The mysteries of pregnancy: The role of law in solving the problem of unknown but knowable maternal-fetal medication risk

University of Cincinnati Law Review

Volumn 79, Issue 1, 2010, Pages 267-322

  Greenwood, Kate ^a  

^a SETON HALL UNIVERSITY   (United States)

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EID: 79953791294     PISSN: 00096881     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (534)

1. See Catalin S. Buhimschi & Carl P. Weiner, Medications in Pregnancy and Lactation: Part I. Teratology, 113 OBSTETRICS & GYNECOLOGY 166, 166 (2009). Medication use in breastfeeding women is similarly understudied.
2. Id.
3. See also Esther E. Sfultz et al., Extent of Medication Use in Breastfeeding Women, 1 BREASTFEEDING MED. 145, 150 (2007) (finding that over a third of the breastfeeding women surveyed took medications that were rated possibly or probably unsafe or were of unknown safety).
4. Janice K. Louie et al., Severe 2009 H1N1 Influenza in Pregnant and Postpartum Women in California, 362 NEW ENG. J. MED. 27,33 (2010).
5. Alicia M. Siston et al., Pandemic 2009 Influenza A(HlNl) Virus Illness Among Pregnant Women in the United States, 303 JAMA 1517,1522-23 (2010).
6. Id. at 1523.
7. Donald G. McNeil Jr., Drugs Urged for Swine Flu in Pregnancy, N.Y. TIMES, May 13, 2009, at A10.
8. Id.
9. See Toshihiro Tanaka et al., Safety of Neuraminidase Inhibitors Against Novel Influenza A(HlNl) in Pregnant and Breastfeeding Women, 181 CAN. MED. ASS'N J. 55, 56-57 (2009)
10. (presenting data derived from a Japanese post-marketing study that followed ninety pregnant women who took Tamiflu in their first trimester, from a report by the manufacturer on sixty-one pregnant women exposed to Tamiflu with unknown timing, from three cases of accidental exposure during clinical trials of Relenza, and from "[a] study using an ex vivo human placenta model");
11. Highlights of Prescribing Information for Relenza, http://us.gsk.com/ products/assets/us-relenza.pdf (last visited Aug. 10, 2010);
12. Highlights of Prescribing Information for Tamiflu, http://www.rocheusa. com/products/tamiflu/pi.pdf (last visited Aug. 10,2010).
13. Ruth Faden et al., A Custom Drug, N.Y. TIMES, May 10, 2009, at WK10.
14. See also Sonja A. Rasmussen et al., Pandemic Influenza and Pregnant Women: Summary of a Meeting of Experts, 99 AM. J. PUB. HEALTH S248, S250 (2009)
15. ("No data are available to address whether dosage adjustment [of anti-influenza medications] is needed; thus, no dosage alterations for pregnant women are recommended at this time.").
16. Rasmussen et al., supra note 8, at S249.
17. Denise J. Jamieson et al., HlNl 2009 Influenza Virus Infection During Pregnancy in the USA, 374 THE LANCET 451,456 (2009).
18. Id.
19. Louie et al., supra note 2, at 33.
20. See also Allison L. Naleway et al., Delivering Influenza Vaccine to Pregnant Women, 28 EPIDEMIOLOGIC REV. 47, 49 (2006)
21. (reporting that pregnant women had the lowest flu vaccine coverage level of all adult groups recommended to receive the vaccine, perhaps due to their expressed concerns about vaccine safety). A recent study found a similar problem with regard to antihypertensive drugs noting "site-specific differences" in the rate of use of such drugs to treat pregnant women with high blood pressure.
22. Susan E. Andrade et al., Outpatient Use of Cardiovascular Drugs During Pregnancy, 17 PHARMACOEPIDEMIOLOGY & DRUG SAFETY 240, 246 (2008).
23. The researchers who conducted the study suggested that health care providers' uncertainty about how to manage hypertension during pregnancy given limited knowledge about the risk-to-benefit profile of the various medications could explain the treatment differences.
24. Id.
25. Jamieson et al., supra note 10, at 456.
26. Siston et al., supra note 3, at 1521.
27. Anne Drapkin Lyerly et al., The Second Wave: Toward Responsible Inclusion of Pregnant Women in Research, 1 INT'L J. OF FEMINIST APPROACHES TO BIOETHICS 6, 7 (2008);
28. Allen A. Mitchell, Systematic Identification of Drugs that Cause Birth Defects - A New Opportunity, 349 NEW ENG. J. MED. 2556,2556-57 (2003)
29. (explaining that "the vast majority of medications cunently in use have not been studied in a way that would reveal moderate teratogenic risks," which the author defines as a risk two to ten times greater than the base-line risk for a specific birth defect).
30. Susan E. Andrade et al., Prescription Drug Use in Pregnancy, 191 AM. J. OBSTETRICS & GYNECOLOGY 398,400 (2004).
31. Lyerly et al., supra note 14, at 8.
32. American College of Obstetricians and Gynecologists, Management of Asymptomatic Pregnant or Lactating Women Exposed to Anthrax, 11 INT'L J. GYNECOLOGY & OBSTETRICS 293, 294-95 (2002);
33. Anne Drapkin Lyerly et al., The National Children's Study: A Golden Opportunity to Advance the Health of Pregnant Women, 99 AM. J. PUB. HEALTH 1742, 1742 (2009)
34. (citing M.A. Andrew et al., Amoxicillin Pharmacokinetics in Pregnant Women: Modeling and Simulations of Dosage Strategies, 81 CLINICAL PHARMACOLOGY & THERAPEUTICS 547,547-56 (2007)).
35. Lyerly et al., supra note 17, at 1742
36. (citing M.F. Herbert et al., Are We Optimizing Gestational Diabetes Treatment with Glyburide? The Pharmacologic Basis for Better Clinical Practice, 85 CLINICAL PHARMACOLOGY & THERAPEUTICS 607, 607-14 (2009));
37. Nicholas J. White et al., New Medicines for Tropical Diseases in Pregnancy: Catch-22,5 PLoS MED. 843,843 (2008).
38. Catalin S. Buhimschi & Carl P. Weiner, Medications in Pregnancy and Lactation: Part 1. Teratology, 113 OBSTETRICS & GYNECOLOGY 166,167 (2009).
39. Id. at 167.
40. Id.
41. Id. at 168.
42. Id. 24. Id.
43. Id.
44. Tim F. Oberlander et al., Effects of Timing and Duration of Gestational Exposure to Serotonin Reuptake Inhibitor Antidepressants: Population-Based Study, 192 BRIT. J. PSYCHIATRY 338, 341-42(2008).
45. Lyerly et al., supra note 14, at 10-11.
46. Barbara A. Noah, Just a Spoonful of Sugar: Drug Safety for Pediatric Populations, 37 J.L. MED. & ETHICS 280, 281 (2009) (discussing the lack of information about the safety and efficacy of drugs when used in pediatric populations).
47. Lyerly et al., supra note 14, at 11-13.
48. See, e.g., Michelle Meadows, Pregnancy and the Drug Dilemma, 35 FDA CONSUMER 16,18 (2001)
49. (quoting Catherine Stika, a physician and assistant professor of obstetrics and gynecology at Northwestern University School of Medicine, as follows: "We'll prescribe an older hypertension drug because its long history hasn't turned up serious safety concerns.... There may be other drugs that are more effective and better tolerated, but we don't use them because we don't know about their safety.").
50. Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831, 30,844 (proposed May 29, 2008) (to be codified at 21 C.F.R. pt. 201).
51. Id. at 30,834.
52. Id.
53. See also Gideon Koren et al., Drugs in Pregnancy, 338 NEW. ENG. J. MED. 1128, 1134 (1998)
54. ("Women often report that their physicians have encouraged them to terminate otherwise wanted pregnancies just to be on the safe side, suggesting that many physicians are unfamiliar with the cunent literature on the safety of drugs taken during pregnancy.").
55. Cf. Anne Drapkin Lyerly et al., Risk and the Pregnant Body, HASTINGS CENTER REP., Nov-Dec. 2009, at 34, 36
56. (discussing a study in which 5% of obstetricians and family physicians surveyed reported that they would recommend abortion to patients who had a radiologic scan in early pregnancy based on their (mistaken) perceptions of teratogenic risk).
57. See Lars Noah, Medicine's Epistemology: Mapping the Haphazard Diffusion of Knowledge in the Biomedical Community, A4 ARIZ. L. REV. 373, 389 (2002) ("[N]o one denies that many medical treatments remain seriously understudied.").
58. Lyerly et al., supra note 33, at 35.
59. Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831, 30,844 (proposed May 29, 2008) (to be codified at 21 C.F.R. pt. 201) (citing sources).
60. Anne Drapkin Lyerly et al., Risk and the Pregnant Body, HASTINGS CENTER REP., Nov.Dec. 2009, at 35.
61. Id. at 39.
62. Id.
63. Id. at 40.
64. See, e.g., Liz Szabo, A 'Drug Drought'for Pregnant Women, USA TODAY, June 3, 2008, available at http://www.usatoday.com/news/health/2008-06-03-pregnant- dnigs-N.htm
65. (reporting that Alan Goldhammer, deputy vice president of regulatory affairs for PhRMA, the trade organization which represents many pharmaceutical and biotechnology companies, said that although drug makers would like to develop drugs for pregnancy complications, they have to consider the potential harmful effects that experimental drugs could have on a fetus).
66. Lyerly et al., supra note 17, at 2.
67. See also The Am. Coll. of Obstetricians & Gynecologists Comm. on Ethics, Ethical Considerations in Research Involving Pregnant Women, 65 INT'L J. GYNECOLOGY & OBSTETRICS 93 (1999).
68. See Laurence B. McCullough et al., A Comprehensive Ethical Framework for Responsibly Designing and Conducting Pharmacologic Research that Involves Pregnant Women, 193 AM. J. OBSTETRICS & GYNECOLOGY 901 (2005).
69. The medical literature provides multiple examples of placebo-controlled studies in pregnant women, suggesting that there are circumstances in which the riskbenefit ratio of such research is favorable.
70. See, e.g., Mark B. Landon et al., A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes, 361 NEW ENG. J. MED. 1339, 1339 (2009);
71. Dwight J. Rouse et al., A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy, 359 NEW ENG. J. MED. 895, 895 (2008);
72. Debra A. Guinn et al., Terbutaline Pump Maintenance Therapy for Prevention of Preterm Delivery: A Double-Blind Trial, 179 AM. J. OBSTETRICS & GYNECOLOGY 874 (1998);
73. Debra A. Guinn et al., Management Options in Women with Preterm Uterine Contractions: A Randomized Clinical Trial, ill AM. J. OBSTETRICS 8c GYNECOLOGY 814 (1997);
74. see also Steve Sternberg, Pregnant Women Taking Part in New HlNl Vaccination Trials, USA TODAY, Sept. 10, 2009, available at http://www.usatoday. com/news/health/2009-09-10-pregnant-swine-fluvaccine-N.htm.
75. Press Release, U.S. Dept. of Health & Human Servs., Food & Drug Admin., Health Organizations to Study Safety of Medications Taken During Pregnancy (Dec. 30, 2009), available at http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/2009/ucml95934.htm.
76. U.S. DEPT. OF HEALTH & HUMAN SERVS., FOOD & DRUG ADMIN., FDA'S SENTINEL INITIATIVE, http://www.fda.gov/Safety/FDAsSentinelInitiative/defauIt. htm (last visited Aug. 12,2010).
77. Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy ana Lactation Labeling, 73 Fed. Reg. 30, 831, 30, 844(propossed May 29, 2008) (to be codified at 21 C.F.R. pt. 201).
78. Id.
79. Id. at 30,841 (noting that depression and migraine headaches can be exacerbated by pregnancy).
80. Michael Schatz & Mitchell P. Dombrowski, Asthma in Pregnancy, 360 NEW ENG. J. MED. 1862,1862(2009).
81. Id.
82. Id.
83. Id. at 1864,1866.
84. Conducting controlled trials "to determine the effects of asthma control, as compared with lack of control, on perinatal outcomes" is not possible due to ethical concerns.
85. Id. at 1866.
86. Joyce A. Martin et al., Ctrs. for Disease Control & Prevention, Nat'l Vital Statistics Reports, Births: Final Data for 2006, Jan. 7, 2009, at 13, available at http://www.cdc.gov/nchs/data/nvsr/ nvsr57mvsr57-07.pdf.
87. Id.
88. Id. at 14.
89. Id.
90. Andrade et al., supra note 11, at 243.
91. Lyerly et al., supra note 14, at 6 (reporting that autoimmune diseases and cancer "commonly occur with pregnancy and often require treatment");
92. Pamela Paul, With Child, With Cancer, N.Y. TIMES, Aug. 31,2008, at MM34 (reporting that the estimated rate of pregnancy-associated cancer is 1 in 1000);
93. Torbjörn Tomson, Which Drug for the Pregnant Woman with Epilepsy?, 360 NEW. ENG. J. MED. 1667, 1667 (2009) (noting that approximately 25,000 children are born to mothers with epilepsy each year and that most women with epilepsy must continue taking medication to treat it during pregnancy);
94. AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS, ACOG PRACTICE BULLETIN NO. 92, USE OF PSYCHIATRIC MEDICATIONS DURING PREGNANCY AND LACTATION (2008).
95. Stephanie J. Ventura et al., Ctrs. for Disease Control & Prevention, Nat'l Vital Statistics Reports, Estimated Pregnancy Rates by Outcome for the United States, 1990-2004, Apr. 14,2008, at 1, available at http://www.cdc.gov/ nchs/data/nvsr/nvsr56/nvsr56-15.pdf.
96. Susan E. Andrade et al., Prescription Drug Use in Pregnancy, 191 AM. J. OBSTETRICS & GYNECOLOGY 398,400 (2004).
97. Douglas D. Glover et al., Prescription, Over-the-Counter, and Herbal Medicine Use in a Rural, Obstetric Population, 188 AM. J. OBSTETRICS & GYNECOLOGY 1039,1041 (2003).
98. Ventura et al., supra note 59, at 12.
99. There are approximately six million pregnancies per year in the United States. Press Release, U.S. Dept. of Health & Human Servs., Food & Drug Admin., FDA Proposes New Rule to Provide Updated Information on the Use of Prescription Drugs and Biological Products during Pregnancy and Breast-feeding (May 28, 2008), available at http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/2008/ucmll6902.htm.
100. CTRS. FOR DISEASE CONTROL & PREVENTION, PREGNANCY RISK ASSESSMENT MONITORING SYSTEM (PRAMS): PRAMS AND UNINTENDED PREGNANCY, http://www.cdc.gov/ prams/PDFs/ PRAMSUnintendPreg.pdf (last visited Feb. 27,2010).
101. David W. Kaufman, et al., Recent Patterns of Medication Use in the Ambulatory Adult Population of the United States: The Slone Survey, 287 JAMA 337,339 (2002).
102. Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831, 30,841 (proposed May 29, 2008) (to be codified at 21 C.F.R. pt. 201). While inadvertent exposure most commonly occurs in early pregnancy, it can occur at any stage.
103. Id.
104. Id.
105. Id.
106. Caroline T. Lagoy et al., Medication Use During Pregnancy and Lactation: An Urgent Call for Public Health Action, 14 J. WOMEN'S HEALTH 104, 105 (2005).
107. Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831, 30,834 (proposed May 29, 2008) (to be codified at 21 C.F.R. pt. 201).
108. Under the current regulations, prescription drug labels must include a "Pregnancy" section with information about the drug's potential to cause birth defects as well as any other reproductive effects.
109. Id. at 30,832.
110. Each product is assigned a letter-A, B, C, D, or X-based on its potential to cause reproductive and developmental adverse effects.
111. Id. at 30,832-33.
112. For categories C, D, and X, a drug's potential to cause harm is weighed against its potential benefit, meaning that the only difference between a drug in category X and a drug in category D could be that there is a safer alternative to the drug in category X.
113. See id. at 30,833.
114. The five categories are defined as follows. A drug is category A if adequate and well-controlled studies have been conducted in pregnant women and shown no "risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters)." 21 C.F.R. §201.57(c)(9)(i)(A)(1) (2010). A drug is category B if animal studies have been conducted and shown no risk but there are no adequate and well-controlled studies in pregnant women, or if animal studies have shown a risk but adequate and well-controlled studies in pregnant women have been conducted and did not show a risk.
115. Id. §201.57(cX9)(i)(A)(2).
116. Category C covers drugs the risks of which have not been studied in pregnant animals or pregnant women; it also covers drugs that animal studies have shown pose a risk to the fetus and that have not been studied in pregnant women, if the drug's benefits may outweigh its potential risks.
117. Id. §201.57(c)(9XiXA)(3).
118. Category D is used: If there is positive evidence of human fetal risk based on adverse reaction date from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks (for example, if the drug is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective).
119. Id. §201.57(c)(9)(iXAX4).
120. Finally, category X is for drugs for which the risk of use in pregnant woman clearly outweighs any possible benefit.
121. Id. §201.57(c)(9)(iXA)(5).
122. In 2008, the FDA issued proposed amendments to the pregnancy labeling regulations which would abolish the category system and replace it with a narrative format that the agency believes would better capture the "complexity of medical decisionmaking about drug use during pregnancy." Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831, 30,838 (proposed May 29, 2008) (to be codified at 21 C.F.R. pt. 201). On April 26, 2010, the Department of Health & Human Services announced that the FDA would release the final regulation by March 2011. Semiannual Regulatory Agenda, 75 Fed. Reg. 21,782, 21,795 (Apr. 26, 2010).
123. Buhimschi & Weiner, supra note 1, at 170.
124. W. Y. Lo & J.M. Friedman, Teratogenicity of Recently Introduced Medications in Human Pregnancy, 100 OBSTETRICS & GYNECOLOGY 465,468 (2002).
125. Id. at 472.
126. Andrade et al., supra note 15, at 400. In addition, 2.1% received a drug unrated by the FDA.
127. Id.
128. Susan E. Andrade et al., Use of Prescription Medications with a Potential for Fetal Harm Among Pregnant Women, 15 PHARMACOEPIDEMIOLOGY & DRUG SAFETY 546, 551 (2006)
129. (noting that the "preponderance of data now suggests unlikely teratogenic potential" for oral contraceptives). Oral contraceptives are used during the early part of about 1% of pregnancies.
130. Buhimschi & Weiner, supra note 1, at 181 (noting that this estimate may be low because the authors did not evaluate drug use in pregnancies that did not go to term whether due to abortion or miscarriage).
131. Erika Hyde Riley et al., Correlates of Prescription Drug Use During Pregnancy, 14 J. WOMEN'S HEALTH 401,402-03 (2005).
132. Andrade et al., supra note 15, at 400.
133. Andrade et al., supra note 74, at 549.
134. This study also included an evaluation by an expert in teratogenecity who found that 1.1% of pregnant women received a teratogenic drug after their first prenatal care visit and that 0.3% received four or more dispensings of a known teratogen.
135. Id.
136. Rileyetal., et al., supra note75,at404.
137. Euni Lee et al., National Patterns of Medication Use Duriifg Pregnancy, 15 PHARMACOEPIDEMIOLOGY & DRUG SAFETY 537, 540 (2006).
138. Janet R. Hardy et al., Safety of Medications Prescribed Before and During Early Pregnancy in a Cohort of 81,975 Mothers from the UK General Practice Research Database, 15 PHARMACOEPIDEMIOLOGY & DRUG SAFETY 555, 562 (2006).
139. S.W. Wen et al., Patterns of Pregnancy Exposure to Prescription FDA C, D and X Drugs in a Canadian Population, 28 J. PERINATOLOGY 324 (2008).
140. Among this study's disturbing findings is the fact that trimethoprim/sulfamethoxazole was the antibiotic most frequently prescribed to pregnant women.
141. Id. at 327.
142. Trimethoprim/sulfamethoxazole is a folic acid antagonist that can cause birth defects and other problems in newborns.
143. Id.
144. There are alternative antibiotics which are equally effective.
145. Id.
146. This suggests that generating safety and efficacy information is only one piece of a larger puzzle. In addition to information gaps, there are dissemination gaps.
147. I. Lacroix et al., Prescription of Drugs During Pregnancy in France, 356 THE LANCET 1735, 1735-36(2000).
148. Id. at 1736.
149. Riley et al., supra note 75, at 408
150. ("Although the prenatal use of many of the category D and X drugs identified in our analysis may place women or their unborn children at unnecessary risk, some of these drugs may have been prescribed after careful consideration that benefits outweigh the risks.").
151. See id. at 401 (noting that there are safer alternatives for many of the category D and X medications that pregnant women are prescribed);
152. Noah, supra note 34, at 377 ("[W]e already have evidence-based medicines, but we most certainly do not yet enjoy fully evidence-based medical practice.").
153. Rebecca S. Eisenberg, The Problem of New Uses, 5 YALE J. HEALTH POL'Y L. & ETHICS 717,718(2005).
154. Id.
155. Id.
156. This risk may be lessened in the maternal-fetal context, because a finding that a drug is unsafe for use during pregnancy could leave its broader market unaffected.
157. Benjamin N. Roin, Unpatentable Drugs and the Standards of Patentability, 87 TEX. L. REV. 503,563 (2009).
158. Id.
159. Eisenberg, supra note 86, at 719-20.
160. Firms are, of course, also subject to a host of other incentives unrelated to the legal regimes discussed. To give just one example, insurance reimbursement may be conditioned on scientifically sound safety and efficacy evidence.
161. See Stephen Siciliano, Randomized Clinical Trial Said Needed to Gain Payment for Novel Therapeutic, A LIFE SCI. L. & INDUS. REP. 236, 236 (2010).
162. Cf. AETNA, CLINICAL POLICY BULLETIN: TERBUTALINE PUMP FOR PRETERM LABOR, http://www.aetna.com/cpb/ medical/date/400-499/0468.html (last visited Apr. 30, 2010) (summarizing the existing evidence on the use of the asthma medication terbuteline off-label for preventing or treating preterm labor and determining that the use was "experimental and investigational," that is, unlikely to be reimbursed).
163. Eisenberg, supra note 86, at 717.
164. Id. at 721;
165. Kevin Outterson, Pharmaceutical Innovation: Law & the Public's Health, 3 7 J.L. MED. & ETHICS 173, 173 (2009)
166. ("While empirical research suggests that patents are an ineffective incentive for innovation generally, patents retain their paradigmatic function in the pharmaceutical and chemistry industries.").
167. Eisenberg, supra note 86, at 721.
168. Id. at 724.
169. But see Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd., 601 F.3d 1359, 1365 (Fed. Cir. 2010)
170. ("This court perceives that the Hatch-Waxman Act will thus ensure that a generic drug for non-patented purposes will not be used for patented purposes via a simple section via certification. Instead, the generic manufacturer will need to alleviate the risk of infringement or induced infringement in a proceeding that fully tests for infringement and its implications, including potential health and safety risks.").
171. Eisenberg, supra note 86, at 724.
172. Obstetrics has been called the '"the least scientific specialty in medicine,'" in part because the mainstays of its drug formulary "hark back to an earlier era."
173. Nicholas M. Fisk & Rifat Atun, Market Failure and the Poverty of New Drugs in Maternal Health, 5 PLoS MED. 22, 22 (2008).
174. See also ATUL GAWANDE, BETTER: A SURGEON'S NOTES ON PERFORMANCE 188 (2007).
175. A recent study which compared drug development in maternal health with the drug pipelines for cardiovascular disease, a mainstream but not leading specialty area, and amyotrophic lateral sclerosis, an orphan disease afflicting just 20,000 patients in the seven main drug markets, found that there are only seventeen drugs under development in obstetrics, compared to six hundred sixty in cardiovascular disease and thirty-four in amyotrophic lateral sclerosis.
176. Id. at 23-24.
177. The authors of the study concluded that "[p]regnant women look set to miss out on the therapeutic advances expected from modern drug R&D in other fields that will benefit from combinatorial chemistry, high throughput screening, pharmacogenomics, bioinformatics, nanotechnology, the '-omic' sciences, and biologies."
178. Id. at 25.
179. As of 2007, the only treatment for two of the three main pregnancy complications (intrauterine growth restriction and pre-eclampsia) was childbirth.
180. Fisk & Atun, supra note 98, at 26.
181. In the United States, there is no available approved treatment for the third (preterm labor), which is managed with drugs and other interventions of questionable efficacy.
182. Id.
183. See also Hyagriv N. Simhan & Steve N. Caritis, Prevention of Preterm Delivery, 357 NEW ENG. J. MED. 477,479 (2009) (noting that "the whole class of labor-inhibiting drugs is largely ineffective").
184. 21 U.S.C.A. §331(d) (West 2010).
185. Eisenberg, supra note 86, at 730.
186. 21 U.S.C.A. §355(d) (West 2010).
187. Eisenberg, supra note 86, at 730.
188. See also Adriane Fugh-Berman & Douglas Melnick, OffLabel Promotion, On-Target Sales, 5 PLoS MED. 1432, 1433 (2008) ("In development, drugs may be promising for several uses, and companies must choose one or two conditions on which to focus research. Ease of approval is the most important factor in this decision.").
189. Eisenberg, supra note 86, at 723 (explaining that firms are entitled to "patent term extensions of up to five years to compensate for some of the time that the patent meter is ticking pending regulatory approval of a new drug, so long as the total remaining patent life after extensions does not exceed fourteen years from the date of approval").
190. 21 U.S.C.A. §355 (c)(3)(E)(ii) (West 2010).
191. Eisenberg, supra note 86, at 725, 730.
192. Once a drug's data exclusivity period has expired, a competitor no longer has to file a new drug application and show that its product is safe and effective. Instead, it can file an abbreviated new drug application (ANDA) based on a showing that the drug is bioequivalent to the already-approved drug. Id. at 727.
193. U.S. FOOD & DRUG ADMIN., DEPT. OF HEALTH & HUMAN SERVS., GUIDANCE FOR INDUSTRY: M3(R2) NONCLINICAL SAFETY STUDIES FOR THE CONDUCT OF HUMAN CLINICAL TRIALS AND MARKETING AUTHORIZATION FOR PHARMACEUTICALS 2 (2010), available at http://www.fda.gov/ downloads/Dmgs/ GuidanceComplianceRegulatorytaforrnation/Guidances/ucm073246.pdf [hereinafter 2010 SAFETY STUDIES GUIDANCE].
194. U.S. FOOD & DRUG ADMIN., DEPT. OF HEALTH & HUMAN SERVS., GUIDANCE FOR INDUSTRY: DETECTION OF TOXICITY TO REPRODUCTION FOR MEDICINAL PRODUCTS 12-13 (1994), available at http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ GuidancesAicm074950.pdf.
195. Wendy E. Wagner, Choosing Ignorance in the Manufacture of Toxic Products, 82 CORNELL L. REV. 773, 774 (1997) (noting the tentative relationship between a product's teratogenicity in animals and its teratogenicity in humans).
196. Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831, 30,841 (proposed May 29, 2008) (to be codified at 21 C.F.R. pt. 201).
197. Koren et al., supra note 33, at 1131.
198. Bonnie Steinbock, Ethical Issues Related to the Inclusion of Pregnant Women in Clinical Trials (11), in 1 WOMEN AND HEALTH RESEARCH: ETHICAL AND LEGAL ISSUES OF INCLUDING WOMEN IN CLINICAL STUDIES 23,23 (Anna C. Mastroianni et al. eds., 1994).
199. THE NAT'L COMM'N FOR THE PROT, OF HUMAN SUBJECTS OF BIOMEDICAL & BEHAVIORAL RES., U.S. DEP'T OF HEALTH, EDUCATION AND WELFARE, REPORT AND RECOMMENDATIONS: RESEARCH ON THE FETUS 12 (1975) ("Preliminary testing of rubella vaccine in monkeys indicated that the vaccine virus did not cross the placenta. In contrast, studies on women requesting therapeutic abortion showed clearly that the vaccine virus did indeed cross the placenta and infect the fetus, indicating the danger of administering the vaccine during pregnancy.").
200. Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831, 30,841 (proposed May 29, 2008) (to be codified at 21 C.F.R. pt. 201).
201. Carl H. Coleman, Rationalizing Risk Assessment in Human Subject Research, 46 ARIZ. L. REV. 1,5 (2004).
202. Id.
203. See 45 C.F.R. §§46.107(a), 46.11 l(aX3), (b), 46.116(b)(1) (2010). As Carl Coleman notes, the Common Rule does not define vulnerability and the examples it gives are diverse. Carl H. Coleman, Vulnerability as a Regulatory Category in Human Subject Research, 37 J.L. MED. & ETHICS 12, 12 (2009). With regard to pregnant women, "it is not clear why any special issues related to capacity or coercion would necessarily arise." Id.
204. 45 C.F.R. §46.107(a).
205. Id. § 46.111(a)(3), (b).
206. Id §46.116(bXl).
207. Lyerly et al., supra note 14, at 18.
208. 45 C.F.R. §46.204(a) (2010).
209. Id. §46.204(d). In the context of pediatric research, the requirement that studies hold out the prospect of direct benefit has been interpreted broadly to include not just "[m]ost research on a drug to cure or alleviate the discomfort of a subject with an underlying disorder or condition" but also placebocontrolled trials in which some number of enrollees receive an inert intervention. I. Glenn Cohen, Therapeutic Orphans, Pediatric Victims? The Best Pharmaceuticals for Children Act and Existing Human Subject Protections, 58 FOOD & DRUG L.J. 661, 694-96 (2003).
210. See also Sanjiv B. Amin et al., Clinical Trials of Drugs Used Off-Label in Neonates: Ethical Issues and Alternative Study Designs, 15 ACCOUNTABILITY IN RES. 168, 171-75 (2008) (discussing the ethical issues arising in active controlled and placebo controlled trials in neonates). Relying on evidence that even children who receive the placebo in placebo-controlled trials benefit from their participation, including from increased care and monitoring, the FDA has announced that placebo-controlled trials can be compatible with the direct benefit requirement. Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products, 66 Fed. Reg. 20,589,20,593 (interim rule Apr. 24,2001).
211. 45 C.F.R. §46.204(d).
212. Id. §46.204(e). Karen Rothenberg opines that: It is incongruous that the paternal consent requirements in Subpart B have remained in place while DHHS regulations on research involving children only require the permission of one parent when such research poses either no greater than minimal risk or the prospect of direct benefit to the child.... Subpart B and its "special" treatment of pregnant women would become symbolic of the regulatory barriers to research that still remain. Karen H. Rothenberg, Gender Matters: Implications for Clinical Research and Women's Health Care, 32 HOUS. L. REV. 1201,1229 (1996).
213. Lyerly et al., supra note 14, at 18.
214. L. Elizabeth Bowles, Note, 77ie Disfranchisement of Fertile Women in Clinical Trials: The Legal Ramifications of and Solutions for Rectifying the Knowledge Gap, 45 VAND. L. REV. 877, 895-96 (1992).
215. U.S. DEPT. OF HEALTH & HUMAN SERVS., FOOD & DRUG ADMIN., GENERAL CONSIDERATIONS FOR THE CLINICAL EVALUATION OF DRUGS 7 (1977). Later in the document, the FDA qualifies its advice, saying that women of childbearing potential should be excluded from Phase I clinical trials "[i]n most cases," id. at 7, and "in general," id. at 10.
216. Id. at 6.
217. Id.
218. Id. at 10.
219. Id.
220. Id. at 6, 10.
221. Id. at 10.
222. Id. at 11.
223. Christine Grady & Colleen Denny, Research Involving Women, in THE OXFORD TEXTBOOK OF RESEARCH ETHICS 407,409 (Ezekiel J. Emanuel et al. eos., 2008).
224. Id.
225. National Institutes of Health: Problems in Implementing Policy on Women in Study Populations, Testimony Before the Subcomm. on Health and the Environment, Comm. on Energy and Commerce, 101st Cong. 3-4 (1990) (statement of Mark Nadel, Associate Director, National and Public Health Issues, Human Resource division), available at http://archive.gao.gov/d48tl3/141859.pdf.
226. Karen H. Rothenberg, Gender Matters: Implications for Clinical Research and Women's Health Care, 32 HOUS. L. REV. 1201,1231 (1996).
227. Id.
228. Id.
229. Id. at 142.
230. Grady & Denny, supra note 137, at 410.
231. NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research, 59 Fed. Reg. 11,146 (Mar. 9,1994).
232. 1 COMM. ON ETHICAL & LEGAL ISSUES RELATING TO THE INCLUSION OF WOMEN IN CLINICAL STUDIES, INST, OF MED., WOMEN AND HEALTH RESEARCH: ETHICAL AND LEGAL ISSUES OF INCLUDING WOMEN IN CLINICAL STUDIES 194-95 (Anna C. Mastroianni et al. eds., 1994) [hereinafter INST. OF MED.].
233. Id. at 195.
234. Id. at 198.
235. Rothenberg, supra note 126, at 1239.
236. Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs, 58 Fed. Reg. 39,406,39,409-11 (July 22, 1993).
237. Id. at 39,411.
238. Id.
239. See, e.g., Stanford University Research Compliance Office, Stanford Consent Form Template with HIPAA 5, available at http://humansubjects.stenford. edu/research/medical/ med-consent.html#forms (last visited Nov. 12, 2010) (suggesting that informed consent forms incorporate the following language: "If you are a woman who is able to get pregnant, it is expected that you will use an effective method of birth control to prevent exposing a fetus to a potentially dangerous agent with unknown risk. If you are pregnant or currently breast feeding, you may not participate in this study.").
240. E-mail from Anne Drapkin Lyerly, Associate Professor of Obstetrics & Gynecology, Duke Univ. Sch. of Med., to Kate Greenwood, Research Fellow and Lecturer in Law, Seton Hall Univ. Sch. of Law (July 30,2009, 11:49 EST) (on file with author).
241. 2010 SAFETY STUDIES GUIDANCE, supra note 108, at 18-19.
242. Id.
243. U. S. GEN. ACCOUNTING OFFICE, GAO-01-754, WOMEN'S HEALTH: WOMEN SUFFICIENTLY REPRESENTED IN NEW DRUG TESTING, BUT FDA OVERSIGHT NEEDS IMPROVEMENT 3 (2001).
244. Lyerly et al., supra note 14, at 6. See also Diego F. Wyszynski, Pregnancy Exposure Registries: Academic Opportunities and Industry Responsibility, 85 BIRTH DEFECTS RES. PART A: CLINICAL & MOLECULAR TERATOLOGY 93, 93 (2009) ("[P]regnant women are actively excluded from clinical trials[.]").
245. Comments of Pharm. Res. and Mfrs. of Am. on Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831 (May 29,2008).
246. Comments of Public Citizen on Content and Format of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30,831 (May 29,2008).
247. Id.
248. Id.
249. Lo & Friedman, supra note 71, at 465.
250. 21 C.F.R. §202.1(eX6)(i) (2010).
251. Rebecca Dresser & Joel Frader, Off-Label Prescribing: A Call for Heightened Professional and Government Oversight, 37 J.L. MED. & ETHICS 476,477 (2009).
252. Wash. Legal Found, v. Friedman, 13 F. Supp. 2d 51,55-56 (D.D.C. 1998), amended by 36 F. Supp. 2d 16 (D.D.C. 1999), vacated in part by Wash. Legal Found, v. Henney, 202 F.3d 331 (D.C. Cir. 2000).
253. 21 U.S.C.A. §355(c)(3)(E)(iii) (West 2010).
254. Eisenberg, supra note 86, at 729.
255. Friedman, 13 F. Supp. 2d at 70-71 (D.D.C. 1998).
256. 21 C.F.R. §314.70(b) (2010).
257. Ass'n of Am. Physicians & Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204,206 (D.D.C. 2002).
258. Citizen Petition Regarding the Food and Drug Administration's Policy on Promotion of Unapproved Uses of Approved Drugs and Devices; Request for Comments, 59 Fed. Reg. 59,820, 59,821 (Nov. 18,1994).
259. Buckman Co. v. Plaintiffs' Legal Comm., 531 U.S. 341, 350 (2001) (citing 21 U.S.C. §396 (1994 & Supp. V)).
260. The FDA does allow certain company communications about off-label uses. For example, companies can distribute, among other things, peer-reviewed medical journal articles that discuss such uses. See U.S. FOOD & DRUG ADMIN., DEPT. OF HEALTH & HUMAN SERVS., GUIDANCE FOR INDUSTRY - GOOD REPRINT PRACTICES FOR THE DISTRIBUTION OF MEDICAL JOURNAL ARTICLES AND MEDICAL OR SCIENTIFIC REFERENCE PUBLICATIONS ON UNAPPROVED NEW USES OF APPROVED DRUGS AND APPROVED OR CLEARED MEDICAL DEVICES (2009), available at http://www.fda.gov/ RegulatoryInformation/Guidances/ucml25126.htm.
261. 21 U.S.C.A. §§331 (d), 355(a) (West 2010).
262. U.S. FOOD & DRUG ADMIN., supra note 174.
263. 21 U.S.C.A. §321(p) (West 2010).
264. §321(m). But cf. §321(k) (defining "label" more narrowly, to include "a display of written, printed, or graphic matter upon the immediate container of any article").
265. Kordel v. United Stetes, 335 U.S. 345,350 (1948).
266. U.S. FOOD & DRUG ADMIN., supra note 174
267. (citing 21 U.S.C. §352(f); 21 C.F.R. § 201.100(c)(1)).
268. 21 U.S.C.A. §352(f)(1) (West 2010).
269. 21 C.F.R. §201.100(c)(1) (2010).
270. Id. §201.128.
271. See, e.g., Wash. Legal Found, v. Friedman, 13 F. Supp. 2d 51, 70 (D.D.C. 1998) (holding that "defendants have proved to this court's satisfaction
272. Catherine Larkin, Lilly Wins Backing to Use Antidepressant Cymbaltafor Back, Arthritis Pain, BLOOMBERG, Nov. 4, 2010, http://www.bloomberg.com/news/ 2010-l 1-04/lilly-wins-backing-to-use-antidepressantcymbalta-for-back-arthritis- pain.html (citing an analyst's estimate that the approval of a supplemental new drug application for the antidepressant Cymbalte will result in a $500 million increase in annual sales).
273. Marc Iskowitz, Pfizer Nearly Doubles Amount Spent on E-Detailing, MMM-ONLINE, Jan. 19, 2010, http://www.mmm-online.com/pfizer-nearly-doubles- amount-spent-on-e-detailing/article/ 161727/.
274. See PHARM. RES. & MFRS. OF AM., CODE ON INTERACTIONS WITH HEALTHCARE PROFESSIONALS 9-10 (2008) (setting forth ethical guidelines for company-run "Speaker Programs and Speaker Training Meetings").
275. See Puneet Manchanda & Elisabeth Honka, The Effects and Role of Direct-to-Physician Marketing in the Pharmaceutical Industry: An Integrative Review, 5 YALE J. HEALTH POL'Y L. & ETHICS 785, 785-86 (2005) ("The marketing efforts directed at physicians comprise personal selling through sales representatives (detailing); sampling (provision of drugs at no cost); physician meetings and events; and advertisements in medical journals." (citations omitted)); Running a Hospital, http://runningahospitel.blogspot.com/ 2009/05/3-l-l-0.html (May 26, 2009, 06:37 PM) (questioning the efficacy of an advertisement for an atrial fibrillation catheter that appeared on plastic bags handed out by airport security; commenters noted that the distribution of the bags coincided with a meeting of the Heart Rhythm Society).
276. John E. Calfee et al., Direct-to-Consumer Advertising and the Demand for CholesterolReducing Drugs, 45 J.L. & ECON. 673,678 (2002).
277. Sara T.M. Kremer et al., Generaltations on the Effectiveness of Pharmaceutical Promotional Expenditures, 25 INT'L J. RES. MKTG. 234,244 (2008).
278. Id.
279. IMS, IMS Facts at a Glance, http://www.irnshealm.com/portel/site/ imshealth/menuitem (follow "About Us... more" hyperlink; then follow "Facts-At-a-Glance" hyperlink) (last visited Feb. 25,2010).
280. IMS, Total U.S. Promotional Spend by Type, 2009, http://www.imshealth. com/ deployedfiles/imshealth/Global/Content/StaticFile/Top-Line-Data/ PromoUpdate2009.pdf (last visited Nov. 8,2010).
281. See Leslie Kushner, Note, Incentivizing Postmarketing Pharmaceutical Product Safety Testing with Extension of Exclusivity Periods, 19 FORDHAM INTELL. PROP. MEDIA & ENT. LJ. 519, 537-39 (2009) (discussing impact of safety findings on sales of the anemia drug Aranesp and the multiple sclerosis drug Tysabri).
282. Lauren Hammer Breslow, Note, The Best Pharmaceuticals for Children Act of 2002: The Rise of the Voluntary Incentive Structure and Congressional Refusal to Require Pediatric Testing, 40 HARV. J. ON LEGIS. 133,152-53 (2002).
283. Transcript of Testimony of David Healy at 20, Kilker v. SmithKline Beecham Corp. (Pa. Ct. Com. P1. Sept. 16, 2009 Morning Session) (No. 1813) (attorney for the plaintiff Sean Patrick Tracey representing to the court that "Dr. Ruppersberger has testified that the GSK sales reps came to his office and pushed him to prescribe this drug to women of childbearing age because it was a Category C").
284. Transcript of Testimony of Suzanne Parisian at 31-32, Kilker v. SmithKline Beecham Corp. (Pa. Ct. Com. Pl. Sept. 18, 2009 Afternoon Session) (No. 1813) (reviewing a memorandum for sales representatives and affirming that "[i]t says study, reinforce what you have already been telling physicians. No SSRI has been shown to have superior safety versus Paxil for use during pregnancy[.]").
285. Jef Feeley & Sophia Pearson, Glaxo Ordered to Pay $2.5 Million for Paxil Defects (Update4), BLOOMBERG, Oct. 13, 2009, http://www.bloomberg. com/apps/ news?pid=20601103&sid=apENrx2KUBcY.
286. Id.
287. Jef Feeley & Triste Kelley, Glaxo Said to Have Paid $1 Billion Over Paxil Suits, BLOOMBERG, July 20, 2010, http://www.bloomberg.com/news/2010- 07-20/glaxo-said-to-have-paid-lbillion-to-resolve-paxil-birth-defect-lawsuits. html.
288. Ellen Wright Clayton, Liability Exposure When Offspring Are Injured Because of Their Parents ' Participation in Clinical Trials, in 2 WOMEN AND HEALTH RESEARCH: ETHICAL AND LEGAL ISSUES OF INCLUDING WOMEN IN CLINICAL STUDIES 108 (Anna C. Mastroianni et al. eds., 1994).
289. Id. at 109.
290. Id. at 103, 109.
291. Adopted by almost all jurisdictions, the learned intermediary doctrine provides that manufacturers are not obliged to warn patients directly; giving an adequate warning to the physicians who prescribe the drug suffices.
292. See Margaret Gilhooley, Learned Intermediaries, Prescription Drugs, and Patient Information, 30 ST. LOUIS U. LJ. 633,634 (1985).
293. Edward J. Saunders & Jeanne A. Saunders, Drug Therapy in Pregnancy: The Lessons of Diethylstilbestrol, Thalidomide, and Bendectin, 11 HEALTH CARE FOR WOMEN INT'L 423,423 (1990).
294. Jane E. Brody, Shadow of Doubt Wipes Out Bendectin, N.Y. TIMES, June 19,1983, at E7.
295. Koren et al., supra note 33, at 1129.
296. Joseph Sanders, The Bendectin Litigation: A Case Study in the Life Cycle of Mass Torts, 43 HASTINGS L.J. 301,321 (1992).
297. Id. at 317, 321.
298. Joseph Sanders, From Science to Evidence: The Testimony on Causation in the Bendectin Cases, 46 STAN. L. REV. 1, 7 (1993).
299. Wagner, supra note 110, at 829-30.
300. Id.
301. Id.
302. Id.
303. RESTATEMENT (THIRD) OF TORTS: PRODUCTS LIABILITY §6(d) (1998). Many medications are used "off-label" in pregnant women, for example nifedipine, an anti-hypertensive drug, and terbuteline, an anti-asthmatic drug, both of which are prescribed to arrest pre-term labor. Courts have held that manufacturers are liable for failure to warn of known risks attendant to off-label uses if the uses are reasonably foreseeable.
304. See Knipe v. Smithkline Beecham, 583 F. Supp. 2d 602, 629 (E.D. Pa. 2008) (citing cases).
305. RESTATEMENT (THIRD) OF TORTS: PRODUCTS LIABILITY §6 cmt. g (1998). See also id. §10 cmt. c (charging sellers with "knowledge of what reasonable testing would reveal" and noting that "courts traditionally impose a continuing duty of reasonable care to test and monitor after sale to discover product-related risks.").
306. Lindsay v. Ortho Pharm. Corp., 637 F.2d 87,91 (2d Cir. 1980).
307. Lars Noah, This is Your Products Liability Restatement on Drugs, IA BROOK. L. REV. 839, 907 (2009).
308. Transcript of Opening Statement of Sean Patrick Tracey at 31-32, 49-50, Kilker v. SmithKline Beecham Corp. (Pa. Ct. Com. Pl. Sept. 15,2009) (No. 1813).
309. Home v. Novartis Pharms. Corp., 541 F. Supp. 2d 768, 782-83 (W.D.N.C. 2008) (internal citation omitted).
310. George Conk and others have argued that, whatever its precise contours, the tort law duty to test approved products for safety issues is inadequate. See Lars Noah, Platitudes about "Product Stewardship" in Torts: Continuing Drug Research and Education, 15 MICH. TELECOMM. & TECH. L. REV. 359, 360 (2009)
311. (citing George W. Conk, Punctuated Equilibrium: Why §402A Flourished and the Products Liability Restatement Languished, 26 REV. LITIG. 799, 856-62, 878-80 (2007);
312. Margaret A. Berger & Aaron D. Twerski, Uncertainty and Informed Choice: Unmasking Daubert, 104 MICH. L. REV. 257 (2005)).
313. Conk believes that companies have or should have a duty of "product stewardship" which flows "from the manufacturer's design experience and from the marketer's observation of its product's performance in the field."
314. George W. Conk, The True Test: Alternative Safer Designs for Drugs and Medical Devices in a Patent-Constrained Market, 49 UCLA L. REV. 737, 749 (2002).
315. Lars Noah has argued in opposition to proposals like these that a "duty to investigate all foreseeable uses to which health care professionals might put an approved drug would be entirely unmanageable, and it would threaten to deprive intended users of a valuable product."
316. Noah, supra note 216, at 907.
317. See, e.g., PETER W. HUBER, LIABILITY: THE LEGAL REVOLUTION AND ITS CONSEQUENCES 155 (1988)
318. (quoting statement of pharmaceutical company president that no one in his or her "right mind" would develop products for pregnant women because of the liability exposure);
319. Fisk & Atun, supra note 98, at 26
320. (ascribing the failure to "test (let alone develop) drugs in pregnancy" to "risk aversion to the possibility of teratogenicity" which "is exacerbated by high lifelong settlement costs for a baby damaged in utero" and "by a jury-determined tort process, which favours punitive damages");
321. Vanessa Merton, Impact of Current Federal Regulations on the Inclusion of Female Subjects in Clinical Studies, in 2 WOMEN AND HEALTH RESEARCH: ETHICAL AND LEGAL ISSUES OF INCLUDING WOMEN IN CLINICAL STUDIES 65, 76 n.2 (Anna C. Mastroianni et al. eds., 1994) (predicting that, absent regulatory compulsion, liability concerns would remain "formidable obstacles to the participation of women as subjects in biomedical research");
322. Comment of DV Jr. to Ed Silverman, Nothing in the Oven for Pregnancy Complications, PHARMALOT, June 4, 2008, http://www.pharmalot.com/2008/06/ nothing-inthe-oven-for-pregnancy-complications ("While acknowledging the problem, I have to say a drug company would be C-R-A-Z-Y to investigate a product in pregnant women in today's litigation-friendly environment.");
323. Comment of Ol Cranky to Ed Silverman, Nothing in the Oven for Pregnancy Complications, PHARMALOT, June 4, 2008, http://www.pharmalot.com/2008/06/ nothing-in-the-ovenfor-pregnancy-complications ("The risk would have been way too huge for most companies to consider years ago - now it would be absolute suicide.").
324. Randi Zlotnik Shaul et al., Legal Liabilities in Research: Early Lessons from North America, BMC MED. ETHICS 6:4, June 2005 http://www.biomedcentral.com/ content/pdf/1472-6939-6-4.pdf.
325. 21 C.F.R. §312.50(2010).
326. See, e.g.. Craft v. Vanderbilt Univ., 18 F.Supp.2d 786, 789 (M.D. Tenn. 1998)
327. (Plaintiffs, previously pregnant women and the children they were carrying, who were non-consenting subjects of experiments involving radioactive iron, sued under multiple federal and state law theories including battery, negligence, and medical malpractice.).
328. For example, in Berman v. The Fred Hutchinson Cancer Research Ctr., No. C01-0727L (W.D. Wa. Aug. 8, 2002),
329. the court found that the plaintiffs consent was invalid because she was promised, falsely, that she could receive a chemotherapy drug intravenously if she could not tolerate oral administration. Courts have also found that the failure to disclose certain conflicts of interest can invalidate consent.
330. See, e.g., Darke v. Estate of Isner, 17 Mass. L. Rptr. 689 (Mass. Super. Ct. 2004)
331. (holding that a doctor could be subject to medical malpractice liability under Massachusetts law for failing to disclose to his patient that he had a financial interest in the clinical trial that he recommended to his patient).
332. Anna C. Mastroianni, HIV, Women, and Access to Clinical Trials: Tort Liability and Lessons from DES, 5 DUKE J. GENDER L. & POL'Y 167, 179-80 (1998).
333. See Noah, supra note 216, at 839 n.293;
334. Jill Wadlund, Heading off a Clinical Trial Liability Lawsuit, 12 APPLIED CLINICAL TRIALS 50,50 (2003).
335. An unreported case of note is Crayton v. UT Med. Group Inc., No. CT-007219-04 (Tenn. Cir. Ct. Dec. 28, 2004),
336. which involved a pregnant woman who participated in a clinical trial evaluating the safety and efficacy of two drugs used to prevent maternal-fetal transmission of the HIV virus. Andrew M. Ballard, Wrongful Death Lawsuit Filed in Tennessee Over Clinical Trial Using AIDS Drug Nevirapine, MED. RES. L. & POL'Y REP., Jan. 2005, available at http://healthcenter.bna.com/pic2/hc.nsf/id/ BNAP-68LRCB70penDocument (reporting on Crayton).
337. The woman's baby was delivered by cesarean section after the woman developed severe side effects.
338. Id.
339. The woman died two days later.
340. Id.
341. The plaintiffs' claimed that the two defendant pharmaceutical companies "failed to adequately warn consumers of the potential adverse side effects associated with their products and were negligent in the design, manufacture, testing, advertising, warning, marketing, and sale of the drugs."
342. Id.
343. See Diaz v. Hillsborough County Hosp. Auth., No. 8:90-CV-120-T-25B, 2000 U.S. Dist. LEXIS 14061 (M.D. FIa. Aug. 7, 2000);
344. Craft, 18 F. Supp. 2d 786;
345. Wetherill v. Univ. of Chicago, 570 F. Supp. 1124 (N.D. 111. 1983);
346. Mink v. Univ. of Chicago, 460 F. Supp. 713 (N.D. 111. 1978).
347. The lead plaintiff in the Diaz case, Flora Diaz, participated in a study of drugs used to accelerate fetal lung development which randomized pregnant women between standard treatment with corticosteroids and an experimental combination of corticosteroids and thyroid hormone.
348. Richard S. Saver, Medical Research and Intangible Harm, IA U. CIN. L. REV. 941, 977 (2006).
349. Her allegations with regard to the consent process have implications for research involving pregnant women generally.
350. Id.
351. Her counsel argued that she suffered from the therapeutic misconception, in part because of class and language barriers, but also because when her consent was sought she was experiencing a high-risk pregnancy and had been treated with pain-killing medications.
352. Id.
353. Diaz is noteworthy because it "was likely the first time research subjects recovered substantial monetary awards in the absence of credible physical injury claims."
354. Id. at 978.
355. After extensive discovery, the plaintiffs in Diaz, a certified class of approximately 5,000 pregnant women, settled with the defendant medical center for $3.8 million.
356. Id.
357. The plaintiffs' novel dignitary harm constitutional claim was central to their success.
358. Id.
359. Ordinary informed consent and negligence claims would have failed because the plaintiffs and their babies did not receive substandard medical care and could not demonstrate any physical harm.
360. Id.
361. See Miller v. Dacus, 231 S.W.3d 903,909-10 (Tenn. 2007) (citing cases).
362. 45 C.F.R. §46.204(d), (e) (2010). Anna Mastroianni points to the Supreme Court's decision in UA W v. Johnson Controls, Inc. as further support for the claim "that the informed consent of the woman will preclude the imposition of liability," noting that the Court commented in dicta that "'[i]f, under general tort principles, Title VII bans sex-specific fetal-protection policies, the employer fully informs the woman of the risk, and the employer has not acted negligently, the basis for holding an employer liable seems remote at best.'"
363. Mastroianni, supra note 225, at 180
364. (quoting UAWv. Johnson Controls, Inc., 499 U.S. 187,208 (1991)).
365. T.D. v. N.Y. State Office of Mental Health, 650 N.Y.S.2d 173, 191-92 (N.Y. App. Div. 1996).
366. See Grimes v. Kennedy Krieger Inst., 782 A.2d 807 (Md. 2001).
367. 45 C.F.R.§ 46.204(b) (2010).
368. Noah, supra note 34, at 451
369. ("Courts sometimes struggle to determine precisely when a seller should have known that its product presented a risk of injury, whether the failure to provide a warning caused the plaintiffs injury given the fact that physicians may learn of new risk information from a variety of other sources, and whether the content and method selected for communicating the information was adequate in light of limitations in the way health care professionals discover and assimilate new information.").
370. Transcript of Closing Statement of Chilton Varner at 117, 127, 145,
371. Kilker v. SmithKline Beecham Corp. (Pa. Ct. Com. Pl. Oct. 8,2009) (No. 1813).
372. Kushner, supra note 193, at 541-42
373. ("[E]ven in the absence of data demonstrating an unsafe product, pharmaceutical manufacturers are not shielded from products liability or products liability litigation. Such suits disincentivize pharmaceutical manufacturers from postmarket safety testing because evidence of safety has little economic value if it does not reduce the costs of litigation and liability.").
374. Ventura et al., supra note 59, at 3, 24.
375. The miscarriage rate for unrecognized pregnancies, that is, those that begin and end so early in gestation that the woman never knew she was pregnant, is believed to be much higher.
376. Id. at 24.
377. Press Release, The American College of Obstetricians and Gynecologists, ACOG Issues New Guidelines on Managing Stillbirths (Feb. 20, 2009), http://www.acog.org/from-home/ publications/press-releases/nr02-20-09-2.cfm.
378. Dept. of Health & Human Servs., Ctrs. for Disease Control & Prevention, Update on Overall Prevalence of Major Birth Defects - Atlanta, Georgia, 1978-2005, 57 MORBIDITY AND MORTALITY WEEKLY REP. 1,2-3 (2008), available at http://www.cdc.gov/mmwr/PDF/wk/mm5701.pdf.
379. * - A Prospective Cohort Study for the Investigation of Drug Use in Pregnancy, 35 INT'L J. CLIN. PHARMACOLOGY & THERAPEUTICS 572, 572 (1997)
380. ("The prevalence of congenital malformations requiring medical intervention or affecting the quality of life is about 70 per 1,000 births [i.e. 0.7%]. Accounting for approximately one third of all deaths in the first year of life, they represent the single most frequent cause of infant mortality-" (citations omitted)).
381. Irl et al., supra note 239, at 572.
382. Id.
383. Id.
384. Arthur Allen, Prepare for a Vaccine Controversy, N.Y. TIMES, Aug, 1, 2009, at WK10 ("[P]regnant women will be urged to get the vaccine because doctors have seen how H1N1 can cause especially nasty infections during pregnancy. But about one in seven pregnancies ends in a miscarriage, so nearly 1,500 of 10,000 women in early pregnancy will miscarry this fall-whether or not they get the H1N1 vaccine.");
385. Ely se Tanouye, Suits Involving Defunct Bendectin Chill Development of Pregnancy Medications, WALL ST. J., June 22, 1993, at Bl
386. ("[This] is a particularly daunting research area for the pharmaceutical companies because drugs can both cause birth defects and be blamed for ones that would have occurred anyway.").
387. Clayton, supra note 200, at 104.
388. Id.
389. Id. at 104 n.4.
390. Tanouye, supra note 243, at B1.
391. Wendy K. Mariner, Compensation for Research Injuries, in 1 WOMEN AND HEALTH RESEARCH: ETHICAL AND LEGAL ISSUES OF INCLUDING WOMEN IN CLINICAL STUDIES, 113, 118 (Anna C. Mastroianni et al. eds., 1994).
392. See, e.g., Editorial, Drug Development for Maternal Health Cannot Be Left to the Whims of the Market, 5 PLOS MED. 841, 842 (2008) (arguing that any mechanism to encourage "the testing and collection of data on old and new drugs" in pregnancy would need to "specifically accept liability when harm occurs");
393. Lyerly et al., supra note 14 at 17 (recommending that "the liability concerns that animate so much of the behavior around research and drug development during pregnancy" be addressed at the federal and state levels);
394. see also, e.g., James M. Wood et al., Product Liability for Stem Cell Research and Therapies -A Proposal, 18 HEALTH LAWYER 1 (2005) (recommending adoption of an alternative compensation system for stem cell research);
395. William M. Brown, Déjà Vu All Over Again: The Exodus from Contraceptive Research and How to Reverse It, 40 BRANDÉIS L.J. 1 (2001) (contraceptive research);
396. Andrew R. Klein, A Legislative Alternative to "No Cause" Liability in Blood Products Litigation, 12 YALE J. ON REG. 107 (1995) (blood products);
397. Gregory C. Jackson, Comment, Pharmaceutical Product Liability May Be Hazardous to Your Health: A No-Fault Alternative to Concurrent Regulation, A1 AM. U. L. REV. 199 (1992) (all drug products);
398. H. William Smith, III, Note, Vaccinating AIDS Vaccine Manufacturers Against Product Liability, A1 CASE W. RES. L. REV. 207 (1992) (AIDS vaccine).
399. National Childhood Vaccine Injury Act of 1986,42 U.S.C. §300aa-34 (2006).
400. Breslow, supra note 194, at 142 n.78
401. (quoting Wyeth Laboratories executive who testified before Congress that his company had stopped marketing the diphtheria, tetanus, and pertussis vaccine "because of extreme liability exposure, cost of litigation and the difficulty of continuing to obtain adequate insurance").
402. Notably, before the legislation creating the VICP was enacted, a second manufacturer resumed manufacturing and distributing the vaccine.
403. Lainie Rutkow et al., Balancing Consumer and Industry Interests in Public Health: The National Vaccine Injury Compensation Program and Its Influence During the Last Two Decades, 111 PENN. ST. L. REV. 681, 696 (2007).
404. Id. at 688-703.
405. Id. at 684.
406. 42 U.S.C. §300aa-15(a), (e)(1)(A) (2006).
407. Id. §300aa-15(a)(4), (d).
408. Id. §300aa-15(a)(2).
409. Id. §300aa-15(i)(2);
410. 26 U.S.C. §9510(b)(1) (2006);
411. 26 U.S.C. §4131(a), (b) (2006).
412. Health Res. & Servs. Admin., U.S. Dep't of Health & Human Servs., Nat'l Vaccine Injury Comp. Program, Statistics Reports, http://www.hrsa.gov/ vaccinecompensation/statistics-report.htm (last visited Nov. 9,2010).
413. 42 U.S.C. §300aa-l 1(a)(1) (2006).
414. Id.
415. Rutkow et al., supra note 252, at 686
416. ("For example, a person would be eligible for VICP compensation if he or she received a measles, mumps, and rubella (MMR) vaccination and experienced anaphylactic shock zero to four hours later.").
417. 42 U.S.C. §300aa-14(e) (2006).
418. Id. §300aa-11(c)(1);
419. 42 U.S.C. §300aa-13(a)(1) (2006).
420. Id. §300aa-l 1(C)(1)(C)(ii).
421. Rutkow et al., supra note 252, at 684.
422. 42 U.S.C. §300aa-12(e) (2006).
423. Id. §300aa-12(f).
424. Id. §300aa-21.
425. Id. §300aa-22(bXl).
426. With certain exceptions a vaccine shall be presumed to be accompanied by proper directions and warnings if the vaccine manufacturer shows that it complied in all material respects with all requirements under the Federal Food, Drug, and Cosmetic Act... and section 351 of the Public Health Service Act... (including regulations issued under such provisions) applicable to the vaccine and related to vaccine-related injury or death for which the civil action was brought[.]
427. Id. §300aa-22(bX2).
428. In October 2010, the Supreme Court heard oral argument in a case in which the plaintiff has challenged the scope of the National Vaccine Injury Compensation Act's preemption provisions.
429. See Posting of Matthew Scarola to SCOTUSblog, http://www.scotusblog.com/ 2010/10/ argument-recap-court-considers-vaccine-design-defect-liability/ (Oct. 14,2010,11:08 AM).
430. 42 U.S.C. §300aa-22(c) (2006).
431. Id §300aa-23(d)(2).
432. Ross D. Silverman, Litigation, Regulation, and Education - Protecting the Public's Health through Childhood Immunization, 360 NEW. ENG. J. MED. 2500,2501 (2009).
433. Anthony Ciolli, Religious & Philosophical Exemptions to Mandatory School Vaccinations: Who Should Bear the Costs?, 74 Mo. L. REV. 287, 297 (2009)
434. (explaining that if a "relatively small percentage of a religious community's population" decide against immunization, the negative externalities could include a loss of herd immunity and a resulting epidemic).
435. Rutkow et al., supra note 252, at 681.
436. INST. OF MED., supra note 146, at 169.
437. Id.
438. Rutkow et al., supra note 252, at 726.
439. Michelle M. Mello & Troyen A. Brennan, Legal Concerns and the Influenza Vaccine Shortage, 294 JAMA 1817,1820 (2005).
440. Cohen, supra note 124, at 662
441. (quoting S. REP. No. 105-43, at 3 (1997)).
442. Id at 663-65.
443. Id. at 667.
444. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, §§501-505A, 121 Stat. 823, 876-89 (to be codified at 21 U.S.C. §355a).
445. 21 U.S.C.A. §355a (West 2010).
446. Id. §355a(c)(1).
447. Cohen, supra note 124, at 666.
448. Eisenberg, supra note 86, at 730.
449. 21 U.S.C.A. §355a(b)(1), (c)(1) (West 2010).
450. Id. §355a(1).
451. Id. §355a(j).
452. Id §355a(e)(2), (f)(6)(D).
453. Id. §355a(n)(1)(A).
454. Id.
455. U.S. Food & Drug Admin., Pediatric Exclusivity Statistics as of November 30, 2009, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/ucm050006.htm (last visited Jan. 7,2010).
456. Jennifer S. Li et al., Economic Return of Clinical Trials Performed Under the Pediatric Exclusivity Program, 297 JAMA 480,480 (2007).
457. U.S. GOV'T ACCOUNTABILITY OFFICE, GAO-07-557, PEDIATRIC DRUG RESEARCH: STUDIES CONDUCTED UNDER BEST PHARMACEUTICALS FOR CHILDREN ACT 5 (2007).
458. Carissa M. Baker-Smith et al., The Economic Returns of Pediatric Clinical Trials of Antihypertensive Drugs, 156 AM. HEART J. 682,682 (2008).
459. U.S. FOOD & DRUG ADMIN., PEDIATRIC LABELING CHANGES THROUGH DECEMBER 24,2009 (2009), http://www.fda.gov/dowrdoads/ScienceResearch/SpecialTopics/ PediatricTherapeuticsResearch/ UCM163159.pdf.
460. Li et al., supra note 295, at 487.
461. The GAO is more generous, determining that 87 percent of the drugs granted pediatric exclusivity between 2002 and 2005 had "important labeling changes" as a result of the studies conducted.
462. U.S. GOV'T ACCOUNTABILITY OFFICE,
463. supra note 296, at 4.
464. Daniel K. Benjamin, Safety and Transparency of Pediatric Drug Trials, 163 ARCHIVES PEDIATRICS & ADOLESCENT MED. 1080,1083 (2009).
465. See Programs Affecting Safety and Innovation in Pediatric Therapies: Hearing Before the Subcomm. on Health of the H.Comm.on Energy and Commerce, 110th Cong. (2007) (Statement of Lori M. Reilly, Vice President, Policy & Research, Pharmaceutical Research Manufacturers of America), http://energycornmerce.house.gov/images/stories/Documents/Hearings/PDF/ 110-he-hrg.052207.Reillytestimony.pdf (urging reauthorization of both the BPCA and the PREA).
466. Noah, supra note 28, at 282-83.
467. 21 U.S.C.A. §355a(bX2), (c)(2) (West 2010).
468. Li et al., supra note 295, at 481.
469. Id. at 483-84.
470. A 2006 industry survey yielded a higher estimated cost: $20 million to complete a BPCA written request. Christopher-Paul Milne & Jon B. Bruss, The Economics of Pediatric Formulation Development for Off-Patent Drugs, 30 CLINICAL THERAPEUTICS 2133, 2138 (2008)
471. Milne and Bruss point out that the estimates used by Li and his co-authors do not include the cost of developing pediatric formulations of a drug.
472. Id.
473. They note that multiple formulations may be necessary to meet the needs of children at various stages of development; they could include "suspensions, sprinkles, oral solutions, coated granules for reconstitution in water, and adult pumps converted to deliver smaller doses."
474. Id.
475. Li et al., supra note 295, at 484-85.
476. Baker-Smith et al., supra note 297, at 685.
477. Id.
478. Id. at 686.
479. Breslow, supra note 194, at 167-69.
480. See THE HENRY J. KAISER FAMILY FOUND., PRESCRIPTION DRUG TRENDS (2010), available at http://www.kff.org/rxdrugs/upload/3057-08.pdf.
481. Breslow, supra note 194, at 189.
482. 42 U.S.C.A.§ 284m (West 2010).
483. Id § 284m(b).
484. 21 U.S.C.A. § 355a(n)(1)(B) (West 2010).
485. Benjamin, supra note 300, at 1085.
486. Cf. Roin, supra note 89, at 561 (noting the government's "history of grossly underfunding clinical research").
487. Milne & Bruss, supra note 305, at 2138-39 ("[M]anufacturers who attempt to respond to Written Requests must begin the investigation with a highly resource-intensive, time-consuming, and risky experiment in formulation development.").
488. Another way to address this would be to de-link the grant of market exclusivity from a drug's patent term, that is, to grant exclusivity to any manufacturer who studied any drug, whether on- or offpatent, in pregnant women. See Roin, supra note 89, at 564 (recommending that Congress authorize the FDA to reward companies that submit new drug applications for drugs with weak or no patent protection with periods of exclusivity).
489. Cf. Mitchell, supra note 14, at 2557 ("It is a matter of concern that pregnancy registries for specific drugs, often operated by manufacturers, seek to recruit patients receiving different drugs into separate registries and a patient receiving multiple drugs into multiple registries. Such competition for patients and practitioners can and may dilute or fragment the efforts of pregnancy registries that focus on a wide range of drugs.").
490. Kevin Outterson, Death from the Public Domain?, 87 TEX. L. REV. SEE ALSO 45, 53 (2009), http://www.texaslrev.com/sites/default/files/seealso/vol87/pdf/ 87TexasLRevSeeAlso45.pdf (suggesting that the benefit of avoiding bias could compensate in whole or in part for any inefficiencies associated with government funding).
491. This is not to suggest that government-funded research is always free of conflicts of interest. Notably, investigators who receive government funding to conduct clinical research often have financial relationships with pharmaceutical companies as well. See, e.g., Letter from Charles E. Grassley, Ranking Member, U.S. Senate Comm. on Fin., to James W. Wagner, President, Emory Univ. (June 2, 2009), http://s.wsj.net/public/resources/documents/WSJ-LttrEmoryUni-090609.pdf
492. (discussing the case of Dr. Zachary Stowe, who in 2007 received $154,400 from GlaxoSmithKline, much of it for talks promoting GSK's antidepressants, at the same time that he served as principal investigator on several NIH grants related to antidepressant use by pregnant women). The NIH has announced plans to amend its conflict of interest regulations to better police these relationships. Responsibility of Applicants for Promoting Objectivity in Research for Which Public Health Service Funding Is Sought and Responsible Prospective Contractors; Proposed Rule, 75 Fed. Reg. 28,688, 28,689 (May 21, 2010).
493. William O. Cooper et al., Major Congenital Malformations after First-Trimester Exposure to ACE Inhibitors, 354 NEW ENG. J. MED. 2443, 2448 (2006).
494. In an accompanying editorial, J.M. Friedman opined as follows: Clearly, more research on the teratogenic potential of ACE inhibitors in early pregnancy is needed. This is not the last word on the subject, but it is shocking to realize that it is almost the first. .... Not knowing the teratogenic risks of these drugs really does matter.... Birth defects caused by teratogenic treatments are preventable, and babies and their mothers are being harmed unnecessarily because we do not know enough about which treatments to use and which to avoid. J.M. Friedman, ACE Inhibitors and Congenital Anomalies, 354 NEW. ENG. J. MED. 2498, 2499 (2006).
495. Krista S. Crider et al., Antibacterial Medication Use During Pregnancy and Risk of Birth Defects, 163 ARCHIVES OF PEDIATRICS & ADOLESCENT MED. 978, 978-79 (2009).
496. The Second Wave: Toward the Responsible Inclusion of Pregnant Women in Medical Research, http://kennedyinstitute.georgetown.edu/secondwave/; http://www.bioethicsinstitute.org/WEB/PAGE/901/SECTIONID/379/PAGELEVEL/2/ INTERIOR.ASP# (last visited Feb. 23, 2010).
497. Rebecca Dresser, Priority Setting in Biomedical Research, 11 VIRTUAL MENTOR 322, 322-25 (2009), http://virtualmentor.ama-assn.org/2009/04/msoc1-0904. html.
498. Lyerly et al., supra note 17, at 3.
499. The Second Wave organized a meeting of a group of experts including government officials in April 2009 "to identify barriers, articulate the costs of ignorance, and fashion consensus proposals that can immediately begin to make a difference in pregnant women's health." The Second Wave: Toward the Responsible Inclusion of Pregnant Women in Medical Research, http://kennedyinstitute.georgetown.edu/secondwave/, http://www. bioethicsinstitute.org/WEB/PAGE/901/SECTIONID/379/PAGELEVEL/2/INTERIOR.ASP# (last visited Feb. 23, 2010).
500. H.R. Rep. No. 111-220, at 136 (2009).
501. Press Release, U.S. Dept. of Health & Human Servs., Food & Drug Admin., Health Organizations to Study Safety of Medications Taken During Pregnancy (Dec. 30, 2009), available at http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/2009/ucm195934.htm.
502. Id.
503. Id.
504. Id.
505. Id.
506. 21 U.S.C.A. § 355(k)(3)(B)(ii) (West 2010).
507. Id.
508. U.S. Food & Drug Admin., FDA's Sentinel Iniative - Background, http://www.fda.gov/Safety/FDAsSentinelInitiative/ucm149340.htm (last visited May 3, 2010).
509. Angela Scheuerle et al., Measurements of Birth Defect Prevalence: Which Is Most Useful as a Comparator Group for Pharmaceutical Pregnancy Registries?, 85 BIRTH DEFECTS RESEARCH PART A: CLINICAL AND MOLECULAR TERATOLOGY 611, 619 (2009) ("Pregnancy registries are designed to monitor for 'signals' of increased risk and to provide reassurance when sufficient unaffected exposed pregnancies are collected.");
510. Kristine E. Shields et al., Monitoring Outcomes of Pregnancy Following Drug Exposure, 27 DRUG SAFETY 353, 353 (2004) ("[T]he strength of the registry lies in its ability to gather pregnancy outcome reports early in the life of a product and to recognise and analyse unusual birth defects.");
511. Dianne L. Kennedy et al., Pregnancy Exposure Registries, 27 DRUG SAFETY 215, 218 (2004) (noting that registries are "seriously constrained" in their ability to detect modest increases in risk in the range of two to five-fold).
512. Mitchell, supra note 14, at 2558.
513. 21 U.S.C.A. § 355(k)(4)(D)(i)(II)(bb) (West 2010).
514. Human Rights Council, Report of the Special Rapporteur on the Right of Everyone to the Enjoyment of the Highest Attainable Standard of Health, Paul Hunt, Annex, Mission to GlaxoSmithKline, ¶ 40, U.N. Doc. A/HRC/11/12/Add.2 (May 5, 2009) (prepared by Paul Hunt) ("Pharmaceutical companies also have a responsibility to ensure that medicines are developed for... pregnant and lactating women....").
515. 21 U.S.C.A. § 355c (a) (West 2010).
516. Id. § 355c (d).
517. Id. § 355c (a)(3).
518. Id. § 355c (a)(2)(b).
519. Id. § 355c (a)(4).
520. Id.
521. Id. § 355c(b).
522. U.S. FOOD & DRUG ADMIN., DEP'T OF HEALTH & HUMAN SERVS., PEDIATRIC LABELING CHANGES THROUGH DECEMBER 24, 2009 (2009), http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/ PediatricTherapeuticsResearch/UCM163159.pdf.
523. 21 U.S.C.A. § 355c(aX3) (West 2010).
524. OFFICE OF THE COMM'R, U.S. FOOD & DRUG ADMIN., GUIDANCE FOR INDUSTRY: HOW TO COMPLY WITH THE PEDIATRIC RESEARCH EQUITY ACT 9 (2005).
525. PETER BARTON HUTT ET AL., FOOD AND DRUG LAW 727 (3rd ed. 2007) (explaining that while the FD&C Act does not explicitly authorize the FDA to condition approval on a commitment to conduct postepproval testing, the agency has been doing so since the 1960s);
526. Kennedy et al., supra note 336, at 218 ("When the purpose of the pregnancy exposure registry is to assess margins of safety of a product or to monitor for potential harm, it is appropriate to initiate the registry as soon as possible, such as at the time of initial marketing, when a new indication is approved, or when patterns of use reveal that the product is used by women of reproductive age.").
527. 21 U.S.C.A. § 355(o)(3XB) (West 2010).
528. OFFICE OF THE COMM'R, U.S. FOOD & DRUG ADMIN., DRAFT GUIDANCE FOR INDUSTRY: POSTMARKETING STUDIES AND CLINICAL TRIALS - IMPLEMENTATION OF SECTION 505(O) OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT 7 (2009).
529. Id. at 8.
530. See, e.g., Report on the Performance of Drug and Biologies Firms in Conducting Postmarketing Commitment Studies; Availability, 72 Fed. Reg. 5069, 5070 (Feb. 2, 2007) (reporting that 37% of new drug applications and abbreviated new drug applications and 47% of biologies license applications had "open postmarketing commitments with annual reports due, but not submitted within 60 days of the anniversary date of U.S. approval.").
531. 21 U.S.C.A. § 355(o)(3)(E) (West 2010).
532. Id. § 333(f)(4)(A).
533. HUTT ET AL., supra note 350, at 727.
534. Bonnie Rochman, The Risks (and Rewards) of Pills and Pregnancy, TIME, June 8, 2009, available at http://www.time.com/time/magazine/article/0,9171, 1901482-1,00.html.