanations of tragic situations.  She writes, \'93We want answers. Then we want to fix whatever it is that caused the bad thing to happen. The truth is, we cannot fix everything. There are not answers to everything.\'94
}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Sandra Thompson, }{\i 
Answers Are Elusive in Tragedy\rquote s Aftermath}{, }{\scaps St. Petersburg Times}{, Apr. 20, 2002, at 1B}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 Despite its contention that no 
evidence suggests that Accutane causes depression, Roche has sent to more than 10,000 dermatologists a brochure concerning depression and suicide.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Hobson, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{.}}}{\f0\fs24   FDA approved the brochure and Roche prepared it with the help of outside experts.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  The brochure informs dermatologists about the psychiatric issues most likely to be encountered in Accutane users and provides them with guidance in identifying signs of depression and other psychiatric disorders.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Accutane\rquote s alleged depression victims find it more difficult th
ose with Accutane related birth defects to prove that the drug caused their illness.  Yet the alleged risk has the potential to provide an even more compelling rationale for regulation.  Accutane\rquote 
s teratogenicity primarily puts fertile female patients and their unborn children at risk.  Psychiatric risks, by contrast, may effect both men and women, young and old  
\par }\pard\plain \s1\ql \li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {I.  Patent Expiration
\par }\pard\plain \ql \fi720\li0\ri0\sb100\sa100\sbauto1\saauto1\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
Roche itself has voiced new concerns about t Accutane\rquote s risks and the importance of Accutane regulation.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Lewis Krauskopf, }{\i Generic Accutane Faces Delays: Roche Calls for Stringent Safety Rules}{, }{\scaps The Record}{
 (Bergen County, NJ), Feb. 23, 2002, at A14.}}}{\f0\fs24   The last Accutane patent expired on February 7, 2002.  On February 5}{\f0\fs24\super th}{\f0\fs24 
, Roche filed a petition with the FDA asking it not to approve generic versions of the drug until generic manufacturers instituted the rigorous safety precautions Roche has already put in place.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Roche
 has argued that the distribution of generic versions of the drug could complicate the already difficult task of tracking fetal exposures to the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Critics of Roche allege that the petition is merely designed to ward off competitors; generic makers of the drug are usually able to sell their product more cheaply.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In the first nine months of 2001, Accutane was the company
\rquote s third best-selling drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{
\i See id.}}}{\f0\fs24   It accounted for $498 million in sales.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Mylan Laboratories reports that it expects to win approval of
 its generic version this year, and generics are predicted to captured at least 20 to 25 percent of the U.S. Accutane market within a year.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Although the Roche petition could delay approval of generic products, the safety concerns at stake are formidable}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   FDA is reviewing the petition and has 180 days to comment.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par 
\par }\pard\plain \s2\qc \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel1\adjustright\rin0\lin0\itap0 \b\scaps\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {IV.  Regulatory Dilemmas Exemplified by Accutane Regulation

\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 \tab 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 Accutane regulation and FDA\rquote s growing emphasis on post-approval controls emerge amidst  fundamental regulatory dilemmas.  These bas
ic tensions, inherent in a regime that seeks to maximize both drug safety and availability, are placed into sharp relief by the Accutane experience.
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }{\b\f0\fs24 
\par A.  Pre-Approval Clinical Testing:
\par }{\f0\fs24 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 Despite the increasing attention paid to post-approval regulation, Dr Jane Henney has emphasized, \'93
it is imperative that FDA maintain high standards in its pre-market decision-making and at the same time examine whether risks are managed throughout the healthcare delivery system.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Henney, supra note }{\field{\*\fldinst { NOTEREF _Ref7896420 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800390036003400320030000000}}}{\fldrslt {130}}}{, at 1.}}}{\f0\fs24   Pre-market drug testing plays an important role in ensuring drug safety.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Yet Accutane exemplifies the limits of even the most rigorous pre-market testing.  
\par To best investigate drug safety, pre-clinical tests should study the drug\rquote s effect on patients resembling those who will actually take the drug and under conditions that mirror those patients actual circumstances.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7763554 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 10.}}}{\f0\fs24 
  Yet the people for whom the drug is intended usually have characteristics that make them particularly vulnerable to the excessive danger of a pre-approval study\emdash illness and advanced age for example.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 11.}}}{\f0\fs24 
  Thus, the very patients most likely to use a drug post-marketing may be excluded from the pre-approval tests.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In addition, women and racial and ethnic minorities are often underrepresented in studies, despite increasing belief that
 drugs may affect different races and sexes differently.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Pregnant women are often excluded from clinical studies to avoid jeopardizing the health of the fetus.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In their place, laboratory animals are tested.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Yet sometimes even female laboratory animals are excluded because their hormonal changes complicate studies.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Pre-clinical testing of Accutane exemplifies this problem.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Laboratory tests showed that Accutane was teratogenic in rabbits and rats.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Thus, women were excluded from most test centers.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24  
 Elsewhere, female participants were subject to several requirements to prevent fetal exposures; they needed to have a negative pregnancy test before receiving the drug, use effective contraceptives while taking the drug and agree to abort any pregnancy c
onceived during treatment.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i 
See id.}}}{\f0\fs24   Because of these safeguards, no documented cases of Accutane related birth defects emerged from the tests.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   As a result, the drug\rquote 
s original labeling only reported that birth defects had occurred in laboratory animals.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Some h
ave criticized the omission of explicit reference to the risks of birth defects in humans and the failure to require that post-approval female patients comply with the same pregnancy prevention program required of female pre-approval test subjects.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   While
 Krause argues that ethical constrains often make the study of pregnant women infeasible, the Accutane experience suggests, for her, that special care should be taken to ensure that the potential risks to excluded test populations are well publicized.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par The Accutane experience also suggests that the most carefully designed pre-approval tests may fail to detect a drug\rquote s side effects.  There were no reports of psychiatric side effects during Accutane\rquote s clinical trials.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }
{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{ (statement of Dr. Jonca Bull)}}}{\f0\fs24   Accutane\rquote 
s link with depression remains uncertain and this may account for the lack of reports.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Reports of depression post-marketing are lower than reports of the illness in the general population.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Dr. Douglas G. Jacobs, Associate Clinical Professor of Psychiatry at Harvard Medical School and consultant to Roche, contends that there is no biochemical basis for Accutane\rquote s alleged association with psychiatric disorders.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }
{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{ (statement of Dr. Douglas G. Jacobs)}}}{\f0\fs24 
  Yet if depression is a rare side effect of the drug, then like many rare risks, it may only appear after much larger numbers of people use the drug outside of the controlled testing environment.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Teff, supra note }{\field{\*\fldinst { NOTEREF _Ref7794649 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390034003600340039000000}}}{\fldrslt {32}}}{, at 579.}}}{\f0\fs24 
  Some risks are so rare that they will only appear is a very small proportion of people treated with the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   FDA\rquote s post-marketing initiatives reflect growing acceptance of the \'93unpalatable truth\'94
 that mass marketing is mass experimentation.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super 
\chftn }{  }{\i See id.}}}{\f0\fs24   
\par Pre-approval testing is particularly ill-equipped to detect psychiatric risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ 2000 Psychiatric Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7846004 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800340036003000300034000000}}}{\fldrslt {300}}}{ (statement of Dr. Erick Turner, FDA), 101}}}{\f0\fs24 
  At the 2000 Advisory Committee Hearings, Dr. Erick Turner reported that \'93when these drugs are being developed, there\rquote s very rarely, if ever, an a priori suspicion that the drug might cause depression.  So, it\rquote 
s not rigorously looked for.  Usually this comes up post-marketing, and they\rquote re picked up as case reports by clinicians.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\par B.  Off-label Usage
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 Charles H. Stoney Jackson, Jr., father of an Accutane patient who committed suicide has demanded, \'93
How can a doctor prescribe a medication that is clearly licensed to be used as a treatment of last resort and for the most severe cases of acne.  Clay's [his son\rquote s] acne was very mild, there was no reason for Clay to be using Accutane.\'94}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{
, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{ (statement of Charles H. Stoney Jackson, Jr.)}}}{
\f0\fs24 
\par Once a drug is approved for marketing, individual doctors may decide how and when to prescribe that drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 12.}}}{\f0\fs24   Following company prescribing guidelines included in a drug\rquote s package insert is voluntary.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Of course, physicians are often encouraged to comply with the guidelines by the desire use the drug safely, to provide the best service to the patient and to avoid malpractice litigation.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{  1991  Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7839309 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, at 156 (statement of Dr. Mary Spraker) (arguing against limitations on off-label use of Accutane.)}}}{\f0\fs24 
  Yet off-label use is only indirectly constrained by these concerns.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Off-label usage is a feature of American drug regulation intimately connected with the traditional assumptions about pre-approval testing.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 12.}}}{\f0\fs24 
  If the FDA takes into account uses and abuses of the drug in addition to those for which the drug was originally developed, then the pre-approval trials would demonstrate the safety of most off-label uses.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 12.}}}{\f0\fs24   Indeed FDA\rquote 
s safety evaluation considers other probable uses or potential abuses of a drug when there is specific evidence that such use or abuse is likely to occur.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  However, the inherent limitations of the pre-approval process call into question the wisdom of off-label usage.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 12-13}}}{\f0\fs24   Off-label usage compounds the difficulty of generalizing safety results to patient populations that differ significant
ly from test groups and the risk of overlooking rare or long-term side effects.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 13}}}{\f0\fs24 
  The applicability of safety data to actual patient populations lessens as the drug is prescribed for conditions other than those for which the drug was intended.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Nevertheless, there are significant advantages to off-label usage.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Allowing off-label usage preserves physician autonomy and permits the doctors most familiar with the nuances of a patient\rquote 
s condition to determine that particular patient\rquote s need for a drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1991 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7839309 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, at 136 (testimony of Dr. Shupack)}}}{\f0\fs24   Strict constraints on a doctor\rquote 
s ability to prescribe off-label often require general practice rules that overlook the optimal treatment for the individual.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In addition, innovative uses of a drug may be discovered when physicians have the flexibility to prescribe off-label.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7763554 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 13}}}{\f0\fs24 
  It would be prohibitively expensive to test each potentially beneficial drug use from the laboratory stage forward.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par }\pard\plain \s18\ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
Because doctors may prescribe Accutane off-label, they have been able to treat other skin disorders with the drug.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{
 (testimony of Dr. Gary L. Peck) ( noting that Accutane has been used to treat acne fulmanenet, meyhahans hidradentitis supparativa and keratonization disorders)}}}{  In addition, the drug is used as a cancer treatment.}{\cs20\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
  Accutane contains fenretinide, a substance shown to kill cancer cells including cervical cancer and myeloid leukemia.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Carolyn Susman, }{\i \lquote Bad\rquote   Medicine Turned Good}{, }{\scaps Palm Beach Post}{, Apr. 4, 2002, at 1E.  }}}{
  Memorial Sloan Kettering currently uses the drug as part of its Neuroblastoma Program to combat the rare, and often fatal, childhood cancer.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
\par In stark contrast to Jackson\rquote s testimony is another father\rquote s applause of Accutane\rquote s off-label use; Scott Finestone credits Accutane with prolonging the life of his son, a neuroblastoma patient receives Accutane therapy.}{\cs20\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
  When administered along with bone marrow transplants, Accutane significantly improves remission in children with high risk neuroblastoma.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
  Doctors have also tried, albeit unsuccessfully to date, to use Accutane to treat non-small-cell lung cancer.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{  Prohibiting off-label use risks stifling such creativity.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
Nevertheless, many critics charge that Accutane is over-prescribed for milder acne cases.}{\cs20\f0\fs24\super {\*\bkmkstart _Ref7917994}\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Diane Knich, }{\i Acne Drug Safeguards; Acne Drug Restrictions, Pregnancy Tests Aim to Curb Birth Defects}{, }{\scaps Wash. Post}{, Apr. 9, 2002, at F01.  
}}}{\f0\fs24 {\*\bkmkend _Ref7917994}  As early as September 1983, Ralph Nader affiliated- Health Research Group charged that Accutane was being \'93overprescribed.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Hilts, supra note }{\field{\*\fldinst { NOTEREF _Ref7899821 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800390039003800320031000000}}}{\fldrslt {217}}}{.}}}{\f0\fs24   The drug had been approved in 1982 to treat \'93severe recalcitrant acne.\'94}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Critics have insisted that the drug was only intended for those with the most serious form of the disease; only in these cases did the drug\rquote s risks seem acceptable.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Yet the drug was widely touted in the media as a miracle cure for acne generally.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 21.}}}{\f0\fs24   
\par Worries about over-prescription dominated debates at the 1988 Advisory Committee Hearings.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i generally}{, }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{.}}}{\f0\fs24   Dr. David Graham, Group Leader of the Epidemiology Br
anch of the Office of Epidemiology and Biostatistics argued that Accutane was too frequently prescribed for mild acne cases.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 29 (statement of Dr. David Graham) (a
rguing that he found that excess of use in new female pat between the ages aged 15-44 could have been as high as 15-fold greater than those with the approved indication.)}}}{\f0\fs24 
  To limit off-label use, Public Citizen petitioned FDA in May 1988 to limit Accutane prescribing to board-certified or board eligible dermatologists.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ 2000 Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7846004 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800340036003000300034000000}}}{\fldrslt {300}}}{, at 198 (statement of Larry Sasich, Public Citizen).}}}{\f0\fs24 
  Dermatologists would have had to register with FDA and receive an FDA prescriber number under this scheme.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The petition demanded that Accutane prescribers certify that they had read and had promised to follow the drug\rquote s labeling and
 regulations.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
\f0\fs24   Public Citizen also called upon FDA to prohibit pharmacists from filling prescriptions from unregistered doctors and to subject both non-compliant doctors and pharmacists to criminal prosecution.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard\plain \s21\ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {Yet dermatologists participating in the 198
8 Advisory Committee hearings strongly disputed Graham\rquote s estimates and objected to the negative portrayal of the dermatologist they implied.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i e.g.,}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7795153 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{
, at 110 (statement of Dr. John H. Strauss, Professor and Head, Department of Dermatology, University of Iowa) (stating, \'93As a dermatologist, I feel we have been indicted on the basis of evidence that can be easily challenged.\'94)}}}{
  They regarded Graham\rquote s data and methodology as flawed and argued that most Accutane use was appropriate.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 113.}}}{  They also noted that Accutane prescriptions decreased dramatically since Accutane-related birth defects were first reported in 1983.}{
\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 110}}}{
  They also rejected Graham\rquote s claim that 85 percent of the female patients treated with Accutane had not initially been treated with antibiotics.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 97.}}}{
  Instead they argued that, in the vast majority of cases, dermatologists only use Accutane after ensuring that the patient\rquote s disease is resistant to safer forms of therapy.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {}}}{  
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 Yet, Dr. Lynn Silver, a pediatrician and public health expert 
on the staff of the Health Research Group, contended that regardless of the exact proportion of Accutane patients lacking the indicated condition, a significant amount of off-label use was occurring.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\
h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 146 (statement of Dr. Lynn Silver)}}}{\f0\fs24   For Silver, \'93 Even if only one-half of the prescriptio
ns for women was inappropriate this means that one-half of the birth defects and one-half of the abortions which occur to affected women, occurred to women who did not have a valid reason for taking this drug.\'94}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Silver\rquote s remarks beg a fundamental questio
n implicit in the off-label usage debate.  What exactly constitutes a valid reason for taking the drug?  Varying answers to the question reflect different conceptions of acne.  Although doctors of all specialties share the power to prescribe Accutane, the
y do not share a view on the appropriate circumstances in which to use it.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ generally }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{.}}}{\f0\fs24   Their disagreement reflects how notions of a disease influence its regulation.  
\par While many dermatologists view acne as incredibly intrusive on daily life, many pediatricians suggest that these concerns pale in comparison to the devastation of birth defects.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Indeed, Dr. James L. Mills of the National Institute of Child Health and Human Development, noted that the physicians present at the 1988 hearings were split into two opposing camps; the dermatologists and the pediatricians.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Dr. James L. Mills, }{\i 
Protecting the Embryo From X-rated Drugs}{, 333 }{\scaps N. Engl. Jrnl of Med}{. 124 (1995).}}}{\f0\fs24   
\par Dermatologists suggest that disfiguring acne causes as many emotional as physical scars.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i e.g.,}{ }{\i 2000 Pregnancy Prevention Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{
, at 210-211 (statement of Dr. Stephen L. Webster, former secretary-treasurer and president of the American Academy of Dermatology, a clinical professor of Dermatology at the University of Minnesota Medical School and a clinical practitioner in Wisconsin.
}}}{\f0\fs24   Dermatologists make a compelling claim that Accutane heals psychological as well as physical wounds.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24    This not
ion of Accutane was put forward at the 2000 Committee hearings by Dr. Stephen Webster.  One of his patients, a 22-year old female college graduate with cystic acne had a marketing degree and several job interviews, but \'93
her cystic acne is quite prominent, and in the marketing world this severely hampers her chance at a position.  This acne scars more than her skin, it also scars her self-image.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Severe cystic acne had a similar effect on a 24 year old investment banker Dr. Webster treated.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Dr Webster reports, \'93the marked facial acne cysts with a potential to scar make it difficult for him to establish his credentials\'85
will people invest their money with someone with an \lquote adolescent\rquote  disease like acne.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Thus for Dr. Webster, \'93The effects of cystic scarrin
g acne in any patient, but especially in young adults starting their careers, can be extensive and go beyond the skin by effecting their lives.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Similarly, Nancy Vargo, President of the Dermatology Nurses Association testified that a teenager in her family suffered from acne that \'93
lowered his sense of self-worth and confidence and inhibited his ability to establish relationships with his peer and with others\'85Accutane\'85not only cured his acne\'85but the teenager came alive\'85he can go about the business of growing up.\'94}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{
 at 191 (statement of Nancy Varga)}}}{\f0\fs24   
\par Yet others counter that Accutane-exposed babies rarely have the opportunity to grow up at all.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 46 (statement of Dr Graham)}}}{\f0\fs24 
  They are afflicted with severely disfiguring, physically and mentally debilitating disabilities that rarely afford them the chance to live independently.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Indeed, Krause suggests that the very severity of their condition makes it easy to overlook their plight.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 28.}}}{\f0\fs24 
  While many Thalidomide victims are of normal intelligence and can tell a compelling story of the challenges their disabilities present, Accutane victims cannot voice their suffering.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Indeed they may not even appear publicly in mere photographs.
}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{
, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{ (statement of Dr. Graham).}}}{\f0\fs24 
  At the 1988 Advisory Committee Hearings such photos were deemed so disturbing they were hidden from view.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Instead, the disabilities were merely discussed verbally.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Initially, Accutane patient labeling contained a photograph of a baby afflicted with Accutane-related birth defects.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 19.}}}{\f0\fs24   Later however, even this photo was replaced with a drawing, again making the victim\rquote 
s suffering seem less real.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i 
See id.}}}{\f0\fs24   By contrast, acne patients can speak of their trauma and were seen repeatedly.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{.}}}{\f0\fs24   Thus, care must be taken to adequately represent the plight of those exposed to Accutane during pregnancy.
\par This danger is far less likely to affect the alleged psychiatric victim
s of Accutane.  The high profile suicides of B.J. Stupak and Charles Bishop are anything but invisible.  At the September 2000 Advisory Committee Hearings, former Accutane patients testified to the psychiatric illnesses they had struggled with, allegedly 
as a result of their Accutane use.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{
\i See}{ }{\i e.g.}{ 2000 Psychiatric Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7846004 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800340036003000300034000000}}}{\fldrslt {300}}}{
, at 144 (statement of Kimberley Smith)}}}{\f0\fs24   Thirty-six year old Kimberly Smith described herself as an \'93Accutane survivor\'94
 after reporting that Accutane induced depression, edginess, stress and despair cost her her job and her sense of well-being.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Ms. Smith testified that although her skin cleared after taking Accutane, her life crumbled with the mood disorders she experienced.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Debate over Accutane\rquote s appropriate use reflects concerns about physician and patient autonomy.  Some scientists have taken a quantitative approach to defining severe cystic acne problem, noting, for example, definitions of \lquote severe\rquote 
 cystic acne as 10 or more deep cystic inflammatory lesions, each of 4 millimeter or more in diameter.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 24-25 (statement of Dr. David Graham)}}}{\f0\fs24   The drug\rquote s labeling defines severe recalcitrant nodul
ar acne stating, \'93Nodules are inflammatory lesions with a diameter of 5mm or greater.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  Roche, Accutane Label, 6 (2002), available at }{\field\flddirty{\*\fldinst {\cf0  HYPERLINK "http://www.fda.gov" }{\cf0 {\*\datafield 
00d0c9ea79f9bace118c8200aa004ba90b0200000003000000e0c9ea79f9bace118c8200aa004ba90b2800000068007400740070003a002f002f007700770077002e006600640061002e0067006f0076002f000000}}}{\fldrslt {\cs22\cf0 http://www.fda.gov}}}{/}{\cf17 cder}{
/drug/infopage/accutane/default.htm}}}{\f0\fs24   Yet doctors have questioned  the applicability of these quantitative approaches to the actual practice of dermatology.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1991 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7839309 \\
h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, 222, 134 (statement of Dr. Jerome L. Shupack)}}}{\f0\fs24   Dr. Jerome L. Shupack opposed special post-mar
keting restrictions on Accutane, arguing \'93you cannot practice medicine by committee,\'94 and explained:
\par }\pard\plain \s18\ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
I appreciate the efforts to quantitate [sic] what is quantitatable,[sic] but in the final analysis there are many factors which have not been looked at her
e, including, for one, the emotional impact of the disease, which you really cannot quantify in terms of the number of cysts or the number of pustules or what-have-you, which ends up going into the decision process\'85
there are aspects to duration which are a
lso quantifiable and which, again go into the decision-making progress [sic] on a day-to-day basis.  For example, how much money has the patient already spent on the treatment of acne during the preceding eight to 10 years, how many drugs has he taken, ho
w many side affects has he already had from the other drugs he has taken?}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par Dr. Shupack\rquote s remarks underscore one of the advantages of entrusting doctors with the decision to determine each patient\rquote s individual needs.  General definitions of severe acne and 
regulations based on uniform standards cannot captured the nuances of patient needs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In 1988, Dr. Gary Peck, Senior Investigator in the Dermatology Division of the NIH echoed Dr. Shupack\rquote s concerns asking:
\par }\pard\plain \s21\ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\par }\pard \s21\ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 {How many scars do you need, how many new acne c
ysts do you need while on conventional therapy?  How long do you have to remain on conventional therapy before you are deemed adequate to have Accutane.  I think this decision may vary with each physician.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\
h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{ (statement of Dr. Gary Peck).}}}{
\par }\pard\plain \s18\ql \fi720\li0\ri0\sb240\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\b\f0\fs24 C.  Adverse Reaction Reporting}{\f0\fs24 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 If physicians cur
rently have the authority to prescribe off-label, they also have the ethical responsibility to report adverse reactions to the drugs they prescribe.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 15.}}}{\f0\fs24 
  Yet the Accutane experience has highlighted weaknesses in a post-marketing surveillance programs reliant on voluntary physician reports.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par As discussed in Part II, FDA relies on an Adverse Event Reporting System (AERS) to detect adverse drug events.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Noah, supra note }{\field{\*\fldinst { NOTEREF _Ref7782337 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700380032003300330037000000}}}{\fldrslt {35}}}{.}}}{\f0\fs24   Health care professionals and consumers voluntarily submit MedWatch forms detailing adverse events.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The drug
 manufacturers receive approximately 94% of these forms and are required to submit them to FDA.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See 2000 Psychiatric Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7846004 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800340036003000300034000000}}}{\fldrslt {300}}}{ at 104-107 (statement of Dr. Marilyn Pitts, safety evaluator in the FDA Office of Postmarketing Research)}}}{\f0\fs24 
  These submissions must be submitted to FDA within 15 days if the event reported is serious and absent from the packages label.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The remainder of the MedWatch
 forms are sent directly to FDA from the consumer or health care professional.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   MedWatch forms are the basis for individual records stored in AERS, a computer database developed in 1969 and updated in 1997.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  These records undergo computer analysis to detect patterns of adverse reactions.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par The advantages of this system lie in its simplicity.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   A small number of reported events easily signals problems to FDA and prompts further investigation.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{.}}}{\f0\fs24   In addition, the system\rquote 
s simplicity makes it a relatively inexpensive surveillance device.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The system is also facilitates hypotheses generation regarding adverse events and provides valuable case material.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Nevertheless, FDA acknowledges the system\rquote s limitations.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The MedWatch forms often lack important data.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}}}{\f0\fs24   
Reporter often neglect to provide information requested of them.  The forms also request descriptions of the event, but the quality of these case studies varies.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i See id.}}}{\f0\fs24   
\par There is also substantial, unpredictable amounts of under-reporting.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24   Although manufacturers are required to do so, they rely on the voluntary reports of health care workers and consumers when making these reports.
}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24 
  Health care professionals and consumers may fail to report an event because they are unaware of the event or of its possible association with drug exposure.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24   They may also simply avoid the burdens of reporting.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24 
  Reporting also occurs unpredictably.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{
  See id.}}}{\f0\fs24   Serious publicized events may prompt reports, a Dear Doctor letter containing warnings about a drug or publications regarding the dr
ug in the scientific or lay media often sparks reports; events out of the public eye may go unreported}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24  
\par AERS reports signaled potential Accutane problems to FDA and prompted further action.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 16.}}}{\f0\fs24   Accutane related pregnancy outcomes were reported to FDA by mid-1983.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ id, at 7.}}}{\f0\fs24 
  In response, FDA was able to increase warnings against the drug\rquote s use in pregnant women and develop education campaigns about the drug\rquote s risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Similarly, reports of depression in Accutane users reached FDA via its passive post-marketing monitoring system by the mid-1980s.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i See}{ }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\
h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{ (statement of Dr. Jonca Bull)}}}{\f0\fs24   These reports prompted FDA to change the drug\rquote 
s labeling, educate dermatologists about psychiatric events and further investigate the potential psychiatric risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Yet AERS fails to provide the data essential to scientific investigation of the reported conditions.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 48 (statement of Dr. David Graham)}}}{\f0\fs24 
  An accurate assessment of the rates of pregnancy exposure to Accutane may be important in deciding how restrictive an Accutane pregnancy prevention program should be.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In 1988, Dr. Graham argued that pregnancy-e
xposure to Accutane had been greatly underreported under the passive surveillance system.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   There was often an extensive lag between the occurrence of an exposure and its report to FDA.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  In the months leading up to the 1988 hearings, FDA received reports of exposures that had occurred more than nine months prior to the report.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Dr. Graham also reported that induced abortion after an Accutane exposure is not regularly reported to FDA.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ }}}{\f0\fs24   Graham pointed to figures showing that 55 suspected pregnancy exposure
s from Michigan Medicaid and three from Group Health did not readily reach FDA\rquote s attention.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Concerns about \'93the inertia of physician reporting in the United States\'94 have been raise with regard to many drugs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In Accutane\rquote s case, the general problem of under-reporting may be exacerbated by an obstetrician\rquote 
s actual unawareness of a patient\rquote s Accutane use.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Dermatologists generally prescribe Accutane; patients may fail to inform their obstetricians of an Accutane prescription.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   If the patient\rquote s child then 
suffers a birth defect, the obstetrician may consider the defect a product of chance.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   As a result, Graham argued, \'93that the tip of the iceberg has been reported to the manufacturer and FDA.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  There is a whole universe of pregnancy exposure about which we have no direct information.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24  
\par Similar problems have arisen in studying Accutane\rquote s possible psychiatric risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ 2000 Psychiatric Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7846004 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800340036003000300034000000}}}{\fldrslt {300}}}{, at 101 (statement of Dr. Erick Turner).}}}{\f0\fs24 
  Indeed the detection and reporting of psychiatric problems like depression may be even more difficult.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id}}}{\f0\fs24   Dr. Turner reports that depression is a particularly under-recognized condition.  He explains: 
\par }\pard\plain \s18\ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
Symptoms are often not obvious and cannot be proven wit an x-ray or lab test which may lead to some increased reluctance on the part of the person to come forward and they might dismiss it thinking, well maybe it\rquote s all just in my head\'85
symptoms often get dismissed by both the person experiencing the depression, as well as perhaps family members or possibly even health care professionals.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id., at 96}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par Under-reporting may be especially prevalent in adolescents, a group especially likely to suffer from acne.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{., at 96-97.}}}{\f0\fs24 
  Adolescents often hide symptoms or have symptoms different from clinically depressed adults.  Adolescent drug and alcohol problems, a common symptom of depression, are often considered a cause of the illness.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{.}}}{\f0\fs24 
  Mood-swings are also frequently considered natural adolescent experiences rather than signs of depression.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Further complicating the problem is the possibility that patients perceptions of acne severity itself may contribute to depression.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   People may
 be especially unwilling to diagnose adolescents with a potentially stigmatizing disease.  
\par By limiting Accutane to certain prescribers and requiring patient registration, countries like Britain have monitored adverse events more closely.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Kolata, supra note }{\field{\*\fldinst { NOTEREF _Ref7766421 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360036003400320031000000}}}{\fldrslt {22}}}}}{\f0\fs24   As discussed fu
rther below, the advantages of closer monitoring may be outweighed disadvantages such as reduced drug availability.  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {D.  Accutane Education
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 \tab 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 Successful risk management is as much about communicating information as it is about gathering it.  Education, r
ather than distribution limitations, had been the hallmark of Accutane regulation from its approval in 1983.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 17-20.}}}{\f0\fs24   As increasing numbers of birth defects were reported in the 1980s, Accutane\rquote 
s labeling was consistently changed to include increasingly stronger, more detailed warnings.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Roche also advertised the drug\rquote s risk\rquote s in medical and pharmacy journals.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In May 1984, FDA\rquote 
s Dermatologic Drugs Advisory Committee rejected restrictions on the drug\rquote s availability and favored further warnings to ensure proper use and minimize its risks.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 18.}}}{\f0\fs24 
  These publicity efforts continued until the 1988 Advisory Committee suggested unusually strict limits on the drug\rquote s use.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Yet FDA was reluctant to limit access to the drug.  Instead it required risk communication measures such as revised patient labeling.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   On September 19, 1988, unique \'93Pregnancy Prevention Kits
\'94 were distributed.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{
 at 19.}}}{\f0\fs24   Labels then depicted children with typical Accutane related deformities, a \'93non-pregnancy symbol\'94 on every page.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Revised physician labeling advi
sed against prescribing the drug to patients who failed to understand its risks and that patients have a negative pregnancy test within 2 weeks of beginning treatment.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Also developed were a detailed informed consent form, a revised patient brochure also 
featuring the Accutane victim depiction, and blister packaging with non-pregnancy symbols on the packaging of each dose and tear-off post-cards for patients to provide information about informed consent.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   By October 1989, Roche had  launched an unusual ad
vertising campaign directed at dermatologists and stressing Accutane\rquote s risks rather than its benefits.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   By 1991, the company had also developed an Accutane videocassette for patients to view in the doctor\rquote s office.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 20.}}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 \tab Yet critics such as Public Citizen have regarded education and publicity as a the mere \'93
Pavlovian response to drug safety issues by manufacturers and the FDA.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1988 Hearings}{ supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 201 (statement of Larry Sasich)}}}{\f0\fs24   Public Citizen\rquote 
s suggestion that warnings have been a mere automatic reaction to Accutane risks overlooks the thoughtful care and preparation devoted to Accutane education campaigns.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Nevertheless, commentators have raised legitimate concern about the efficacy of the Accutane warnings.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 Krause lauded FDA for the creativity of its post-marketing Accutane education efforts, but critic
ized the initially lax warnings accompanying the drug; the drugs failure to clearly indicate that it could caused birth defects in human patients was troubling.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 21.}}}{\f0\fs24   In addition, Krause noted that literature based warnings written only in English might have m
ade it more difficult for the illiterate and non-English speakers to access information.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par Perhaps the most formidable obstacle to successful warnings were mass media reports of the drug\rquote s benefits. The portrayal of Accutane as a \'93miracle cure\'94 probably inc
reased consumer demand.  By contrast, physicians, rather than consumers, were the primary audience for many of the Accutane education efforts.  While Roche engaged in a risk education campaign, it also ran advertisements touting the drug\rquote 
s psychological benefits }{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i See}{ }
{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{, (statement of Dr.. Jonca Bull}}}
{\f0\fs24   Krause suggests that more intense mass media campaigns should have publicized Accutane\rquote s dangers.
\par At the 2000 Advisory Committee meeting, Dr. Peter Honig of FDA\rquote s Office of Postmarketing Drug Risk Assessment expressed FDA\rquote s waning confidence even in doctor-targeted warnings.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ 2000 Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, at 31 (statement of Dr. Peter Honig).}}}{\f0\fs24 
  Citing experiences with other drugs such as Seldane, Dr. Honig argued that labeling changes and passive educational campaigns have traditionally done relatively little to manage risk.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   He concluded, \'93I think it is clear tha
t labeling changes and Dear Doctor letters are relatively ineffective ways of communicating risk if your intention is changing behavior\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i Id.}}}{\f0\fs24 
\par Dr Honig detailed obstacles to translating education into action.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   His study points to labeling fatigue\emdash the difficult
y of changing behavior with numerous labeling revisions if the initial revisions are ineffective.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Information overload and the law of diminishing returns works against behavior change in these cases.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Citing research on clinical practice guidelines, Dr. Honig discussed factors limiting physicians\rquote  adherence to clinical practice guidelines.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Unawareness of the guidelines, lack of familiarity with them, disagreement with them and doubt that adherence will produce results can be major impediments to adherence.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In addition, \'93the inertia of previous practice\'94
 can contribute to the problem; as recommendations change frequently adherents to the most recent advice dwindles.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Finally, there are \'93external barriers\'94 of inconvenience and confusion.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 35.}}}{\f0\fs24   These external barriers may only worsen as managed care systems proliferate.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Noah, supra note }{\field{\*\fldinst { NOTEREF _Ref7782337 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700380032003300330037000000}}}{\fldrslt {35}}}{, at }}}{\f0\fs24   Shorter patient visits and patient-doctor relationships hinder education efforts.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Pregnancy prevention and psychiatric illness alike implicate sensitive personal issues difficult to discuss with strangers.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Frequent doctor changes and briefer visits are not conducive to such education efforts.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par Thus, as problems with effective education become apparent, emphasis on post-approval restrictions look more appealing.  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {E.  Post-Approval Controls
\par }\pard\plain \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 \tab 
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
Post-approval controls may minimize the occurrence of adverse events.  Yet these safety controls may also carry the price of limited drug access.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 1991 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7839309 \\
h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, at 157 (statement of Dr. Mary Stupak)}}}{\f0\fs24 
  Indeed by making it more difficult to obtain a drug, post-approval controls may foster an unregulated underground market for the drug featuring little, if any, safety precautions for drug users.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Safety controls can also intrude on the autonomy and privacy of the patients themselves, conditioning prescriptions on invasive requirements.  The Accutane experience illustrates all of these concerns.  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 \tab Some have proposed that Accutane should only be distributed from regional centers.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Such a program would mirror the British model of Accutane regulation under which Accutane may only be prescribed by a select group of dermatologists.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Kolata, supra note }{\field{\*\fldinst { NOTEREF _Ref7766421 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360036003400320031000000}}}{\fldrslt {22}}}{.}}}{\f0\fs24 
  Patients are referred to one of these specialists by their own doctors and must be warned of the risks of pregnancy, given a written warning, required to sign a consent form and to agree to an immediate abortion if they become p
regnant while taking the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i 
See id.}}}{\f0\fs24 
\par \tab Dr. Mary Spraker objected to this proposal citing concerns about inconvenience to the patient, increased cost and a questionable reduction of actual pregnancy exposures.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See }{\i 1991 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7839309 \\h 
}{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, at 157 (statement of Dr. Mary Spraker)}}}{\f0\fs24   This \'93regional center\'94 concept may make it far more
 difficult for patients outside of major cities to obtain the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Patients from rural areas may have to travel miles for care.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 2000 Pregnancy Prevention Hearings}{, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7839298 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, at 178 (statement of Dr. Barbara Reed, dermatologist, American Academy of Dermatology.)
}}}{\f0\fs24   Even city residents could find it difficult to find a registered pharmacy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   The program imposes both physical and psychological barriers to Accutane use.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  By forcing a patient to switch from an unregistered to an registered doctor, we disrupt a crucial doctor-patient relationship in which the evaluation of a patient\rquote s reliability and the necessity of discussing sensitive pre
gnancy prevention issues are paramount concerns.  Financial barriers may also rise.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Dr. Spraker further argues that such a regulatory system would increase the cost of the already expensive Accutane.}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See }{\i 1991 Hearings}{, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7839309 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, at 157.}}}{\f0\fs24   The tightly monitored anti-psychotic drug Clozapine 
has effectively been rationed by the price increases under its mandatory monitoring system.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24   
\par \tab In addition, Dr. Spraker questioned the ultimate efficacy of a \'93center use\'94 approach.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   She noted that despite receiving pregnancy counseling and receiving the 
drug from a limited center patients can still become pregnant while using the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24 
  Dr. Barbara Reed likened conception while on Accutane to other risk-taking behaviors such as reckless driving and doubted that any amount of monitoring and education could \'93legislate pregnancy prevention.\'94}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See }{\i 2000 Pregnancy Prevention Hearings}{, supra note }
{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, at 179.}}}{\f0\fs24 
\par \tab Indeed, such a regulatory regime might spur unauthorized use of the drug, a phenomenon likely to produce more, not less, pregnancy exposures.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{.}}}{\f0\fs24   The regime might pressure people to engage in drug sharing.
}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i id}{.}}}{\f0\fs24 
  Alternatively, those unable to obtain the drug legally may look to underground markets.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Recently, Accutane was found among several prescription drugs seized in a raid of Contra Costa, California supermarkets.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Kate Darby Rauch, }{\i 
Contra Costa County Seizes Hundreds of Illegal Pharmaceuticals in Raid}{, }{\scaps Contra Costa Times}{, Apr. 19, 2002.  }}}{\f0\fs24   The drugs, which appear to have been manufactured in Me
xico, were sold over-the-counter to anyone with the ability to pay.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   California officials suspect that the practice is widespread.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 The Internet may only exacerbate this problem.  The Roaccutane Action Group has alleged that it has already obtained Accu
tane by placing an online order for the drug under the names of teenagers.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ 2000 Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, 147 (statement of Liam Grant) (Roaccutane is the trade name of Isotretinoin in Britain.)}}}{\f0\fs24 
  It received the drug from South Africa within only 10 days of the request, accompanied by a prescription from a doctor with a South African address.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{ at 157.}}}{\f0\fs24   The Group paints a frighteni
ng portrait of Internet drug marketing explaining, \'93all you need is a credit card.  No medical consultation.  No meeting between patient and doctor.  No blood tests.  No birth control safeguards.  No monitoring of patients.\'94}{\cs20\f0\fs24\super 
\chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }\pard\plain \s1\ql \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel0\adjustright\rin0\lin0\itap0 \b\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {F.  Patient Autonomy
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par While c
oncern about the underground drug market centers on its extreme lack of government regulation, critics of post-marketing regulation worry about excessive government intrusions.  Just as dermatologists have called for physician autonomy, many participants 
in the Accutane debate have called for patients\rquote  autonomy, particularly female patient\rquote s autonomy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Krause, supra note }{\field{\*\fldinst { NOTEREF _Ref7763554 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360033003500350034000000}}}{\fldrslt {3}}}{, at 28.}}}{\f0\fs24   
\par Concerns about fetal exposure are well justified.  A fetus exposed to Accutane only 15 days after fertilization may suffer from birth defects and many wome
n are unaware of their pregnancies at this point.  Effectively monitoring pregnancy status is thus particularly important during Accutane therapy.  Indeed, some have asked if a self-pregnancy test could accompany each daily dose of the drug to facilitate 
monitoring.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 200
0 Pregnancy Prevention Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, 252.}}}{\f0\fs24 
 (252).  In a similar vein, some have suggested that patients be required to prove that they use several forms of contraception.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{  }{\i 2000 Pregnancy Prevention Hearings}{, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7839298 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{
, at 289 (statement of Dr. Michael Greene, Department of Obstetrics and Gynecology, Mass General Hospital).}}}{\f0\fs24   Others advocate the mandatory use of injectable contraceptives.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id. }}}{\f0\fs24 
\par Among the most passionate advocates of pregnancy prevention measures are thalidomide victims.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See 2000 Pregnancy Prevention Hearing, supra note }{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, at 206 (statement of Randall Warren, CEO of the Thalidomide Victims Association.)}}}{\f0\fs24 
  The Thalidomide Victims Association of Canada testified at the 2000 Advisory Committee hearings in support of pregnancy prevention measures.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24   The group was formed in 1988 to support and empower Canadian \'93
thalidomiders\'94.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{
\f0\fs24   In 1995, the Association became involved in the thalidomide licensing issue; it demanded the implementation of a mandatory compliance program to minimize pregnancy exposures to thalidomide used in women with severe illnesses.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24   Thalidomide wa
s licensed under the restrictive STEPS program which requires a mandatory physician, patient and pharmacy registry.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{\f0\fs24   Only those registered may prescribe, dispense or use the drug.  Registry is prohibitively expensive and few if any doctors in private prac
tice can afford those cost.  In addition, relatively few patients have been registered.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i House Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7834885 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330034003800380035000000}}}{\fldrslt {37}}}{. (statement of  Dr. Pariser)}}}{\f0\fs24 
\par Since then the Thalidomide group has become involved in debates over the management of many teratogenic drugs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See 2000 Pregnancy Prevention Hearing, supra note }{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, at 206 (statement of Randall Warren, CEO of the Thalidomide Victims Association.)}}}{\f0\fs24   It is determined \'93
to remind those making these decisions [as to the risks and benefits of Accutane] that the risks can always be lessened by responsible thinking\'85
If mandatory compliance lessens pain for just one family, creating one less victim, it is worth it.  No amount of compensation can amount to a healthy body.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id., at 209.}}}{\f0\fs24 
\par }\pard\plain \s18\ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {Accutane\rquote 
s use in teenagers makes the risk of pregnancy exposure more troubling.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{, at 148 (statement of Dr. Lynn Silver)}}}{
  Teenagers often fail to report their sexual activity and are especially unlikely to use birth control.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See }{\i 1988 Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7795153 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700390035003100350033000000}}}{\fldrslt {2}}}{. (statement of Dr. Nancy Lee, Division of Reproductive Health, CDC)}}}{  As Dr. Amarilyas Vega noted, \'93
We know that sexual activity status from not being sexually active to becoming sexually active may change overnight.\'94}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 2000 Pregnancy Prevention}{ hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, 51 (statement of Dr. Amarlyas Vega)}}}{  This is particularly true for adolescents.}{\cs20\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i See id.}}}{
  They often report that they fail to use birth control because they do not expect to have intercourse.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{  Despite reporting abstinence to their dermatologists, they may unwittingly expose their unborn child to Accutane.}{\cs20\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See id.}}}{
  As the Thalidomide Victims Association reminds, the consequences of such exposures could be devastating.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See }{\i 2000 Pregnancy Prevention Hearings}{, supra note }{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, at 206 (statement of Randall Warren).}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 However, the competing interest in patient auton
omy counsels against restrictive drug regulatory regimes.  Dr. Michael Greene expressed alarm at some of the pregnancy prevention programs contemplated by fellow participants in the 2000 hearings.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 2000 Pregnancy Prevention Hearings}{, supra note }{\field{\*\fldinst {
 NOTEREF _Ref7839298 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, (statement of Dr. Michael Greene)}}}{\f0\fs24 
  For him, many of these schemes would intrude too deeply on women\rquote s autonomy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{ }{\i See id.}}}{\f0\fs24   He explained:
\par }\pard\plain \s18\ql \li720\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin720\itap0 \fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {If a woman is fully informed \endash  I\rquote 
m not talking about a child or a minor, but if a fully informed woman says that she is abstinent and says that, recognizing everything that we\rquote ve had to say about the risks associated with taking Accutane that she doesn\rquote t need and doesn
\rquote t want contraception, I would have a tough time telling that adult woman that she can\rquote t make that decision for herself, as an obstetrician/gynecologist.  So I view with a little bit of alarm some of what I 
consider to be rather draconian proposals that would ride roughshod over an adult, competent woman\rquote s autonomy.}{\cs20\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par Dr. Barbara Reed, a dermatologist who initially spent 12 years practicing gynecology, opposed mandatory registration of Accutane patients for similar reasons.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 179 (statement of Dr. Barbara Reed)}}}{\f0\fs24 
  She suggests the dangers of a slippery slope that would increasingly limit women\rquote s freedom in the name of the unborn.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  For her, Accutane use implicates the same issues involved in fetal alcohol syndrome and other diseases related to a pregnant women\rquote s risky behavior.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{.}}}{\f0\fs24   Reed asks, \'93
Are we going to have a registry for buyers and sellers of non-steroidal anti-inflammatory drugs and alcohol.  Cigarettes is another one.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{.}}}{\f0\fs24 
\par These concerns are not new.  At the 1991 Advisory Committee hearings, Dr. Mary Spraker, a practicing academic pediatric dermatologist, rejected proposals that every patient take an oral, injectable or implant able contraceptive, despite the patient
\rquote s commitment to abstinence or the continued use of her current contraception device.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  See 1991 Hearings, supra note }{\field{\*\fldinst { NOTEREF _Ref7839309 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003300300039000000}}}{\fldrslt {201}}}{, at 158 (statement of Dr. Mary Spraker.)}}}{\f0\fs24 
  Dr. Spraker insisted that the patient should possess the ultimate power to make contraceptive decisions; she argued that doctors should respect a patient\rquote 
s unwillingness to undertake the risks of contraceptive use, to experience invasive device placement procedures or to incur the expense of implant able contraceptives.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   She argued, \'93
 The patients, once given the alternatives with the prospective pros and cons, has the right to participate in the choice of her own contraceptive.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{.}}}{\f0\fs24   We need to recogn
ize that as physicians we can guide our patients, but we do not have, and do not want, the power to control them.\'94}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id}{.}}}{\f0\fs24 
\par Perhaps most invasive are requirements found in some European countries, such as Britain, mandating that female Accutane patients agree to abort any pregnancy that occurs while taking the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Kolata, supra note }{\field{\*\fldinst { NOTEREF _Ref7766421 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700360036003400320031000000}}}{\fldrslt {22}}}{.}}}{\f0\fs24 
  Such a proposal in U.S. drug regulation would directly engage the controversial abortion issue.  Roche\rquote s pregnancy counseling program includes discussion of emergency contraception and the \lquote morning-after pill,\rquote 
 and at least some commentators have argued that Roche should pay for the therapeutic abortions often elected by women whose children have been exposed to the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 2000}{ }{\i Pregnancy Prevention Hearings}{, supra note }
{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, at 223.}}}{\f0\fs24 
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
\par }{\b\f0\fs24 G.  System to Manage Accutane Related Teratogenicity (S.M.A.R.T.)
\par }\pard \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 FDA announced its new S.M.A.R.T program amidst this debate.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ FDA Press Office, supra note }{\field{\*\fldinst { NOTEREF _Ref7917742 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003900310037003700340032000000}}}{\fldrslt {266}}}{, at 1}}}{\f0\fs24   The program reflects FDA\rquote 
s growing commitment to more active post-marketing regulation.  Yet it also illustrates continued respect for both patient and doctor autonomy.  While S.M.A.R.T. includes unusually r
estrictive post-approval drug regulation, it does not go as far in monitoring and limiting Accutane use as many advocates for Accutane controls would have liked.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Knich, supra note }{\field{\*\fldinst { NOTEREF _Ref7917994 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003900310037003900390034000000}}}{\fldrslt {402}}}{.}}}{\f0\fs24   Indeed S.M.A.R.T. is not as dramatic a departure from the traditional focus of Accutane regu
lation on warnings and education, rather than distribution limitations.
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 \tab 
S.M.A.R.T. exemplifies the kind of active post-marketing regulation contemplated by the Task Force.  Rather than merely recommending that doctors test female patients for pregnancy, t
he program requires that two pregnancy tests be performed both prior to commencing therapy and each month thereafter throughout the course of the therapy.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ FDA Press Office, supra note }{\field{\*\fldinst { NOTEREF _Ref7917742 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003900310037003700340032000000}}}{\fldrslt {266}}}{, at 1.}}}{\f0\fs24   Prescribers sign a \'93Letter of Understanding\'94
 promising to perform these tests.  The program similarly requires the choice of two forms of birth control, unless absolute abstinence will be practiced during therapy and for one month after its completion, or the patient has had a hysterectomy.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Placement of the Accutane Qualification sticker on the doctor\rquote s prescription form certifies compliance with the safeguards.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  These measures are unusually specific and mandatory.  In addition, signing and returning the form essentially registers the doctor to prescribe the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   In addition patients are required t
o sign and return an informed consent form which effectively registers them as well.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par \tab Also unusual is S.M.A.R.T.\rquote s prohibition of pharmacy distribution of Accutane to those without an Accutane Qualification sticker.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Roche had questioned the wisdom of 
placing pharmacists in an essentially regulatory role with regard to doctors and argued that such a role extends beyond pharmacy practice guidelines by intruding too extensively on the practice of medicine.}{\cs20\f0\fs24\super \chftn {\footnote 
\pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ }{\i 2000 Pregnancy Prevention Hearings}{, supra note }
{\field{\*\fldinst { NOTEREF _Ref7839298 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003800330039003200390038000000}}}{\fldrslt {1}}}{, at 153.}}}{\f0\fs24 
  Yet S.M.A.R.T. forbids pharmacists from filling prescriptions lacking the sticker.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ FDA Press Office, supra note }{\field{\*\fldinst { NOTEREF _Ref7917742 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003900310037003700340032000000}}}{\fldrslt {266}}}{, at 2.}}}{\f0\fs24   It also requires them to fill prescriptions within seven days of the prescription\rquote 
s date and to distribute a large medication guide with the drug.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Knich, supra note }{\field{\*\fldinst { NOTEREF _Ref7917994 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003900310037003900390034000000}}}{\fldrslt {402}}}{.}}}{\f0\fs24   One pharmacist has called the measures \'93extraordinary\'85almost a matter of overkill.\'94}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
\par \tab These limitations fall squarely within the post-approval controls suggested by the Task Force on Risk Management.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Report, supra note }{\field{\*\fldinst { NOTEREF _Ref7779381 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003700370039003300380031000000}}}{\fldrslt {41}}}{, at 92-94}}}{\f0\fs24   The Report explicitly suggested the imposition of safety programs for risky products. }{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{.}}}{\f0\fs24 
  It noted increasing acceptance by the medical profession\rquote s acceptance of post-marketing regulation of such programs.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}{, at 92.}}}{\f0\fs24   Press reports on S.M.A.R.T. label it \'93unusually strict\'94
 and note its departure from traditional reliance solely on medical professionals to informally implement pregnancy prevention standards.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Knich, supra note }{\field{\*\fldinst { NOTEREF _Ref7917994 \\h }{
{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003900310037003900390034000000}}}{\fldrslt {402}}}{.}}}{\f0\fs24 
\par \tab Nevertheless, Public Citizen argues that S.M.A.R.T. is not enough of a departure from tradition.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Dr. Sidney Wolf continues to call for limitation of Accutane prescribing to select specialists.  He remains concerned about possible 
over-prescription of the drug and views the limitation on prescribers as the best means of combating the problem.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   S.M.A.R.T., however, is more protective of preserving access to the drug.  It is also more protective of women\rquote 
s autonomy than other proposals for more restrictive regimes.  Unlike proposals ventured at Advisory Committee Hearings, the program also permits those who promise to practice absolute abstinence to forgo birth control while taking the drug.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  In addition, the Continuing Medical Education course that Roche has developed for physicians remains optional.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ FDA Press Office, supra note }{\field{\*\fldinst { NOTEREF _Ref7917742 \\h }{{\*\datafield 
08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003900310037003700340032000000}}}{\fldrslt {266}}}{, at 2.}}}{\f0\fs24   The program certainly does not mandate the termination of pregnancies conceived during therapy.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   
\par \tab Although the program is easily categorized as a form of \'93risk intervention\'94 in the language of the Task Force\rquote 
s Report, its primary means of effecting change may occur through its risk communication aspects.  The required consent forms, and Letters of Understanding and Medication Guides contain substantive information on risks.}{\cs20\f0\fs24\super \chftn 
{\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24   Yet, in 
themselves, the very hurdles doctors and patients must clear in order to obtain the drug signals the perceived importance of the risks at stake.  Regardless of the content of the warnings, these obstacles alone communicate FDA\rquote 
s concerns about pregnancy pr
evention.  Thus it may have a cautionary effect on both prescribers contemplating the appropriateness of Accutane therapy for their patients and on patients engaging in a pregnancy prevention strategy.  The program mandates certain behavior\emdash 
the frequent pregnancy tests and use of birth control in sexually active women\emdash but it has a large educational component as well.}{\cs20\f0\fs24\super \chftn {\footnote \pard\plain 
\s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See id.}}}{\f0\fs24 
  Thus it follows in the tradition of the risk communication emphasis in Accutane regulation.  
\par \tab Yet according to Jonathan Wilkin, director of FDA's Division of Dermatologic and Dental Drug Products Division, FDA is prepared to impose even stricter regulation if S.M.A.R.T. fails to reduce Accutane \endash related birth defects.}{
\cs20\f0\fs24\super \chftn {\footnote \pard\plain \s19\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs20\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs20\super \chftn }{  }{\i See}{ Knich, supra note }
{\field{\*\fldinst { NOTEREF _Ref7917994 \\h }{{\*\datafield 08d0c9ea79f9bace118c8200aa004ba90b02000000080000000c0000005f0052006500660037003900310037003900390034000000}}}{\fldrslt {402}}}{.}}}{\f0\fs24 
  Thus S.M.A.R.T. may be just the beginning both of Accutane\rquote s post-marketing controls and of post-marketing regulation more broadly in American drug policy making.  
\par 
\par }\pard\plain \s2\qc \li0\ri0\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel1\adjustright\rin0\lin0\itap0 \b\scaps\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {V.  Conclusion
\par }\pard\plain \ql \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f108\fs22\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 
\par Accutane exemplifies the central conflict in drug regulation between ensuring drug safety and maximizing drug availability.  The Acutance experienc
e reflects a growing trend towards recognizing the need for stronger post-marketing drug regulation in striking the correct balance between these goals.  S.M.A.R.T. takes a dramatic step towards implementing the risk management suggestions of the Task For
ce on Risk Management in the fight to protect patients from Accutane\rquote 
s teratogenic risks and alleged psychiatric consequences.  Yet, perhaps wisely, it does not impose as intrusive a regulatory regime as possible thereby preserving as much patient and physi
cian independence as possible in combating a potentially serious illness.  
\par }\pard \ql \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f0\fs24 
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