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{\author Julia Claire Green}{\operator Chad and Sarah Ludington}{\creatim\yr2003\mo2\dy21\hr13\min37}{\revtim\yr2003\mo2\dy21\hr13\min37}{\printim\yr2002\mo3\dy19\hr19\min27}{\version2}{\edmins1}{\nofpages40}{\nofwords9481}{\nofchars54046}
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\par }\pard \s29\qr \li0\ri360\widctlpar\tqc\tx4320\tqr\tx8640\aspalpha\aspnum\faauto\adjustright\rin360\lin0\itap0 {\f1\fs20  Julia Green, page
\par }}{\headerf \pard\plain \s28\ql \li0\ri0\widctlpar\tqc\tx4320\tqr\tx8640\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\par }}{\footerf \pard\plain \s29\ql \li0\ri0\widctlpar\tqc\tx4320\tqr\tx8640\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\par }}{\*\pnseclvl1\pnucrm\pnstart1\pnindent720\pnhang{\pntxta .}}{\*\pnseclvl2\pnucltr\pnstart1\pnindent720\pnhang{\pntxta .}}{\*\pnseclvl3\pndec\pnstart1\pnindent720\pnhang{\pntxta .}}{\*\pnseclvl4\pnlcltr\pnstart1\pnindent720\pnhang{\pntxta )}}
{\*\pnseclvl5\pndec\pnstart1\pnindent720\pnhang{\pntxtb (}{\pntxta )}}{\*\pnseclvl6\pnlcltr\pnstart1\pnindent720\pnhang{\pntxtb (}{\pntxta )}}{\*\pnseclvl7\pnlcrm\pnstart1\pnindent720\pnhang{\pntxtb (}{\pntxta )}}{\*\pnseclvl8
\pnlcltr\pnstart1\pnindent720\pnhang{\pntxtb (}{\pntxta )}}{\*\pnseclvl9\pnlcrm\pnstart1\pnindent720\pnhang{\pntxtb (}{\pntxta )}}\pard\plain \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f1\fs22 
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\par }\pard\plain \s27\qc \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f1\fs22\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\fs32 Babies, Blemishes and FDA:
\par }\pard \s27\qc \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\fs32  A History of Accutane Regulation in the United States
\par 
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\par }\pard \s27\qr \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {By Julia Green
\par Harvard Law School
\par Food and Drug Law
\par Peter Hutt
\par  March, 2002
\par }\pard \s27\qj \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\page }{\b 
\par }{The acne drug Accutane is one of the most dangerous products on the market today.  The drug causes serious side-effects, most notably birth defects.  Accutane is also one of the most effective prescription drugs available.  This combination\emdash 
unique efficacy coupled with unique risk\emdash has posed a serious challenge for the Food and 
Drug Administration (FDA).  Over the past two decades, FDA has grappled with how manage the completely preventable but persistently serious problem of Accutane-induced birth defects.  On several occasions, the product spurred FDA to take unprecedented reg
ulatory action.
\par }\pard\plain \qj \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f1\fs22 
In 1975  when American researchers for Hoffmann-La Roche began studying the chemical, isotretinoin, they were struck by its remarkable effectiveness.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Accutane and Pregnancy}{\i\scaps\f1 , }{\scaps\f1 Wash. Post}{\f1 
, Apr. 26, 1988 at A17.}}}{\f1\fs22   The drug, which Roche Laboratories sells as Accutane, is an extremely powerful antidote t
o acne, unmatched by any other treatment.  85% of patients who take Accutane achieve full remission after a typical course of treatment (about five months).}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Robert S. Stern, }{\i\f1 
A Uniquely Effective Drug Is Teratogenic:  The Case of Isotretinoin, }{\f1 320 }{\scaps\f1 New Eng. J. Med }{\f1 1007 (1989).}}}{\f1\fs22   Because of its exceptional power to cure acne, Accutane has been praised as a \'93miracle drug.\'94}{
\cs18\f1\fs22\super \chftn {\footnote \pard\plain \ql \li0\ri0\nowidctlpar\faauto\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\fs20\super \chftn }{\f1\fs20  }{\i\f1\fs20 See e.g.}{\f1\fs20  Jennifer Frey, }{\i\f1\fs20 
For the Stupaks, 'Miracle' Drug Casts a Light on Son's Suicide}{\f1\fs20 , }{\scaps\f1\fs20 Wash. Post, }{\f1\fs20 Jan. 19, 2001, at C1.}}}{\f1\fs22   Just last year, }{\i\f1\fs22 FDA Consumer Magazine}{\f1\fs22 \emdash FDA\rquote s own magazine\emdash 
pronounced the drug \'93the biggest breakthrough in acne drug treatment over the last 20 years.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Michelle Meadows, }{\i\f1 The Power of Accutane, }{\scaps\f1 FDA Consumer}{\f1 , Mar. 1, 2001, at 18.}}}{\f1\fs22 
\par }\pard \qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\f1\fs22 \tab This may seem like undue attention for a simple pimple remedy, but in actuality severe acne can be a seriously debilitating condition.  A recent article in the }{
\i\f1\fs22 Archives of Family Medicine }{\f1\fs22 noted, \'93Although acne is not a life-threatening disease, it has significant physical and psychological ramifications such as permanent scarring, poor self-image, social inh
ibition, depression and anxiety.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 Diane Thiboutot, }{\i\f1 New Treatments and Therapeutic Strategies for Acne,}{\f1  9 }{\scaps\f1 Arch. Fam. Med}{\f1  179, 179-180 (2000).}}}{\f1\fs22   The type of acne indicated for Accutane treatment\emdash severe recalcitrant cystic acne\emdash 
is an extremely disfiguring condition caused by a chronic oil and gland disorder.  Much more than the familiar blackheads, the condition i
s marked by tremendous pus filled lesions which typically spread across the entire face and neck leaving behind pitted scars.  One FDA official noted that the cysts can be }{\f1\fs22\cf1 so "cosmetically crippling that {\*\bkmkstart Document0zzSDUNumber4}
{\*\bkmkend Document0zzSDUNumber4}people cannot get jobs."}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs18\f1\super \chftn }{\f1  }{\f1\cf1 Cristine Russell, }{\i\f1\cf1 FDA Steps Up Warnings to Doctors, Blood Banks on Risks of Acne Drug,}{\f1\cf1  }{\scaps\f1 Wash. Post}{\i\f1\cf1 , }{\f1\cf1 
Mar. 30, 1984, at A1 (quoting Dr. Carnot Evans, an FDA medical officer).}}}{\f1\fs22\cf1   A patient described in the }{\i\f1\fs22\cf1 Journal of the American Medical Association }{\f1\fs22\cf1 (}{\i\f1\fs22\cf1 JAMA}{\f1\fs22\cf1 
) became so displeased  by his appearance that he dropped out of college.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Acne Drug Depression Warnings Highlight Need for Expert Care,}{\f1  279 JAMA 1057 (1998).}}}{\f1\fs22\cf1 
  According to Jennifer Hansen, a 21 year-old taking Accutane who keeps an online Accutane journal, }{\f1\fs22\cf1 "This medicine has given me my 
life back. . . .  I am now confident, happy and very excited about life.  I no longer feel inferior and can actually look people in the eyes."}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Jennifer Hansen, }{\i\f1 Jenn\rquote s Accutane Journal, }{\f1 (2002) }{\i\f1 at }{\f1 
http://jmhpr.tripod.com/accutanediary/index.html.  There is no indication that Jennifer Hansen is affiliated with Roche\rquote s pharmaceutical company, Hoffmann-La Roche.  The very fact that this young adult keeps a
 journal dedicated to her experiences with Accutane\emdash and posts it on the internet\emdash testifies to the power of the drug.}}}{\f1\fs22\cf1 
\par \tab Since its release, Accutane has provided tremendous revenue to its marketer, Roche;  the drug brings in over $700 million a year for the Swiss company\rquote 
s prescription drug unit, Hoffmann-La Roche.  About 12 million people worldwide (including 5 million Americans) have taken Accutane, which is called Roaccutane outside the United States.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Mary Duenwald, }{\i\f1 After 20 Years, Debate Over Drug Persists, }{\scaps\f1 N.Y. Times}{
\f1 , Jan. 22, 2002 at F7.}}}{\f1\fs22\cf1   In 2000, Accutane sales totaled $759.4 million\emdash 8% of total prescription drug sales.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1\cf1 Roche's U.S. Patent for Accutane Expires}{\f1\cf1 , Wa
ll St. J., Feb. 13, 2002, at B9.}}}{\f1\fs22\cf1 
\par \tab But as productive as it is, both as a money-maker and a therapy, Accutane also has the potential to destroy lives.  Accutane is an extremely dangerous teratogen:  it can cause severe birth defects 
when taken during pregnancy.  About one quarter of babies born who have been exposed to Accutane during gestation have major congenital deformities.  Those babies born without major malformations frequently develop severe learning disabilities.  A whole s
egment of Accutane babies do not even survive pregnancy:  40% are spontaneously miscarried.  Dr. Edward Lammer, a medical geneticist and consultant to FDA, describes the overall risk posed by Accutane:
\par }\pard \qj \li720\ri720\nowidctlpar\faauto\rin720\lin720\itap0 {\f1\fs22\cf1 This is an extraordinarily high absolute risk, really c
omparable, in terms of environmental exposures, only to Thalidomide or certain congenital infections.  There is no other medication that poses an absolute risk anything remotely close to this, even medications used to treat cancer during pregnancy.}{
\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 Testimony of Dr. Edward Lammer before the Dermatologic Drugs Advisory Committee, Sep. 18 2000, }{\i\f1 available}{\f1  }{\i\f1 at }{\f1 http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3639t1a.pdf.}}}{\f1\fs22\cf1 
\par 
\par }\pard \qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\f1\fs22\cf1 \tab Acco
rding to Dr. Lammer, brain abnormalities are the most typical problem for Accutane babies, even babies who appear normal at birth (i.e. babies not counted in the 25%).  In addition, Accutane commonly inhibits the development of the bones and cartilage of 
the face.  Children may be born with no ears at all;  sometimes there are small slits in the place of ears.  Heart defects, which often grow fatal, characterize the third most common problem described by Dr. Lammer.}{\cs18\f1\fs22\cf1\super \chftn 
{\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id.}}}{\f1\fs22\cf1 
  Many of the Accutane babies who do not suffer from congenital deformity have abnormally low IQ scores.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Testimony of Dr. Jane Adams before the Dermatologic Drugs Advisory Committee, Sep. 18 2000, }{\i\f1 available}{\f1  }{\i\f1 at }{\f1 
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3639t1a.pdf.}}}{\f1\fs22\cf1 
\par \tab Since its approval in 1982, references to Accutane have peppered the pages of law reviews and other publications.  The drug has become an example for academics and others proposing reform.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 See e.g. }{\f1 Joan H. Krause, }{\i\f1 
Accutane:  Has Drug Regulation in The United States Reached Its Limits?,}{\f1  6 }{\scaps\f1 J. L. & Health}{\f1  1 (1992);  }{\f1\cf1 Barry R. Furrow}{\f1 , }{\i\f1 
Enterprise Liability for Bad Outcomes from Drug Therapy:  the Doctor, the Hospital, the Pharmacy, and the Drug Firm, }{\scaps\f1 Drake L. Rev}{\f1  377 (1996).}}}{\f1\fs22\cf1  
 The popular media also have related the problem of Accutane babies episodically through the19 years since Accutane-induced birth defects first appeared in 1983.  But none of these accounts has offered a full history of Accutane in the U.S.
\par }\pard \qj \fi720\li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\f1\fs22\cf1 This paper take
s a journalistic approach, tracing the chronology of Accutane in the U.S. in order to fill in the gaps of the story that has inspired so much controversy.  Accutane has repeatedly pushed the frontier of FDA regulation, as the agency struggled to adapt its
 
tools to meet the challenge of an extremely effective and extremely dangerous medication.  By emphasizing the evolving American response to the high level of risk associated with Accutane, I hope to provide the material needed to evaluate the strengths an
d weaknesses of our current regulatory framework. 
\par }\pard \qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\f1\fs22\cf1 
\par }\pard\plain \s20\qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 \f1\fs24\cf1\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\b\fs22 Discovery and Pre-Market Approval}{\fs22 : }{\b\fs22 1970-1982
\par }{\fs22 Perhaps the biggest challenge in chronicling Accutane has been to decipher the early history of the drug.  Most of the information about Accutane\rquote s development,
 testing and approval only began to emerge ten years after the drug reached the market.  Creating a narrative has required piecing together fragments of the puzzle which surfaced over the course of the past decade.   
\par }\pard \s20\qj \fi720\li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 One might blame Roche:  the company has repeatedly gone to court demanding that material describing the development of Accutane be kept private.}{\cs18\fs22\super 
\chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Hoffmann-La Roche v. Yoder}{\f1 
, 950 F. Supp. 1348 (Ohio 1997);  }{\i\f1 Hammock v. Hoffmann-La Roche}{\f1 , 622 A.2d 546 (N.J. 1996).  }}}{\fs22 
  Of course, all manufacturers have the right to maintain confidentiality of trade secrets.  But some believe that the Roche exploits that authority in order to keep certain details\emdash details which might reflect poorly on the company\emdash obscured.
}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 The searches conducted by Frank Yoder, Mark Somerson, and the advocacy group Public Citizen are discussed below.}}}{\fs22   Questions about Roche\rquote s disclosure practices recur throughout for the Accutane story. 
\par }\pard \s20\qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 \tab Dr. Werner Bollag first studied the chemical compound, 13-cis retinoic ac
id at Roche laboratories in Switzerland during the 1960s.  Bollag tested the compound as a treatment for skin cancer, and in 1971, discovered the drug\rquote 
s ability to cure acne.  But Bollag also realized that the drug could cause serious birth defects. The co
mpound derived from vitamin A, a known teratogen.  When it proved ineffective as a cancer therapy he abandoned the project.  In a frequently quoted article from }{\i\fs22 Retinoids Therapy, }{\fs22 Bollag explained, \'93
At that time [the 1970s], in the psychological climate engendered by the thalidomide tragedy, it would be inconceivable to develop an agent with teratogenic properties for the treatment of such a common complaint as acne.\'94}{\cs18\fs22\super \chftn 
{\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in}{\f1  Diane Nygaard, }{\i\f1 
Accutane:  Is the Drug a Prescription for Birth Defects, }{\scaps\f1 Trial}{\f1 , Dec. 1988 at 81; Krause }{\i\f1 supra }{\f1 note 14, at 7.}}}{\fs22 
\par \tab In 1975, two scientists at the National Institutes of Health (NIH) started testing Hoffmann-La Roche\rquote 
s 13-cis retinoic acid (then known as isotretinoin) as a treatment for a severe skin disorder called lamellar ichthyosis.   In their research, Drs. Frank Yoder and Gary Peck accidentally discovered that the chemical also cleared up acne.  Subj
ects who had been covered with pimples returned to the office with clear skin.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Mark D. Somerson, }{\i\f1 Swiss Researcher Never Published Acne Drug Studies, }{\scaps\f1 Columbus Dispatch}{\f1 , May 1, 1996, at 2C.}}}{\fs22 
  On November 27, 1976 Yoder and Peck published their findings in the British medical Journal, }{\i\fs22 Lancet.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Gary L. Peck and Frank W. Yoder, }{\i\f1 Treatment of Lamellar Ichthyosis and Other Keratinizing Dermatoses with an Oral Synthetic Retinoid}{\f1 , 2 }{\scaps\f1 Lancet}{
\f1  1172 (1976).}}}{\i\fs22   }{\fs22 According to the two doctors, Hoffmann-La Roche never informed them of Werner Bollag\rquote s work.  \'93I didn\rquote t know about the 1971 studies until 1986,\'94 Peck later told the }{\i\fs22 Columbus Dispatch,}{
\fs22  \'93My first reaction was that I wasn\rquote t sure that I believed it in the first place.\'94}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Somerson }{\i\f1 supra }{\f1 note 18.}}}{\fs22   For years, Yoder and Peck believed that they were the first to discover the isotretinoin as an acne cure.  
\par \tab Isotretinoin became Accutane, and in clinical trials researchers carefully avoided exposing pregnant women to the drug.  Hoffmann-La Roche had conducted animal studies, and offspring of subjects showed facia
l deformities much like the ones that have subsequently been seen in Accutane babies.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Nygaard }{\i\f1 supra }{\f1 note 17at 81 (citing FDA\rquote s, Summary Basis of Approval, NDA 18-662, Jan. 15, 1982).}}}{\fs22 
  Most test centers excluded women.  Those researchers who did include women in trials required a negative pregnancy test and contraceptive use.  In an affidavit, David Benjamin who monitored the clinical trials in 1977 and 1978 explained, \'93
I felt that the risk of giving birth to a deformed child. . . was so great as to make it ethically improper and scientifically foolish to give Accutane to women who were not using an effective form of contraception.\'94
  According to Benjamin, one woman involved in a clinical trial became pregnant, and the company urged her to have an abortion.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Mark D. Somerson and Jill Riepenhoff, }{\i\f1 Patient was Urged to Get an Abortion;  Researcher Feared Defects in Accutane User\rquote s Baby, }{\scaps\f1 
Columbus Dispatch}{\f1 , Apr. 8, 1996 at 1C (quoting Benjamin\rquote s 1994 affadavit for Fetterolf v. Hoffmann-La Roche, }{\f1 651 N.E.2d 1309, (Ohio 1995)).}}}{\fs22 
  When Roche submitted Accutane for FDA approval in July of 1981, the company reported that no human babies had been exposed to the drug.
\par \tab FDA referred the application to the Dermatologic Drugs Advisory Committee, one of many panels of outside experts who provide FDA with independent recommendations about drug applications and other FDA policies.  FDA
 provides administrative support to the Dermatologic Drugs Advisory Committee, which includes several dermatologists, other medical experts and a consumer representative.  FDA generally follows advisory committees\rquote 
 recommendations, though they are not binding.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{
\f1  Information about FDA\rquote s advisory committees is available at the Center for Drug Evaluation and Research website, }{\i\f1 at }{\f1 http://www.fda.gov/cder/audiences/acspage/index.htm.}}}{\fs22   
\par }\pard \s20\qj \fi720\li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 
In January 1982 the Dermatologic Drugs Advisory Committee suggested FDA approve Accutane.  But the Committee also urged that the label be revised.  In its application for Accutane, Roche had written \'93Teratogenicity was observed in rats at a . . . d
ose of 150 mg/day.  In rabbits, a dose of 10 mg/day was teratogenic. . . and induced abortions.   There are no adequate and well-controlled studies in pregnant women.\'94}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in }{\f1 Jill Riepenhoff and Mark D. Somerson, }{\i\f1 
Company Soft-Pedaled Accutane Tie to Birth Defects in 1982,}{\f1  }{\scaps\f1 Columbus Dispatch}{\f1 , May 19, 1996 at 2D. }}}{\fs22   Roche suggested a pregnancy risk rating of C.  There are five risk categories:  A, B, 
C, D and X, and a rating of C indicates that \'93
studies in animals have revealed adverse effects of the fetus and there are no controlled studies in women. . . .  Drugs should be given only if the potential benefit justifies the potential risk to the fetus.\'94
  FDA insisted that Roche upgrade the warning for Accutane and classified it as category X, which indicates that the risk to fetus clearly outweighs any possible benefit from using the drug during pregnancy.}{\cs18\fs22\super  \chftn {\footnote 
\pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Testimony of Dr. Col
onel Evans before the Dermatologic Drugs Advisory Committee, 37 (May 8, 1989) }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane/29t1.pdf.}}}{\fs22    
\par Clearly, the absence of human birth defects was the direct result of Hoffmann-La Roche\rquote 
s testing conditions:  all female participants were given pregnancy tests and contraceptives, and the one woman who did become pregnant aborted.  Although FDA heightened the pregnancy risk rating for the drug,  t
he original label did not suggest the careful precautions that Roche itself had used during clinical trials.  Instead, the label noted the fact that there had been no evidence of birth defects in humans.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in }{\f1 Krause }{\i\f1 supra }{\f1 note 14, at 17.}}}{\fs22    
\par In May 1982, nine months after the application had been submitted, FDA announced approval of Accutane.  The drug had been classified \'931A,\'94 top priority, and awarded fast track approval. According to a Hoffmann-La Roche spokeswoman quoted in the }{
\i\fs22 Washington Post}{\fs22 , }{\fs22 "Approval came through so fast that it came as quite a surprise to everyone\'85\'94  }{\fs22 Caught off guard, Hoffmann-La Roche took an extra four months preparing to launch the drug.  }{\fs22 
The United States was the first country to approve Accutane.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs18\f1\super \chftn }{\f1  Penny Chorlton, }{\i\f1 FDA Outpaced Firm on Acne Drug, }{\scaps\f1 The Wash. Post}{\f1 , Sept. 14, 1982 at A17. }}}{\fs22 
\par }{\fs22 
\par }\pard \s20\qj \li0\ri0\sl480\slmult1\keep\keepn\nowidctlpar\faauto\rin0\lin0\itap0 {\b\fs22 Early Marketing: 1984-1987\tab 
\par }\pard \s20\qj \fi720\li0\ri0\sl480\slmult1\keep\keepn\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 In September 1982, Accutane arrived to a warm welcome.  \'93}{\fs22 There has never been a drug like it}{\fs22 \'94 }{\i\fs22 Newsweek }{\fs22 reported.}{
\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Matt Clark, }{\i\f1 
Now a Real Cure for Acne, }{\f1 Newsweek, Sep. 13 1982, at 56 (quoting Dr.. Eugene Farber, chief of dermatology at Stanford University School of Medicine).}}}{\fs22    }{\i\fs22 U.S. News and World Reports }{\fs22 
stated that Accutane could clear up most cases of acne within a few months.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Remedy for Acne, }{\scaps\f1 U.S. News and World Report}{\f1 , Oct. 11, 1982 at. 83.}}}{\fs22 
  During the first six months of marketing, doctors wrote 200,000 prescriptions for Accutane\emdash many more than even Hoffmann-La Roche had expected.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Riepenhoff and Somerson, }{\i\f1 supra }{\f1 note 24.}}}{\fs22 
\par }\pard \s20\qj \fi720\li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 
At the same time, some of the doctors who had studied the drug began to voice alarm.  Dr. Henry J. Roenigk had been chairman of the dermatology department at Northwestern University
 and participated as a researcher for Roche during clinical trials. In May 1982\emdash just as FDA granted approval\emdash Roenigk published an article in the }{\i\fs22 Journal of Dermatology}{\fs22  about Accutane\rquote 
s potential to cause birth defects.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{
\i\f1 Quoted in }{\f1 Mark D. Somerson and Jill Riepenhoff, }{\i\f1 Drug Had A Reputation in Europe, Doctor Recalls, }{\scaps\f1 Columbus Dispatch}{\f1 , Apr. 27, 1996 at 1C. }}}{\fs22   Dr. Frank Yoder, one of the two NIH
 scientists who had seemingly discovered the acne remedy, wrote a letter to }{\i\fs22 JAMA }{\fs22 
in January 1983.  ''I wish to express my concern and anxiety over the potential tragedy that might arise from abuse and misuse of Accutane. . . .  The potential toxicity of this drug has been seriously under-emphasized.''}{\cs18\fs22\super \chftn 
{\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Frank W. Yoder, }{\i\f1 Isotretinoin:  A Word of Caution,}{\f1 
 249 JAMA 350 (1983).}}}{\fs22    
\par Hoffmann-La Roche reproached the scientists for releasing information obtained while working for the company.  Yoder claims that he received a hostile phone call from Roche executives.  According to him, R
oche representatives  ''angrily told me I should not be writing that sort of confidential information. I didn't agree with them. I thought the public good must be served.''  (Roche has not confirmed this account.)  Shortly afterward the company sent lette
rs to all scientists who had participated in clinical trials, stressing the confidentiality of information obtained during research sponsored by Hoffmann-La Roche.  In a 1996 court case, a Roche employee testified, \'93
'An investigator had written an article, and we wanted to re-emphasize to all investigators that the information they received was confidential.''}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in }{\f1 Mark D. Somerson and Jill Riepenhoff, }{\i\f1 
Doctor Defends his Articles, }{\scaps\f1 Columbus Dispatch}{\f1 , Apr. 26 1996 at 1A.}}}{\fs22 
\par }\pard \s20\qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 \tab Within a few months, Hoffmann-La Roche began receiving stories about of babies born with severe birth defects to women who had taken Accutane.  In June 1983\emdash 
nine months after the drug had been released\emdash three cases were reported to Roche.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Pregnant Women Given Warning on Acne Drug, }{\scaps\f1 N.Y. Times,}{\f1  Jul. 26, 1983, at A12.  }}}{\fs22   The Company quickly sent out a \'93Dear Doctor\'94
 letter, warning against the dangers of using Accutane during pregnancy.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 
{\cs18\f1\super \chftn }{\f1  }{\cs18\f1\super \chftn }{\f1  }{\i\f1 Accutane and Pregnancy, supra }{\f1 note 1.}}}{\fs22   That August, FDA published an article in }{\i\fs22 Lancet}{\fs22  describing 12 reported cases of \'93adverse pregnancy outcomes
\'94 attributed to Accutane.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 Franz W. Rosa, }{\i\f1 Teratogenicity of Isotretinoin}{\i\scaps\f1 , }{\scaps\f1 Lancet}{\f1  513 (1983).}}}{\fs22 
  Roche distributed red warning stickers to pharmacies for Accutane containers and mailed a second Dear Doctor letter to 500,000 physicians.  The company also revised t
he drug label to include more information about birth defects and a more prominently placed warning.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Testimony of Dr. Jonathon Wilkin before the Dermatologic Drugs Advisory Committee, 37 (Sep.18 2000), }{\i\f1 available}{\f1  }{\i\f1 at }{\f1 
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3639t1a.pdf.}}}{\fs22  
\par \tab In September 1983, the advocacy organization Public Citizen petitioned FDA to further adjust the Accutane label.  Public Citizen\rquote s Health Research Group claimed that the drug\rquote 
s warnings were inadequate and consequently Accutane had been over-prescribed.  The group demanded a boxed warning describing the possibility of birth defects, spontaneous abortions, Chrohn\rquote s disease and several other serious health 
problems.  In addition, Public Citizen asked FDA to require patient package inserts explaining the possible side-effects in non-technical language.  FDA declined Public Citizen\rquote s requests.}{\cs18\fs22\super  \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Larry Sasich, }{\scaps\f1 HRG Publication}{\f1  #1537, }{\i\f1 available at }{\f1 
http://www.publiccitizen.org/publications/release.cfm?ID=4899.}}}{\fs22 
\par \tab In the first 18 months of marketing, about 400,000 patients took Accutane.  By March 1984, Roche collected reports of 20 Accutane babies.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Cristine Russell }{\i\f1 supra }{\f1 note 6.}}}{\fs22 
  The Dermatologic Drugs Advisory Committee convened a meeting to address the problem.
\par }\pard \s20\qj \fi720\li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 On the Committee\rquote s recommendation, FDA had Roche further strengthen Accutane\rquote s warning about bi
rth defects.  The label explicitly suggested that patients use contraceptives beginning a month before therapy.  Roche also took out a \'93Medical Director\rquote s Page\'94 in }{\i\fs22 JAMA}{\fs22 
 to inform doctors who might prescribe the drug.  In addition, FDA advised blood banks to refuse donations from Accutane users.  Although mild by today\rquote s standards, these controls were deemed \'93unprecedented regulatory action\'94
 by FDA spokesman William Grigg.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 
Id.  }}}{\fs22 
\par }\pard \s20\qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 \tab Between 1984 and 1988 Roche delivered seven more Dear Doctor letters warning about Accutane.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Jonathon Wilkin, }{\i\f1 supra }{\f1 note 37 at 36.}}}{\fs22 
  In June 1985, FDA and Roche again upgraded the caution on the label, this time including a boxed warning as Public Citizen had requested in 1983.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Larry Sasich, }{\i\f1 supra }{\f1 note 38.}}}{\fs22 
  At that time, the boxed warning was the most serious directive that FDA employed, short of recall.  Practitioners have suggested that FDA requires a black box warning when it hopes to decrease sales of a drug.}{\cs18\fs22\super \chftn {\footnote 
\pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Raymond G. Mullady, }{\i\f1 Everything You Needed and Wanted
 to Know About Black Boxed Warnings, }{\f1 68 }{\scaps\f1 Def. Couns. J}{\f1 . 50, 54 (2001).}}}{\fs22   But in the years following the revision, Accutane prescriptions remained common and reports of severely deformed babies continued to surface.}{
\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 See e.g.}{\f1 
 Edward Lammer et. al, }{\i\f1 Retinoic Acid Embryopathy}{\f1 , 313 }{\scaps\f1 New Eng. J. Med.}{\f1  837 (1985).}}}{\fs22   
\par 
\par }\pard \s20\qj \li0\ri0\sl480\slmult1\keep\keepn\nowidctlpar\faauto\rin0\lin0\itap0 {\b\fs22 Surviving the Risk of Recall:  1988-1995  
\par }{\fs22 In a private memo dated February 11, 1988 several scientists at FDA\rquote s Division of Epidemiology urged the agency to actively consider taking Accutane off the market.  \'93All efforts to date have been unsuccessfu
l at protecting against pregnancy exposure and the sequalae of birth defects and abortion.\'94
  Based on studies of Michigan Medicaid patients, the authors, Drs. David Graham, Franz Rosa and Carlene Baum, estimated 900 to 1300 Accutane babies had been born in the U.S.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Gina Kolata, }{\i\f1 Anti-Acne Drug Faulted in Birth Defects, }{\scaps\f1 
N.Y. Times, Apr. 22}{\f1 , 1988, at A1.}}}{\fs22   FDA had received reports of only 62 deformed babies.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Krause, }{\i\f1 supra }{\f1 note 14, at 20.}}}{\fs22 
  In March, the Centers for Disease Control (CDC) released a report describing four New Jersey cases of multiple serious birth defects in babies exposed to Accutane before birth.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Accutane and Pregnancy, supra }{\f1 note 1.}}}{\fs22   FDA schedu
led a meeting of the Dermatologic Drugs Advisory Committee for the end of April.  
\par }\pard \s20\qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\fs22 \tab On April 22, four days before the scheduled meeting, an account of the confidential FDA memo appeared on the front page of the }{\i\fs22 New York Times}{\fs22 .}{
\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Kolata, }{\i\f1 supra }{\f1 note 45.}}}{
\fs22   Someone had leaked the document.  News of the large estimated number of Accutane babies\emdash combined with the large number of abortions suggested to have been caused by the drug\emdash 
sparked a craze of media attention.  Journalists questioned whether the manufacturer and doctors had pushed the drug too far and whether FDA had approved the drug too quickly.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 See e.g. }{\f1 Philip J. Hilts and Susan Okie, }{\i\f1 
Accutane:  Recklessness or Reasonable Risk?, }{\f1  }{\scaps\f1 Wash. Post}{\f1 , Apr. 26, 1988, at A17.}}}{\fs22   New York Representative Ted Weiss publicly called on FDA to limit access to the drug.  Weiss also questioned the agency\rquote 
s response, "Why does the FDA proceed merely to schedule another advisory committee meeting?  . . . We must not allow the advisory committee process to be used as an excuse to permit such a seriously birth-deforming drug to remain on the market." }{
\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in }{\f1 
Michael Abramowitz and Philip J. Hilts, }{\i\f1 FDA Eyes Ban on Acne Drug, }{\scaps\f1 Wash. Post}{\f1 , Apr. 23, 1988, at A1. }}}{\fs22   A day later, Hoffmann-La Roche chimed in, indicting the Michigan study as \'93essentially meaningless\'94
 and calling the figures \'93grossly overstated.\'94}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super 
\chftn }{\f1  Phillip M. Boffey, }{\i\f1 Maker of Drug for Acne Calls Birth-Defect Report \'93Invalid,\'94}{\f1  }{\scaps\f1 N.Y. Times}{\f1 , Apr. 23, 1988, \'a7 1, at 1.  }}}{\fs22 
  The company argued that the data had been obtained from too small a sample size for extrapolation and had been misinterpreted by FDA.  Dr. Frank Yoder, by now no friend to Hoffmann-La Roche, gave a statement to the }{\i\fs22 Washington Post,}{\fs22 
 calling the company \'93negligent and wrong\'94 for over-promoting the drug to doctors who were not dermatologists.  Yoder also described the firm safeguards that had been in place during testing to ensure that 
no pregnant women were exposed to the drug.  \'93It is incredible to require that in a study but not in a mass market situation. . . .  This was very, very wrong.\'94  Hoffmann-La Roche officials \'93angrily dismissed\'94 Yoder\rquote s charges.}{
\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Abramowitz and Hilts, }{\i\f1 supra }{\f1 
note 50.}}}{\fs22   
\par \tab One source of controversy was the disparity between Accutane use in the U.S. and that in other countries.  As of April 30, 1988 only three Accutane babies had been born in Europe.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\ql \li0\ri300\widctlpar\aspalpha\aspnum\faauto\adjustright\rin300\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\fs20\super \chftn }{\f1\fs20  Linda Amster, }{\i\f1\fs20 Saturday News Quiz, }{\scaps\f1\fs20 N.Y. Times}{
\f1\fs20 , Apr. 30, 1988, \'a7 1, at 14.}}}{\fs22   A dermatologist in England commented, \'93The U.S. experience is one which horrifies us.\'94}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in }{\f1 Gina Kolata, }{\i\f1 Europeans Placed Stiffer Curbs on Acne Drug, }
{\scaps\f1 N.Y. Times}{\f1 , Apr. 28, 1988, at A1.}}}{\fs22   Most count
ries in Europe strictly limited access to the drug.  In Switzerland, doctors had to register with the government to prescribe it.  In the United Kingdom, only 350 dermatologist had authority to prescribe Accutane and only hospitals could dispense it.  As 
a
 prerequisite to receiving the drug in Britain, a woman had to stipulate that she would be willing to have an abortion.  Sweden never approved Accutane for general use;  dermatologists applied for special permission when a patient had a particular need. I
n Spain, the Ministry of Health kept the name and address of every woman taking Accutane in a special registry.  }{
The European approach to Accutane reflected not just a different regulatory methodology, but also differing circumstances.  In the wake of Thali
domide, Europeans treated all teratogenic drugs extremely cautiously.  According to the British dermatologist quoted above, \'93As a group of doctors who lived through Thalidomide, we are much more careful about using Accutane.\'94}{\cs18\fs22\super 
\chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id.}{\f1   }}}{  }{\fs22 Advocates such as Public Cit
izen pointed to the low number of  Accutane-related birth defects abroad as evidence of the need for restricted access.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Larry Sasich, }{\i\f1 supra }{\f1 note 38.}}}{\fs22   
\par \tab The Committee meeting on April 26th was just as contentious as the public debate that preceded it.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Transcripts }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\fs22   One spectator remarked that the
 doctors had clearly divided into two camps:  the dermatologists versus the pediatricians.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  James L. Mills, }{\i\f1 Protecting the Embryo from X-Rated Drugs,}{\f1  333}{\i\f1  }{\scaps\f1 New. Engl. J. Med}{\f1 . 124, (1995). }}}{\fs22 
  Everyone agreed that Accutane caused birth defects, but the dermatologists asserted that because it was so effective, and because treatment could be limited to a f
ew months, the drug should remain on the market.  Hoffmann-La Roche proposed an aggressive education program to reduce the risk of pregnancy.  CDC\rquote s Dr. J. David Erickson rejected this tactic, \'93the current approach . . . has failed.\'94
  He suggested the drug be dispensed only at a limited number of regional centers.  Others from the Division of Epidemiology presented evidence that the drug was \'93markedly overprescribed.\'94}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Transcripts from the Dermatologic Drugs Advisory Committee, Apr. 26, 1989, }{\i\f1 
available at}{\f1  http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\fs22   Ultimately, the Committee voted 4-to-3 to keep Accutane on the market but with restricte
d access.  The Committee recommended that only a limited number of certified physicians be permitted to dispense the drug.  In addition, women at high-risk of pregnancy would be required to procure a second opinion before receiving Accutane.}{
\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Michael Abramowitz, }{\i\f1 
FDA Advised to Limit Accutane Prescriptions, }{\scaps\f1 Wash. Post}{\f1 , Apr. 27, 1988, at A1.}}}{\fs22 
\par \tab A month later, FDA announced that it would not follow the Committee\rquote 
s recommendation to restrict access to Accutane.  Questioning whether it had the authority to dictate who could prescribe the drug, FDA instead mandated new warnings for the label.  The agency require
d that Hoffmann-La Roche provide informed consent forms to be signed by patients and doctors.  In addition the FDA directed the company to double the type size in the warning; include a picture of a baby deformed by Accutane in the material going to patie
n
ts;  dispense the drug in a blister-pack with warnings on every package;  instruct doctors that they should give both written and oral warnings;  add a symbol of a pregnant woman crossed out on the material given to doctors and patients;  and conduct foll
ow-up studies to determine the efficacy of the new program.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs18\f1\super \chftn }{\f1  Described in the transcripts from the Dermatologic Drugs Advisory Committee Meeting, May 8, 1989, }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\fs22   Again, Accutane had pushed FDA to \'93
an extraordinary new measure,\'94  one which the agency itself described as \'93unprecedented,\'94}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Philip J. Hilts, }{\i\f1 Stong Birth-Defect Warnings to Be Required on Acne Drug, }{\scaps\f1 Wash. Post}{\f1 , May 27, 1988, at A1.}}}{\fs22  and \'93
a very dramatic and innovative approach.\'94}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{
\f1  Lawrence K. Altman, }{\i\f1 Strict Curb Urged on Drug Linked to Birth Defects, }{\scaps\f1 N.Y. Times}{\f1 , May 27, 1988, at A1.}}}{\fs22 
\par \tab Hoffmann-La Roche announced that it would comply with FDA\rquote s requirements.  In addition, the company offered to pay the costs of contraceptive counseling and pregnancy testing for any woman receiving a prescription of Accutane.}{
\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id.}}}{\fs22 
  Taken together Roche titled the new interventio
ns its Pregnancy Prevention Program and implemented the changes in October 1988.  Researchers at the Slone Epidemiology Unit of the Boston University School of Public Health were enlisted to study the efficacy of the program as dictated by FDA.
\par \tab Debates co
ntinued throughout 1989.  On May 8, 1989, the Dermatologic Drugs Advisory Committee again met to discuss Accutane.  The group accepted comments from representatives of Teratology Society of America, the Association for Retarded Citizens of the U.S., the M
a
rch of Dimes, the Accutane Litigation Group, and the American Academy of Pediatrics among others.  Dermatologists presented pictures of patients who had suffered from extremely severe acne and had been cured by Accutane.  Epidemiologists at CDC expressed 
the \'93deep level of concern that we feel. . . about the ongoing very high rate of use.\'94  Hours were spent arguing over the numbers.  Committee members agreed that it was too soon to evaluate Roche\rquote s success in reducing pregnancy\endash 
the Pregnancy Prevention Program was only six months old;  FDA would continue to monitor the situation.}{\cs18\fs22\super  \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Transcripts from the Dermatologic Drugs Advisory Committee Meeting, May 8, 1989, }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\fs22 

\par }\pard\plain \s24\qj \li0\ri115\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin115\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f1\fs22 \tab In the fall a fight broke out in the back pages of the }{\i\f1\fs22 
New England Journal of Medicine.}{\f1\fs22   Robert Stern, a dermatologist in Boston, had written an article describing Accutane as a uniquely effective treatment for acne.  He also described the birth defects caused by the drug and outlined Roche\rquote 
s new Pregnancy Prevention Program remarking on \'93the substantial burden\'94 placed on physicians.  Stern concluded, \'93Our success in facing the ch
allenge of (Accutane) will be important in determining whether other [effective drugs that cause birth defects] become available and how they are used.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Stern, }{\i\f1 supra }{\f1 note 2, at 1009.}}}{\f1\fs22   The September 14th issue of the }
{\i\f1\fs22 New England Journal of Medicine }{\f1\fs22 contained several irate responses to Stern\rquote s piece.  Sidney Wolfe and Andrew Holmes from Public Citizen lambasted Stern for neglecting to disclose his \'93
substantial association with Hoffmann-La Roche,\'94 and suggested that numbers taken from the Slone Study were inaccurate.  Likewise, Drs. Geral
d Faich and Franz Rosa argued that there have probably been many more Accutane babies than have been reported.  They lamented, "It is disappointing that little change has occurred in the rates of use of the drug in women, in spite of considerable publicit
y efforts to educate physicians.\'94  Stern replied noting that the }{\i\f1\fs22 New England Journal of Medicine }{\f1\fs22 had known of his connection to Roche (a fact verified by the editor-in-chief).  He added, \'93
I wrote the Sounding Board article because politics and polemics rather than scientific inquiry were dominating the debate about (Accutane).\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\super \chftn }{ }{\f1 Correspondence, }{\i\f1 
When A Uniquely Effective Drug is Teratogenic:  The Case of Isotretinoin, }{\f1 321 }{\scaps\f1 New Eng. J. Med}{\f1 . 756 (1989).}}}{\f1\fs22   
\par \tab Eight months later the Dermatologic Drugs Advisory Committee met with the Fertility and Maternal Health Drugs Advisory Committee to discuss Accutane.  FDA asked the two groups to 
address this question:  had the pre-1988 adverse public health situation changed in a meaningful way and to a meaningful extent?  The Committees found that it had not.  The continued high level of Accutane use in the at risk population, prescriber non-com
pliance with important components of the program (many reproductive-aged women had not even been given a pregnancy test before starting therapy), and relatively low levels of participation in the Slone survey posed significant concerns for the group.}{
\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 Transcripts from the Dermatologic Drugs Advisory Committee Meeting, May 21, 1990, }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\f1\fs22   But 
the advisory panels decided to give Hoffmann-La Roche another seven months to prove the efficacy of the Pregnancy Prevention Program.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  William Booth, }{\i\f1 
Education Drive on Risks of Accutane Said to Fail, FDA Panels Allow Maker 7 More Months, }{\scaps\f1 Wash. Post}{\f1 , May 22, 1990, at A9.}}}{\f1\fs22 
\par \tab It actually took twelve months for the committees to reconvene\emdash the joint meeting was held in May 1991\emdash and by the time th
e groups came together, the media spotlight had disappeared.  Unlike the previous three Accutane-related meetings, this one received no coverage in the }{\i\f1\fs22 Washington Post }{\f1\fs22 or the }{\i\f1\fs22 New York Times. }{\f1\fs22 
 Also in contrast to the earlier meetings, this one found that Hoffmann-La Roche\rquote 
s interventions achieved results.  Committee members heard data from the Slone study indicating that number of fertile women taking Accutane had declined.  The Slone study suggested a pregnancy rate of 3.6 per 1000 women who used Accutane. 
 And of those women who did become pregnant, 28% reported having had therapeutic abortions\emdash 
a rate comparable to that in the general population.  Increasingly more physicians performed pregnancy tests before prescribing the drug.  Since 1988, approximately 
20% of the women considered for Accutane treatment using the program kit had been disqualified.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Transcripts from the Dermatologic Drugs Advisory Committee Meeting, May 20, 1991, }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm, 51-55.}}}{
\f1\fs22   The September 1991 issue of }{\i\f1\fs22 FDA Consumer }{\f1\fs22 announced that the Pregnancy Prevention Program \'93appears to be working.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Roche Reports Progress in Accutane Warning Program, }{\scaps\f1 FDA Consumer}{\f1 
, Sep. 1991, at 4.}}}{\f1\fs22 
\par }\pard \s24\qj \fi720\li0\ri115\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin115\lin0\itap0 {\f1\fs22 With that, Accutane fell out of the public eye and off of FDA\rquote 
s agenda.  There would be no more Dermatologic Drug Advisory Committee meetings dedicated to Accutane in the 1990s.  In 1995, the}{\i\f1\fs22  New England Journal of Medicine }{\f1\fs22 
published the results of the Slone survey which seemed to suggest that the 
Pregnancy Prevention Program had succeeded.  Just 402 of the 120,000 women who participated in the survey reported pregnancy.  The survey tracked only about half of all women using the Accutane;  consequently it could not be considered conclusive.}{
\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 Allen A. Mitchell, Carla M. Van Bennekom, and Carol Louik, }{\i\f1 A Pregnancy Prevention Program in Women of Childbearing Age Receiving Isotretinoin, }{\f1 333 }{\scaps\f1 New Eng. J. Med}{\f1 . 101 (1995).}}}{\f1\fs22   Noneth
eless, an editorial published alongside the article remarked that it provided \'93some encouraging news.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Mills, }{\i\f1 supra }{\f1 note 58, at 124.}}}{\f1\fs22 
  It seemed the problem of Accutane babies would soon be over.  Journalists and regulators turned their attention elsewhere.
\par 
\par }\pard \s24\qj \li0\ri115\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\adjustright\rin115\lin0\itap0 {\b\f1\fs22 Quieter Conflicts:  1992-1999}{\f1\fs22 
\par Out of the spotlight, Hoffmann-La Roche continued to grapple with the repercussions of Accutane related birth defects.  By the mid 1990s, Accutane had earned the company a significant list of enemies, many of whom were looking to draw blood.  Frank Yode
r, in some ways a patron Saint of Hoffmann-La Roche\emdash after all, his 1976 discovery had resulted in a tremendous money maker for the company\emdash had spent the past fifteen years insulting Roche in the }{\i\f1\fs22 Washington Post}{\f1\fs22 
.   A subset of the plaintiff\rquote s bar called the
 Accutane Litigation Group had also been chipping away at Hoffmann-La Roche.  The company had settled a number of expensive lawsuits.  But each time documents were sealed, which meant new plaintiffs would have to start from scratch.  The plaintiff\rquote 
s bar had become convinced that Hoffmann-La Roche had acted recklessly\emdash 
something which might entitle clients to steep punitive damages.  And the advocacy group, Public Citizen had been complaining vocally about Accutane since 1983.  Over time, the group grew frustrated by FDA\rquote s complacency and convinced of Roche
\rquote s culpability.  In 1996, each of these three adversaries brought Hoffmann-La Roche to court.
\par }\pard\plain \qj \fi360\li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f1\fs22 \tab 
On January 12, 1996 Dr. Frank Yoder sponsored an advertisement in a Columbus}{\i\f1\fs22 , }{\f1\fs22 Ohio newspaper }{\i\f1\fs22 The Daily Reporter}{\f1\fs22 :
\par }\pard \qc \li720\ri720\nowidctlpar\faauto\rin720\lin720\itap0 {\f1\fs22\cf1 UNIQUE SEALED-BID AUCTION}{\f1\fs22 
\par }\pard \qj \li720\ri720\nowidctlpar\faauto\rin720\lin720\itap0 {\f1\fs22\cf1 The entire private collection of Frank W. Yoder M.D. regarding the development, use and misuse of ISOTRETINOIN (Accutane) will be sold by a sealed-bid auction. }{\f1\fs22 
\par }\pard \qj \fi720\li720\ri720\nowidctlpar\faauto\rin720\lin720\itap0 {\f1\fs22\cf1 This sale includes documents relating to the original protocol, lett
ers from European investigators, and a never before distributed or published manuscript titled, "Isotretinoin Birth Defects\emdash A  Preventable Tragedy." }{\f1\fs22 
\par }{\f1\fs22\cf1 Individuals, corporations and all other serious parties are invited to participate in this unique and one 
time event.   The minimum bid is $9.5 million dollars (U.S. Currency) and 20% of the net proceeds will be designated for the prevention of birth defects. }{\f1\fs22 {\*\bkmkstart Document0zzSDUNumber11}{\*\bkmkend Document0zzSDUNumber11}
\par }\pard \qj \li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f1\fs22 On February 11, a similar advertisement appeared in the }{\i\f1\fs22 Washington Post.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in}{\f1  }{\i\f1 Hoffmann-La Roche v. Yoder}{\f1 , 950 F. Supp. at 1351.}}}{
\f1\fs22 \tab 
\par }\pard \qj \fi360\li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f1\fs22 Roche promptly responded w
ith service of process.  The company sued Yoder in federal court, demanding an injunction against the auction and replevin of the documents up for sale.  \'93
Most of the documents involve trade-secret details of research and testing Hoffmann-La Roche performed before the drug was approved by the FDA for sale to the public,\'94 Roche\rquote s attorney Karl Seib said. \'93
These trade secrets would be extremely valuable to Hoffmann-La Roche's competitors.\'94 Seib claimed that Yoder was trying to \'93intimidate and. . . threaten\'94 t
he company into purchasing the material.  (Yoder had called representatives from Roche to inform them of his auction several days before running the ad.)}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in }{\f1 Robert Ruth, }{\i\f1 
Battle Opens Over Acne Drug Documents, Westerville Doctor Says Public Was Misled}{\f1 , }{\scaps\f1 Columbus Dispatch}{\f1 , Mar. 21, 1996, at 1A.}}}{\f1\fs22   Yoder argued that the material did not concern trade secrets, but rather Roche\rquote 
s culpability in cases of Accutane-related birth defects.  In his brief for the court, Yoder\rquote 
s attorney wrote ''Dr. Yoder's assemblage of information is unique in that it provides a road map to Roche's negligence and greed in the early marketing of Accutane. Such information i
s admittedly valuable to victims of Roche's inadequate early warnings.''}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Jill Riepenhoff and Robert Ruth, }{\i\f1 Drug Firm Hid Accutane Data From FDA, Court Papers Say, }{\scaps\f1 Columbus Dispatch}{\f1 , Apr. 1, 1996, at 1A.}}}{\f1\fs22 

\par \tab Roche attorneys also appeared in another Ohio court in attempt to keep documents concealed from the plaintiffs\rquote  attorneys.  In 1994, the Fetterolfs had filed suit against Hoffmann-La Roche for claims arising out of their son\rquote 
s Accutane-related birth defects.  The Fetterolfs\rquote  attorneys had reviewed nearly 40,000 documents at Hoffmann-La Roche\rquote s New Jersey offices.  On April 29, 1996 the plaintiffs petitioned the court to remove a prot
ective order for an additional 9,000 documents.  The plaintiffs suspected that the company had withheld information:  they had been unable to find any correspondence between Hoffmann-La Roche employees in the United States and those who worked at the pare
n
t company in Switzerland.  The plaintiffs supposed that the drug had caused birth defects during testing in Switzerland and that Roche had withheld the information from FDA and researchers in the U.S.  Frank Yoder echoed this allegation when he testified 
in his own case on April 24th;  he claimed that European trials of Accutane had been halted when they resulted in serious birth defects.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Jill Riepenhoff and Mark D. Somerson, }{\i\f1 Accutane Legal Fight Resumes, }{\scaps\f1 
Columbus Dispatch}{\f1 , Apr. 24, 1996, at 1B.}}}{\f1\fs22 
\par          According to a Roche spokeswoman, the Company did not know for sure that Accutane caused birth defects until the first cases were reported in June of 1983.  The chemical that Accutane is derived from, \'93
has been known to be a teratogen since the \lquote 60s,\'94 the spokeswoman said, \'93That\rquote s why it was labeled category X when we launched.  And that\rquote s why there were all of the stringent requirements during the trials.\'94}{
\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Somerson and Riepenhoff, }{\i\f1 supra }{
\f1 note 22.}}}{\f1\fs22 
\par Roche representatives testified that they\rquote d refused access to the 9,000 documents because the Fetterolfs would not sign a protective order.  Hoffmann-La Roche maintained that the order was necessary to protect the company\rquote 
s trade secrets.   But unlike the victims who had preceded them, the Fetterolfs refused: 
\par }\pard \qj \li720\ri720\sb120\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0 {\f1\fs22 
Hoffmann-La Roche has already been permitted to cause irreparable harm to many children by virtue of the tactics it employs to prevent dissemination of th
e truth. The consuming public is entitled to the truth, and (we) would urge this court to remove the cloak of secrecy which (Hoffmann-La Roche) attempts to hide behind.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Jill Riepenhoff and Mark D. Somerson, }{\i\f1 Drug Maker Didn\rquote t Warn Us, Moms Say,}{
\f1  }{\scaps\f1 Columbus Dispatch}{\f1 , Apr. 30, 1996, at 3C.}}}{\f1\fs22   
\par }\pard \qj \fi720\li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f1\fs22 The fate of Roche\rquote s secret documents would ultimately be decided by a third court in
 New Jersey.  In 1986, the parents of Marvin Hammock sued Roche for Marvin\rquote 
s Accutane-induced deformities.  When the parties settled the documents obtained by the Hammocks during discovery were sealed at the request of Roche.  Public Citizen, intervened in the case challenging the decision to seal the documents.  Initially, t}{
\f1\fs22\cf1 he Superior Court granted summary judgment to Roche.  The case visited the appellate and trial courts twice more before arriving at the New Jersey Supreme Court.  That Court highlighted
 the longstanding public policy of public access to information about health, safety and welfare, and held that the documents should be released unless Roche could show good cause for denying access to the public.}{\cs18\f1\fs22\cf1\super \chftn 
{\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Hammock v. Hoffmann-La Roche}{\f1 , 622 A.2d 546.}}}{
\f1\fs22\cf1   On May 9,1996 the Hudson County Superior Court ordered the material unsealed.  In announcing his decision to grant public access, Judge Gallipoli remarked, \'93Quite frankly. . . I don\rquote 
t think these documents amount to a hill of beans.\'94}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in }{\f1 Jill Riepenhoff, }{\i\f1 Judge: Acutane Documents Must Be Opened,}{\f1  }{\scaps\f1 Columbus Dispatch}{\f1 , May 10, 1996 at 3C.}}}{\f1\fs22\cf1 
\par }\pard \qj \li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f1\fs22\cf1 \tab Judge Gallipoli\rquote s assessment proved true:  the documents did not provide the smoking gun that Public Citizen and plaintiffs
\rquote  attorneys had expected.  Records showed that within a year of releasing the drug to the market, company officials became extremely nervous about Accutane-related birth defects and that the fi
rst Accutane baby was born on April 29, 1983.  A memorandum documented a telephone conversation between John Burns, vice president of research for Roche and Dr. Oakley at CDC:  \'93
Burns told Oakley that Roche would recommend that any woman exposed to Accutane during pregnancy have an elective abortion.\'94
  In addition,  the papers showed for the first time that Roche had submitted Accutane with a pregnancy risk rating of C, and that it had been FDA who insisted on upping the warning level.  But the documents co
ntained no evidence of communications between the New Jersey offices and researchers in Europe.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Documents described }{\i\f1 in }{\f1 Riepenhoff and Somerson, }{\i\f1 supra }{\f1 note 24.  }}}{\f1\fs22\cf1  
\par }\pard \qj \fi720\li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f1\fs22\cf1 The following January, when Yoder won his legal battle, his $9.5 million documents proved equally disappointing.}{
\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Hoffmann-La Roche v. Yoder}{
\f1 , 950 F. Supp. 1348. }{\f1\cf1 The court concluded that Yoder\rquote s materials were not protected trade secrets, in part relying on the New Jersey court\rquote s order in }{\i\f1\cf1 Hammock.  }{\f1\cf1 Because the material was}{\i\f1\cf1  }{
\f1\cf1 publicly available it could not constitute a secret.  In addition Roche\rquote s failure to obtain a confidentiality agreement from Yoder in the 1970s undercut the company\rquote s claim.}}}{\f1\fs22\cf1   Nothing in Yoder\rquote 
s collection provided concrete proof of Accutane babies born prior to 1983.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\fs20\super \chftn }{\f1\fs20  In my research, I could not find any information about what Yoder did w
ith his documents after winning his case.  I did, however, make contact with Mark Somerson, one of the reporters who covered the story for the }{\i\f1\fs20 Dispatch.  }{\f1\fs20 
Having reviewed the files, Somerson commented that the collection did not  contain \'93one memo or note that would show that the company knew that the drug caused birth defects.\'94  Email from Mark Somerson, Assistant State Editor, }{\scaps\f1\fs20 
Columbus Dispatch}{\f1\fs20 , to Julia Green (Mar. 7, 2002, 15:37 EST)(on file with recipient).  }}}{\f1\fs22\cf1 
\par }\pard \qj \li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f1\fs22\cf1 \tab The most interesting material to surface during this period came from an Ohio newspaper, the }{\i\f1\fs22\cf1 Columbus Dispatch.  }{
\f1\fs22\cf1 The }{\i\f1\fs22\cf1 Dispatch }{\f1\fs22\cf1 was the only major publication that covered the series of Accutane-related lawsuits in 1996.}{\f1\fs22   As a result of Yoder\rquote 
s allegations, two reporters, Mark Somerson and Jill Riepenhoff, began their own investigation into the development and early marketing of Accutane.  
\par \tab The two were the first to report the confusion over who first discovered Accutane\rquote s ability to treat severe acne.  Dr. Werner Bollag\rquote s role in the drug\rquote s history had been known since the 1983 publication of his article in }{
\i\f1\fs22 Retinoids Therapy,}{\f1\fs22  but those who considered the subject wondered why Hoffmann-La Roche suddenly decided to reconsider Accutane as an acne treatment in 1975\emdash 
four years after Bollag dropped his project.  For example, Diane Nygaard chair of the Accutane Litigation Group had described Roche\rquote s decision to resume testing as \'93inexplicable.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Nygaard, }{\i\f1 supra }{\f1 note 17, at 81.}}}{\f1\fs22   Somerson and Riepen
hoff uncovered part of an explanation:  the company began testing again after Yoder and Peck independently realized that the drug could be used to treat acne and reported their success.
\par }\pard \qj \fi360\li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f1\fs22 \tab In addition, documents obtained through a Freedom of Information Act 
claim filed by Somerson reveal the extent to which Accutane had become a source of tension for FDA.  Several members of FDA felt the agency should take a stronger position against Hoffmann-La Roche.  David Graham, one of the authors of the controversial M
ichigan Medicaid study, criticized Roche\rquote s proposed labeling change in October 1988.  The company had revised the label to read, \'93potentially all fetuses may be affected,\'94 and \'93
physicians and patients should discuss the desirability of continuing the pregnancy.\'94
  Graham suggested that Roche intentionally overstated the risk of birth defects.  ''The effect communicated by this wording to the patient and her physician is that there is virtually a 100 percent risk of severe birth defect and that induced abortio
n should be performed.\'94  According to Somerson\rquote s report, four doctors at FDA who tracked Accutane echoed Graham\rquote 
s concern:  ''Current product labeling serves Roche interests by reducing the number of women who deliver, and this reduces the probability that
 FDA will ever be informed of the exposure, because of massive underreporting. . . .  The firm has not acted in good faith to truly and accurately answer questions relating to Accutane use in women and pregnancy exposure.''  Others at the agency felt it w
as important to convey a significant risk and that exposed fetuses should be aborted.}{\cs18\f1\fs22\super  \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 Mark D. Somerson, }{\i\f1 Memos Bare FDA Split Over Accutane, }{\scaps\f1 Columbus Dispatch}{\f1 , Jul. 14 1996, at 7C.  }}}{\f1\fs22 
\par \tab Somerson\rquote s report also portrays more explicit disputes within the agency.  On May 8, 1989 a member of the Dermatologic Drugs Advisory Committee accused Graham of using \'93Nazi methods of decision-making\'94
 about Accutane.  Meanwhile, Graham criticized the regulatory structure used by FDA.  
\par }\pard\plain \s25\qj \li720\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin720\itap0 \f1\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\fs22 
It is troubling to realize the extreme lack of impartiality which characterizes this committee. . . Dermatologists prescribe the vast ma
jority of (Accutane), and much of the problem with (Accutane) relates to its widespread use beyond the labeled indication. . . .  It goes beyond normal expectations to believe that a committee of dermatologists would find fault with its own profession, or
 recommend that (Accutane) be removed from the market as an imminent hazard. . . .  In this sense, presenting (Accutane) to the dermatology committee is somewhat akin to the notion of the fox in the henhouse.
\par }\pard \s25\qj \fi360\li0\ri720\widctlpar\aspalpha\aspnum\faauto\adjustright\rin720\lin0\itap0 {\fs22 
\par }\pard \s25\qj \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\fs22 For some members of FDA, the problem of Accutane-induced birth defects had presented fundamental questions about the agency\rquote 
s regulatory methods.}{\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id.}}}{\fs22 

\par }\pard\plain \qj \li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f1\fs22 \tab But the reporters were unable to uncover proof of Roche\rquote 
s actual knowledge of Accutane-induced birth defects prior to 1983.  Eventually, Somerson and Riepenhoff abandoned their investigation.}{\cs18\f1\fs22\super  \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Somerson, }{\i\f1 supra }{\f1 note 84.}}}{\f1\fs22    
\par \tab Although Frank Yoder, Public Citizen, the Accutane Litigation Group and the }{\i\f1\fs22 Columbus Dispatch}{\f1\fs22  all failed to produce evidence establishing Hoffmann-La Roche had withheld data from FDA, the ordeal did uncover some q
uestionable behavior.  Why would Hoffmann-La Roche propose a pregnancy risk rating of only C for a product so dangerous that the initial investigator abandoned it?  And why hadn\rquote 
t the company shared information about the earlier research with scientists in the U.S. studying the drug in 1975?  Research done by the }{\i\f1\fs22 Dispatch}{\f1\fs22 
 could also raise concerns about FDA.  Had FDA catered to the manufacturer instead of protecting the public?  Or were a few members\emdash obsessed by some sort of personal vendetta\emdash stirring up unnecessary conflict at the agency?  
\par \tab The information uncovered never congealed into enough of a story to attract mainstream attention.  Outside Ohio, most Americans remained unaware of Hoffmann-La Roche\rquote s ongoing legal troubles.  Consequently, the company 
and FDA escaped scrutiny.
\par }\pard\plain \s2\qj \li0\ri0\sb120\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel1\adjustright\rin0\lin0\itap0 \b\f1\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\fs22 
\par Regulation Resumed:   1999-2002
\par }\pard\plain \qj \li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f1\fs22 
In the past few years, FDA and other government entities have revisited Accutane, questioning whether even more should be done to protect against Accutane-induced birth defects.  Although Roche\rquote s P
regnancy Prevention Program succeeded in maintaining a very low pregnancy rate (2.7 per 1000 women taking Accutane) the number of patients taking Accutane steadily increased after 1991.  Between 1992 and 1999, the number Accutane prescriptions grew by 200
%.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 Testimony from Dr. Amarilys Vega to the Dermatologic Drugs Advisory Committee Meeting, Sep. 18, 2000, }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\f1\fs22 
  Although the risk of exposed pregnancy for any individual woman taking Accutane had decreased, the total number of Accutane babies remained constant because of increased use.
\par \tab CDC signaled the renewed interest in Accutane babies on January 21, 2001 in }{\i\f1\fs22 Mortality and Morbidity Weekly Report.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\i\f1 Accutane-Exposed Pregnancies\emdash California, 1999,}{\f1  49}{\i\f1  }{\scaps\f1 
CDC MMWR Weekly}{\f1  28 (2002). }}}{\f1\fs22   The item, \'93Accutane-Exposed Pregnancies \endash California, 1999,\'94
 described a series interviews that CDC had conducted with 14 women in California who had recently reported Accutane-exposed pregnancies.  The researchers initiated the study in order to \'93draw attention to the continued occurrence\'94
 of Accutane-exposed pregnancies and to \'93learn more about why these exposed pregnancies happened.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id. }{\f1 at 28.  }}}{\f1\fs22   
\par }\pard \qj \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\f1\fs22 The study diagnosed several problems contributing to the exposures.  Although a
ll of the women interviewed knew that Accutane should not be used during pregnancy, none reported having seen all the components of the Pregnancy Prevention Program.  Four women had not seen any of the educational material, aside from what was printed on 
the package.  Most of the women interviewed did not use two forms of birth control\emdash 
eight had not used contraception at all when the pregnancy occurred.  And only ten women took pregnancy tests before taking Accutane.  The study highlighted that doctors continued to ignore many of the requirements of the Pregnancy Prevention Program.}{
\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id.}}}{\f1\fs22 
\par The CDC report also underlined the problem of overuse.  At least half of the respondents reported that they did not have the severe, recalcitrant, nodular acne for which the dru
g is indicated.  One woman described taking Accutane one week each month to prevent oily skin during her period.  In part, the researchers linked increase use of the drug to advertising.  Four of the respondents stated that commercials had contributed to 
their decisions to see a doctor.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{
\i\f1 Id. }{\f1 Hoffmann-La Roche began direct-to-consumer print advertising in 1996 and added television and radio advertisements in 1997.   }}}{\f1\fs22 
\par Within two months, Hoffmann-La Roche announced a new intervention, the }{\i\f1\fs22 Targeted }{\f1\fs22 Pregnancy Prevention Program, which would be geared toward the 0.27% of women who had fallen through the cracks of the previous efforts.  The p
rogram consisted of a new batch of labeling changes;  for example, two pregnancy tests should be timed according to instructions and performed before starting therapy;  doctors should call pharmacists with prescriptions (as opposed to handing written pres
criptions to patients);  and two safe and effective methods of birth control should be used.  FDA approved the new label in May.  Roche also planned to distribute educational packets for patients titled \'93Be Smart, Be Safe, Be Sure,\'94
 and to organize Continui
ng Medical Education classes for doctors who prescribed the drug.  A video would be distributed for doctors to show patients about the risks, and Roche would reiterate the importance of monthly pregnancy testing and counseling.  That spring, Roche distrib
uted pregnancy tests to all doctors known to prescribe Accutane.  The educational video for went out in June.  And in July Roche began visiting individual prescribers to do office training.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 Testimony from Eileen Leach to the Dermatologic Drugs Advisory Committee Meeting, Sep. 18, 2000, }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\f1\fs22 
\par On September 18, 2000 FDA called on  the Dermatologic Drugs Advisory Committee for advice about Accutane.   FDA\rquote s Dr. Jonca Bull posed the question to the Committee.  \'93
From a risk management standpoint, can we in our mission to ensure the safe and effective use of drug products, given societal and regulatory realities, d
evelop a framework that further reduces the known risk of teratogenicity attendant to the use of (Accutane.)\'94
  FDA asked the panel to consider which risk management tools should be used for Accutane and what next steps should be taken, if any, if improved risk management is not realized.  The committee was to reflect on a variety of mechanisms\emdash 
increased risk communication, modified packaging, restricted distribution, mandatory monitoring of patients, and improved informed consent\emdash and formulate a general recommendation for FDA.}{\cs18\f1\fs22\super  \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Testimony from Jonca Bull to the Dermatologic Drugs Advisory Committee Meeting, Sep. 
18, 2000, }{\i\f1 available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\f1\fs22 
\par Hoffmann-La Roche presented data to the Committee suggesting that education would be the best way to reduce pregnancy.  Roche had knowledge of 1,995 cases of pregnancy exposures to Accutane,  70% of which occurred after the initiatio
n of the Pregnancy Prevention Program.  Of those women an estimated 61% had been using only one form of contraception and 34% had failed to use contraception.  14% of the women were unknowingly pregnant at the initial visit with the doctor.  This reflecte
d
 a need for more information about the importance of multiple forms of birth control and pregnancy testing.  Roche also presented figures that showed many doctors had failed to comply with the Pregnancy Prevention Program, prescribing the drug without fir
st testing for pregnancy or obtaining a signed informed consent.  Presumably, outreach efforts could achieve improved doctor participation and fewer pregnancies.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Transcripts from the Dermatologic Drugs Advisory Committee Meeting, Sep. 18, 2000, }{\i\f1 
available at }{\f1 http://www.fda.gov/ohrms/dockets/ac/accutane.htm.}}}{\f1\fs22 
\par The Committee also listened to the usual information about the dangers of Accutane exposure during pregnancy and about the drug\rquote s unique ability to cure acne.  Dr. Lammer, one of the participants in CDC\rquote s 1999 Study, commented, \'93
In terms of medications, in terms of the magnitude of risk and the severity of malformations, this drug is really unique.\'94 Dr. Barbara Reed, a member of the Board of the American Academy of Dermatology, described the risks associated with acne: \'93
There is no single disease which causes more psychic trauma, more maladjustment between parents and children, more general insecurity and feelings of inferiority and greater sums of psychic suffering than does acne.\'94  It was a battle of superlatives.}{
\cs18\f1\fs22\super  \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id.}}}{\f1\fs22 
\par A representative of Celgene, the U.S. manufacturer of Thalidomide, described the program that had been implemented with the release of
 that drug in 1998.  Under the System for Thalidomide Education and Prescribing Safety (STEPS), Celgene required doctors and pharmacies to register with the company to prescribe or dispense the drug.  In addition, all patients participated in a mandatory 
s
urvey tracking their Thalidomide use.  At that time, about 10,500 pharmacies and 900 doctors had enrolled in the program.  Representatives from the Thalidomide Victims Association of Canada, the Organization of Teratology Information Services, the March o
f Dimes, and Public Citizen each pointed to STEPS asking the Committee require Roche to implement a similar program and restrict access to the drug.  A representative from FDA\rquote 
s office of Postmarketing Drug Risk Assessment bolstered their case by belittling Roche\rquote s proposals;  healthcare providers were not \'93lacking for the information or access into the information.  It\rquote s putting it into practice that\rquote 
s the problem.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id.}}}{
\f1\fs22   
\par Dermatologists voiced objections to restricted access programs.  Dr. Reed suggested that 
the system would disrupt the doctor-patient relationship and force patients to find new doctors just to start a new treatment.  Compelling patients to discuss sex and pregnancy with an unfamiliar doctor would undermine education efforts.  Patients in rura
l communities might have to travel long distances to get needed care.  Another dermatologist complained that the suggestion intruded too far into the profession, \'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 or pharmacist, or anyone else. . . .  I am convinced that education . . . is the way to accomplish this.\'94}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Id.}}}{\f1\fs22 
\par The committee voted for a form of restricted access.  In addition to increasing edu
cational efforts, as Roche suggested, the Pregnancy Prevention Program should be modified:  all prescriptions should be limited to 30 day-supplies, and before dispensing Accutane, pharmacists should have to confirm that a negative pregnancy test has been 
d
ocumented.   For women taking the drug, registration in the Program should be mandatory as should participation in the Slone survey.  (Previously, participation in the survey had been voluntary, and Committee members worried that the data were inaccurate.
)  The Committee also recommended that Roche be required to conduct independent surveillance to identify pregnancy exposures.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Kenneth Lyons Jones, Jane Adams, Christina Chambers, J. David Erickson, Edward Lammer and Janine Polifka, }{\i\f1 Isotretinoin and Pregnancy,}{\f1  285 JAMA 2081 (2001).
}}}{\f1\fs22 
\par In a Dear Doctor letter, dated January 9, 2001, FDA announced that educational efforts had not succeeded in eliminating Accutane-exposed pregnancies:  \'93. . . human memory is not an adequate precaution for managing severe risk.\'94
   The Committee had recommended \'93additional systematized measures to manage risk and fully inform patients.\'94  FDA stated that it was working closely with Roche to address the recommendations that were made by the advisory committee.}{
\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 Letter from Janet Woodcock, Center Director, Center for Drug Evaluation and Research to Health Care Providers (Jan. 9, 2001) }{\i\f1 available at }{\f1 http://www.fda.gov/cder/drug/infopage/accutane/accutane-ltr.htm.}}}{\f1\fs22 
\par Nine months later, in October 2001, FDA revealed SMART (the System to Manage Accutane Related Teratogenicity).  The new program, which takes effect on April 10, 2002 will require prescribers to study the SMART \'93Guide to Best Practices,\'94
 provided by Roche and then send a signed \'93Letter of Understanding\'94 to the company certifying knowledge of how to prevent fetal exposure.  Upon receipt of the letter, Roche will send prescribers yello
w qualification stickers.  All prescriptions for Accutane should have attached a special yellow sticker, which indicates that the patient has had a negative pregnancy test and counseling about pregnancy prevention.  The pregnancy test will be repeated eve
r
y month before a new prescription is provided.  Pharmacists will only be permitted to fill prescriptions that have the yellow sticker.  In addition, all female patients must be given the opportunity to participate in the Slone survey.  Participation will 
not be mandatory.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 FDA Talk Paper, FDA, FDA Announces Changes to the Risk Management Program to Prevent Birth Defects Caused by Accutane (Oct. 31, 2001) }{\i\f1 available at }{\f1 http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01113.html.}}}{\f1\fs22 
\par It remains to be seen whether SMART will accomplish the goal of eliminating the tragedy of Accutane babies.  Clearly, the program was designed as a compromise between the desire for European-styled programs which achieve very low rates of
 pregnancy exposure by strictly limiting access, and the conflicting goal of easy availability of medicine to those who need it.  But, while the program may look like a form of restricted access\emdash 
after all, only doctors with special yellow stickers can prescribe the drug\emdash 
in actuality the new protections more serve as hoops to jump through than barriers to access.   Any doctor can send in a Letter of Understanding and obtain the stickers;  qualification is not limited to dermatologists or other healthcare pro
viders with special training.  And like the Letter of Understanding, the sticker itself amounts to nothing more than a statement by a doctor of self-certification.  Conspicuously absent from SMART are any interventions designed to address the problem of o
v
eruse.  The yellow sticker signifies that a patient has received pregnancy tests and counseling, not that a patient has severe cystic acne.  Clearly, SMART caters to the concerns expressed by dermatologists at the September 2000 meeting:  whether or not a
 patient obtains a prescription to Accutane remains almost entirely in the control of the physician.  
\par A few modifications might have given this certification-based form of restricted access more teeth.  For one, Roche might have made its half-day continuin
g medical education class a mandatory prerequisite for certification instead of a recommended event.  In that way, the company would have ensured that doctors who receive stickers actually have been informed of the best practices.  Similarly, FDA might ha
ve followed the Committee\rquote s recommendation and required actual documentation of two negative pregnancy tests\emdash 
instead of just a yellow sticker.  Then it would have been impossible for a doctor to prescribe the drug if he forgot to perform a pregnancy test.  
In order to write a prescription without performing two tests, a doctor would have to actively forge the documentation.   At very least, FDA might have included a diagnosis of severe, recalcitrant acne as one of the preconditions for using the yellow stic
ker;  this would have sent a clear message that Accutane was not appropriate for off-label use.  As it stands, doctors are their own gatekeepers, and their judgment and neglect remain unchecked.
\par }\pard\plain \s26\qj \fi720\li0\ri0\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f1\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\fs22 That said, SMART clearly provides some added value to the exis
ting system.  Presumably, many doctors will actually read the Guide to Best Practices before submitting the letters and will benefit from the increased education.  In addition the yellow stickers might serve as a reminder, triggering doctors to perform pr
egnancy tests and provide counseling.  Taken together the yellow stickers and letter of certification might be interpreted as a contract, and doctors who use the stickers without the requisite protections might be liable for their actions.}{
\cs18\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 
 To succeed under this theory, plaintiffs would have to establish that they had been intended as third party beneficiaries of the contract with Hoffmann-La Roche, and consequently should be entitled to sue.  }}}{\fs22   Or perhaps the 
yellow stickers will form the basis for malpractice liability.  The precautions signified by the sticker suggest a clear standard of care required for the profession.  Maybe the specter of the litigation that might arise from misuse of the stickers will b
e enough to scare doctors into compliance.  More generally, the very fact of such a novel program will undoubtedly convey the message that Accutane poses serious risks and should not be prescribed casually.}{\cs18\fs22\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 See generally Risk Management of Accutane, }{\f1 287 JAMA 578 (2002) (\'93
alerting physicians to the strengthened risk management program for isotretinoin\'94).}}}{\fs22   Over the next few months, we will discover whether this mild form of restricted access proves enough to capture the remaining pregnancy exposures.
\par 
\par }\pard\plain \s2\qj \li0\ri0\sb120\sl480\slmult1\keepn\widctlpar\aspalpha\aspnum\faauto\outlinelevel1\adjustright\rin0\lin0\itap0 \b\f1\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\fs22 A Brief Sidebar:  Accutane Linked to Suicide?
\par }\pard\plain \qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f1\fs22\cf1 The primary focus of future of Accutane regulation may be mental illness.  As of December 31, 2001, 140 Accuta
ne users worldwide (94 in the U.S.) have killed themselves while taking Accutane or within a few months of stopping treatment.  Another 257 patients have been hospitalized for severe depression or attempted suicide.}{\cs18\f1\fs22\cf1\super \chftn 
{\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Duenwald, }{\i\f1 supra }{\f1 note 9.}}}{\f1\fs22\cf1 
  Many reported that the symptoms diminished or disappeared after stopping Accutane treatment;  several patients found that when they resumed taking the drug, depression returned.  Accutane ranks among the top 10 drugs in FDA\rquote 
s database with respect to depression and suicide reports.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs18\f1\super \chftn }{\f1  Diane k. Wysowski, Marilyn Pitts and Julie Beitz, }{\i\f1 Depression and Suicide in Patients Treated with Isotretinoin, }{\f1 344 }{\scaps\f1 New Eng. J. Med}{\f1 . 460 (2001).}}}{\f1\fs22\cf1   But the n
umber of reported cases among Accutane users is actually no greater than that in the general population.  About 6.1% of persons age15-24 have symptoms of severe depression in any given month.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Acne Drug Depression Warnings Highlight Need for Expert Care, supra }{\f1 
note 7, at 1057.}}}{\f1\fs22\cf1   And adolescents and young adults with severe acne may be particularly prone to depression.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  This is a point that Hoffmann-La Roche officials have been quick to point out.  }{\i\f1 
See e.g. }{\f1 Julie Brienza, }{\i\f1 Accutane Maker Warns of Suicide Danger in Patients, }{\scaps\f1 Trial}{\f1 , June 1988, at 90 (\'93
Hoffmann-La Roche spokeswoman Kellie McLaughlin said teenagers traditionally suffer from a higher incidence of depression, making it difficult to determine whether the Drug cause
s depression among its users.  She added that the same hormones that contribute to the formation of acne can also contribute to depression\'94).}}}{\f1\fs22\cf1 
  This makes for a confusing situation:  FDA has collected reports of patients who seem to suffer from depression only while taking Accutane, but there is no increased prevalence of depression in the overall population of users.
\par \tab 
Perhaps because of its prior experiences, FDA has been quicker to require Hoffmann-La Roche warn about the possibility of depression and suicide, even in the absence of clear evidence.  In June 1985 when FDA mandated a black box warning for Accutane, de
pression was included as one of the possible side effects that had been reported.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  The original black box warning is included on Congressman Bart Stupak\rquote s web site }{\i\f1 at }{\f1 http://www.house.gov/stupak/accutane_chronology.htm.}}}{
\f1\fs22\cf1   In 1997, based on case reports of serious psychiatric disorders, FDA approached Hoffmann-La Roche about heightening the warning.  On February 24, 1998 Roche released a new label.  The warning began:  
\par }\pard \qj \li720\ri720\nowidctlpar\faauto\rin720\lin720\itap0 {\f1\fs22\cf1 
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 me
chanism of action has been established for these events.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs18\f1\super \chftn }{\f1  }{\i\f1 Quoted in}{\f1  }{\i\f1 Acne Drug Depression Warnings Highlight Need For Expert Care, supra }{\f1 note 7, at 1057.}}}{\f1\fs22\cf1   
\par 
\par }\pard \qj \li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\f1\fs22\cf1 A month later, the United Kingdom required a similar warning.  According to FDA, doctors should simply act as if Accutane causes suicide.}{\cs18\f1\fs22\cf1\super \chftn 
{\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Duenwald, }{\i\f1 supra}{\f1 
 note 9, (quoting Dr. Jonathon Wilkins, Director of Dermatology at FDA\rquote s Center for Drug Evaluation and Research).}}}{\f1\fs22\cf1 
\par }\pard \qj \fi720\li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\f1\fs22\cf1 More recently, FDA and Hoffmann-La Roche have taken step
s aimed directly at informing patients.  In March 2001, Hoffmann-La Roche published a medication guide that explains the possible association between suicide and Accutane to patients.  The company also unveiled a new informed consent form, which describes
 the concern about suicide and requires patients inform their doctors of any history of mental illness.}{\cs18\f1\fs22\cf1\super  \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Bernard A. Schwetz, }{\i\f1 New Measures to Manage Risks Associated With Accutane, }{\f1 285 JAMA 1146 (2001).  }}}{\f1\fs22\cf1 
  At monthly visits, doctors should check for signs of depression.  This spring the company will send out a new brochure to dermatologists and other prescribing physicians instructing them how to recognize early signs of depression.}{
\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \ql \li0\ri0\nowidctlpar\faauto\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\fs20\super \chftn }{\f1\fs20  Rita Rubin, }{\i\f1\fs20 
From Acne Drug Maker, a Teen Depression Guide}{\i\scaps\f1\fs20 , }{\scaps\f1\fs20 USA Today}{\f1\fs20 , Feb. 26, 2002 at 7D.  }{\f1\fs20\cf1 This was one of the Dermatologic Drugs Advisory Committee\rquote s recommendations in September 2000. }}}{
\f1\fs22\cf1   
\par But Hoffmann-La Roche has also indicated a familiar reluctance to disclose information.  Only in July 1998, 14 months after FDA first approached Hoffmann-La Roche about add
ing suicide to the warning label, did the agency discover that a French study from 1994 showed an association between Accutane and depression.  In March 1997, Roche had added \'93suicide attempt\'94
 to the warning label for Accutane sold in France.  Hoffmann-La Roche never shared the information with FDA.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\super \chftn }{ }{\f1 Bart Stupak, }{\i\f1 Accutane Chronology, available }{\f1 at http://www.house.gov/stupak/accutane_chronology.htm.}}}{\f1\fs22\cf1 
\par In addition, Roche\rquote s marketing demonstrated an insensitivity to the suicide concern.  In 1998, about the same time that FDA required the risk of suicide appear on the label, Roche released a new advertisement f
or Accutane which included the following statement:  \'93Effective treatment of severe recalcitrant nodular acne minimizes progressive physical scarring, as well as negative psychosocial effects such as depression and poor self image.\'94
  On March 5, 1998, FDA sent a warning letter to the company demanding the advertisement be pulled.  According to the agency, \'93Statements in Roche\rquote s promotional materials that Accutane therapy will minimize or improve the patient\rquote 
s psychological status, including depression, are false or misleading and promote an unapproved use.\'94}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Wilkin, }{\i\f1 supra }{\f1 note 37.}}}{\f1\fs22\cf1 
\par And like Accutane-induced birth defects, cases of suicide and depression have generated new adversaries for Hoffmann-La Roche\emdash adversaries driven to take action.  The international organization, \'93}{\f1\fs22 Roaccutane/Accutane Action Group,\'94
 formed in January, 1999.  On its website the group describes the mission:
\par }\pard \qj \li720\ri720\nowidctlpar\faauto\rin720\lin720\itap0 {\f1\fs22 To demand the appointment of an independent national and coordinated international investigation into Accutane/Roaccutane and the manufacturers of the drug
, it's executives and key employees, concerning lack of safety standards, inadequate label warnings, knowledge of side effects concealed at launch of product, accuracy or inaccuracy of results disclosed in pre-trial studies, alteration and manipulation of
 data on side effects, applied by the manufacturers Roche from 1982 to date.}{\cs18\f1\fs22\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 Available at }{\f1 http://www.accutaneaction.com.}}}{\f1\fs22 
\par }\pard \qj \fi720\li720\ri720\nowidctlpar\faauto\rin720\lin720\itap0 {\f1\fs22\cf17 
\par }\pard \qj \fi720\li0\ri0\sl480\slmult1\nowidctlpar\faauto\rin0\lin0\itap0 {\f1\fs22\cf1 One ally of the group is Michigan Congressman Bart Stupak.  On May 14, 2000, Stupak\rquote 
s 17 year-old son B.J. shot himself to death.  B.J. had used Accutane, and a few weeks after his death the Stupaks discovered the link to depression.  Since then, Bart Stupak has worked hard to publicize what he calls \'93spontaneous suicides,\'94
 suicides in seemingly happy people who take Accutane.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
\cs18\f1\super \chftn }{\f1  Frey, }{\i\f1 supra }{\f1 note 3.  }}}{\f1\fs22\cf1   Shortly after B.J.\rquote s death, Stupak told his story on NBC\rquote s \'93Today Show.\'94}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Ed Silverman, }{\i\f1 Acne Drug 
Concerns Head to Congress House Committee to Discuss Suicide Links to Accutane, }{\scaps\f1 N.J. Star Ledger}{\f1 , Aug. 15, 2001, at 29.}}}{\f1\fs22\cf1 
  In addition, Stupak used his political position to pressure FDA and Hoffmann-La Roche to increase regulation of the Drug.  It was Stupak who pushed the company to create an informed consent form and medication guide for patients;  on Stupak\rquote 
s urging Hoffmann-La Roche also terminated advertisements aimed at minors.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 
\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1 Letter from Bart Stupak, Henry Waxman, Tom Barrett, Sherrod Brown, Marge Roukema, Tom Coburn, Zach Wamp and Ed Bryant, Representatives,
 U.S. House of Represantives,  to Jane Henney, Commissioner, FDA and Patrick Zenner, President and CEO Hoffmann-La Roche (Oct. 11, 2000) (urging FDA to require informed consent form, medication guides, and no advertising to minors);  Letter from Patrick Z
enner, President and CEO, Hoffmann-La Roche, to Bart Stupak (Oct. 17, 2001) (informing Stupak that Hoffmann-La Roche would voluntarily implement all of the recommended changes).  }{\i\f1 Available at}{\f1  http://www.accutanelitigation.com/congress.htm.}}
}{\f1\fs22\cf1 
\par Stupak\rquote s case put Accutane on the Congressional agenda;  on December 5, 2000, the House Committee on Government Reform held a meeting, \'93Acne Drug Accutane & It\rquote s Alleged Links to Depression and Suicide.\'94
  The Committee heard testimony from parents of teenagers who committed suicide while taking Accutane.  Representatives from FDA, Hoffmann-La Roche, and the American Academy of Dermatology also participated.}{\cs18\f1\fs22\cf1\super \chftn {\footnote 
\pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Transcript available at http://www.accutaneaction.com/}}}{\f1\fs22\cf1 
  A Congressional hearing was scheduled for October 2001 to probe whether Hoffmann-La Roche and FDA gave consumers adequate warnings about suicide.  Congress postponed the hearing after September 11th.}{\cs18\f1\fs22\cf1\super \chftn {\footnote 
\pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Silverman, }{\i\f1 supra }{\f1 note 118.}}}{\f1\fs22\cf1 
\par But in the aftermath of September 11th, one particular case brought th
e association between Accutane and suicide back into the spotlight.  On January 5th, 2002 15-year-old Charles Bishop flew a small plane into an office building in Tampa, Florida.  Investigators soon discovered a prescription for Accutane among Bishop
\rquote s belongings.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Duenwald, }{
\i\f1 supra }{\f1 note 9.}}}{\f1\fs22\cf1   Toxicology tests by the medical examiner found no Accutane in his blood,  but his mother reported that Charles had taken the drug.  Mrs. Bishop argued that Accutane might be responsible for her son\rquote 
s behavior.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain \s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  Keith Morelli, }{\i\f1 
Final Report Details Boy\rquote s Suicide Flight, }{\scaps\f1 Tampa Tribune}{\f1 , Mar. 13, 2002, at 1.}}}{\f1\fs22\cf1   The copy-cat crime, coupled with 
a suicide note expressing sympathy for terrorists, garnered immediate coverage from all news media;  newspapers throughout the country reported the association between Accutane and suicide.}{\cs18\f1\fs22\cf1\super \chftn {\footnote \pard\plain 
\s17\ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\i\f1 See e.g.}{\f1  Carolyn Susman, }{\i\f1 Accutane Link to Suicide Unconfirmed, }{
\scaps\f1 Palm Beach Post}{\f1 , Jan. 30, 2002 at 3D;\~Debra Rosenberg, }{\i\f1 A Troubled Teenager\rquote s Tragic Final Flight, }{\scaps\f1 Newsweek}{\f1 , Jan. 21, 2002, at 40;  }{\i\f1 No Drugs Alcohol Found in Pilot\rquote s Body,}{\f1  }{\scaps\f1 
Milwaukee J. Sentinel}{\f1 , Jan. 17, 2002 at 10A.}}}{\f1\fs22\cf1 
\par According to an analyst quoted in the }{\i\f1\fs22\cf1 New Jersey Record, }{\f1\fs22\cf1 Accutane sales have dropped by ten percent since 2000 because of increased publicity of Accutane-linked suicides.}{\cs18\f1\fs22\cf1\super \chftn {\footnote 
\pard\plain \ql \li0\ri0\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\cs18\f1\super \chftn }{\f1  }{\f1\fs20 Lewis Krauskopf, }{\i\f1\fs20 Hoffmann-La Roche's P
etition Means Generic Accutane Faces Delay,}{\f1\fs20  }{\scaps\f1\fs20 Record}{\f1\fs20 , Feb. 23, 2002, at 3 (quoting Denise Anderson an analyst with Bank Julius Baer inSwitzerland.}}}{\f1\fs22\cf1 
  Undoubtedly, the association between Accutane and depression will continue to pose a problem for Hoffmann-La Roche.  The manufacturer and FDA continue to struggle with this the highly publicized\emdash but poorly understood\emdash phenomenon.
\par 
\par }\pard \qj \li0\ri0\sb120\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 {\b\f1\fs22 Lessons to Learn
\par }\pard\plain \s31\qj \li0\ri0\sb120\sl480\slmult1\widctlpar\aspalpha\aspnum\faauto\adjustright\rin0\lin0\itap0 \f1\fs22\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {
Without doubt, Accutane is a special drug, one that poses extraordinary challenges for FDA.  Nonetheless, FDA\rquote s experience with Accutane highlights several structural weaknesses in the overall regulatory system.  In addition, Accutane\rquote 
s impact extends beyond the patients who have taken it and the company that markets it.  By pushing FDA to devise new control techniques, Accutane left its mark on the agency.  A
lthough the drug itself remains unique, the story of Accutane provides insight into drug regulation in the United States generally.
\par \tab It is also worth noting how much of the story has been driven by circumstance.  For example, the United States\rquote  relative ea
gerness to approve Accutane must be explained in part by our inexperience with Thalidomide.   Had more babies been deformed by Thalidomide\emdash as they were in Europe\emdash 
fewer would have been exposed to Accutane.  Happenstance, like the fact that one teen suicide 
invoked terrorism or that another was the son of a Congressman, earned tremendous publicity for the potential association between Accutane and depression.  Bart Stupak\rquote 
s position in the House of Representatives enabled him to effect marketing changes withi
n a week.  And politics have influenced regulation in other ways as well.  For example, the controversy surrounding Accutane in the eighties in part derived from the product\rquote 
s relationship to abortion, a politically sensitive issue.  In considering where to point fingers in the Accutane story, we should remember that some portions must be owed to fortuity. 
\par \tab If we conceive of FDA as a safety net designed to protect consumers, then perhaps Accutane babies might be said to have fallen through the holes.  The story of Accutane exposes many of FDA\rquote 
s vulnerabilities.  For one, FDA has no authority over doctors or patients, the two groups who ultimately control whether a fetus will be exposed to Accutane.  A clear conclusion to be drawn from this story is that Dea
r Doctor letters and warnings on labels do not effect significant change on the part of healthcare practitioners.  This inability to control directly the gatekeepers to prescription drugs poses a real limitation for the agency.  Products whose safety depe
nds on behavioral practices will inevitably reach beyond the scope of FDA.
\par \tab The story also raises fundamental concerns about the advisory committee system put in place by FDA.  Are the doctors who would use a particular drug well-suited to decide whether it
 should be allowed on the market?  Accutane provides revenue not only for Hoffmann-La Roche but also for the doctors prescribing it, most of whom are dermatologists.  (Each of the five million Americans who have used Accutane visited a doctor to obtain a 
prescription.)    FDA might consider whether the value added by specialists\rquote  relative expertise is offset by this conflict of interest. 
\par \tab In addition, the story exposes the limitations of liberalism, in particular the idea that educated consumers should be free to make their own choices\emdash and to suffer the consequences.  Accutane\rquote 
s dangers cannot satisfactorily be addressed through consumer warnings:  the victims of Accutane, unborn babies, cannot participate in informed consent.  When choices and consequences
 are not experienced by the same individual, the model no longer makes sense.  Regulatory tools aimed at increasing information may not be adequate protections for third party victims.
\par \tab The Accutane story might be deemed either a triumph or a failure.  In 
public health terms, FDA and Roche have succeeded in achieving tremendous change.  As compared to the general population, the pregnancy rate of 0.27% in Accutane users is extremely low.  A country, such as ours, that has been unable to effect simple behav
ioral modifications, such as flossing, must admire the accomplishment.  On the other hand, FDA\rquote s regulations and Roche\rquote s own interventions have collectively been unable to eliminate Accutane babies.  Accutane-induced birth defects remain }{
\i a preventable}{ tragedy.
\par }\pard\plain \qj \li0\ri0\nowidctlpar\faauto\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f1\fs22\cf1 
\par }\pard \ql \li0\ri0\nowidctlpar\faauto\rin0\lin0\itap0 {\f1\fs20 \line \line }{\f1\fs22\cf1  }{\f1\fs22 
\par }}