Health Policy in Practice

Women’s Health, Pregnancy, and the U.S. Food and Drug Administration Rebekah E. Gee,

MD, MPH,

Susan F. Wood,

PhD,

and Kathryn G. Schubert,

T

he U.S. Food and Drug Administration (FDA) was the first comprehensive consumer protection agency in the United States. The FDA’s regulatory functions began with the passage of the 1906 Pure Food and Drugs Act, a law prohibiting interstate commerce in adulterated or misbranded food and drugs. Since that time, there has been an explosion of scientific progress around drugs, devices, and biologics such as vaccines and, concomitantly, the need for safety assurance and consumer protection has grown. This article covers some of the pertinent history of FDA regulation of medications and devices important to women’s health care, discusses some of the challenges to progress, and advances some proposals for improved safety and efficacy of drugs in pregnant women. As a result of the dearth of studies of drugs in pregnant women, advancing research for this population of patients is especially critical.

HISTORY OF WOMEN’S HEALTH AT THE U.S. FOOD AND DRUG ADMINISTRATION Congress has broadened the legal authority the FDA has to ensure products are safe and effective in part as a result of the deaths and severe disabilities associated with several drugs and devices intended for women’s reproductive health. One notable example is the harm From the Departments of Health Policy and Management and Obstetrics and Gynecology, Louisiana State University, Schools of Public Health and Medicine, New Orleans, Louisiana; the Jacobs Institute of Women’s Health, the Department of Health Policy, School of Public Health and Health Services, George Washington University, and CavarocchijRusciojDennis Associates, LLC, Washington, DC. The authors thank the members of the Health Policy Committee of the Society for Maternal-Fetal Medicine (SMFM) for their significant contributions to this manuscript. Members of the SMFM Health Policy Committee with editing contributions are: Joanne Armstrong, Suneet P. Chauhan, Judette Louis, George R. Saade, and Sindhu Srinivas. Corresponding author: Rebekah E. Gee, MD, MPH, 2020 Gravier Street, New Orleans, LA 70112; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2013 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14

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caused by thalidomide, a drug used in the 1950s and 1960s to quell nausea and alleviate morning sickness in pregnancy. Thalidomide caused thousands of neonates worldwide to be born with phocomelia and many more thousands to die. U.S. Food and Drug Administration reviewer, Dr. Frances Kelsey, was assigned the thalidomide application as her first review in 1960 and did not recommend approval in the United States. By insisting on good scientific data and questioning the manufacturer, she prevented an even greater tragedy here in the United States. Recognized with a President’s Award for Distinguished Federal Service by President Kennedy, Dr Kelsey was also recognized 50 years later, in 2010, by the FDA with the establishment of the Kelsey Award for Excellence and Courage in Protecting Public Health. In 1961, the FDA approved 5 mg Enovid as the first oral contraceptive pill. Although the women’s rights movement had advocated for the development of the pill, the side effects women experienced as a result of the use of this high-dose estrogen pill led women’s advocates to call for the 1970 implementation of the first package insert. Also in the 1970s, the risks of prenatal exposure to diethylstilbestrol (DES) were identified through a classic case–control study that associated increased risk of clear cell vaginal adenocarcinoma in young women with DES exposure.1 Although the lack of efficacy of DES to reduce the risk of miscarriage had been identified in the early 1950s through one of the first randomly controlled clinical studies,2 it continued to be labeled for use in pregnancy until the cancer risk (and other reproductive malformations) was identified. In 1962, Congress passed the Kefauver–Harris Amendments, which gave the FDA authority to ensure that drugs were effective before being marketed and to require that manufacturers report unexpected adverse events. The Dalkon Shield is another women’s health tragedy that has affected the FDA and arguably hampered public acceptance of intrauterine devices. The Dalkon Shield was an intrauterine device that went on

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the market in 1971, before the FDA had the authority to require testing and approval of medical devices. As a result of a faulty device design with filaments wicking bacteria into the uterus and crab-like prongs that may have facilitated entry of pathogens, several deaths and septic abortions ensued. These and other cases led to more than 300,000 lawsuits against the A.H. Robins Company, the manufacturer of the device, forcing the company to file for Chapter 11 bankruptcy.3 Attributable significantly to the Dalkon Shield disaster, in 1976, the Medical Device Amendments to the Food, Drug and Cosmetic Act mandated the FDA to require testing and approval of medical devices such as the intrauterine device. Other areas in women’s health where consumer information based on new data has been important have been toxic shock syndrome associated with tampon use and hormone replacement in postmenopausal women. In part as a result of the thalidomide, Dalkon Shield, and DES tragedies, concerns about drug teratogenicity and damaging reproductive effects led in 1977 to the release of FDA guidelines excluding women of childbearing potential from phase 1 and early phase 2 studies. These guidelines influenced even larger phase 3 studies as well as clinical research funded by the National Institutes of Health. It was not until 1993 that women were again included in all phases of FDA-regulated clinical trials and data began to be evaluated for gender differences in safety and efficacy (these requirements for National Institutes of Health-funded studies began in 1990). In 1994 the FDA’s Office of Women’s Health was created. In obstetric practice, trials for drugs used in pregnancy have been historically lacking. The fear of litigation may in part have contributed. One example is the drug used for morning sickness, originally called Bendectin. This combination of doxylamine and vitamin B6 was removed from the market in 1983 by its manufacturer after hundreds of lawsuits alleged that it caused birth defects. However, there was then and continues to be no credible scientific evidence of an association between Bendectin and birth defects. This drug was reintroduced in 2013 with FDA approval under the name Diclegis. Likely attributable in part to this history, drug manufacturers are wary to request approval from the FDA for pregnancy indications. As a result, there are multiple examples in the field of obstetrics where medications used for a pregnancy indication have not been approved by the FDA for these indications. Examples of such drugs in off-label but very routine use are vaginal progesterone for the prevention of

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prematurity, misoprostol for cervical ripening, and various drugs used as tocolytics. In addition, the device used for continuous fetal heart rate monitoring was introduced before a wide research base supported it. Although this monitor is in near universal use, there continues to be a lack of uniformly convincing evidence to support that its use has improved perinatal outcomes.

CURRENT CLIMATE AND U.S. FOOD AND DRUG ADMINISTRATION ACTIONS ON PHARMACEUTICAL RESEARCH IN WOMEN’S HEALTH Attributable partly to litigation concerns, pharmaceutical and biologics companies and device developers have been wary of conducting research studies in pregnant women. Most human data for new products come from the premarket studies, known as phase 1 (small safety and dosing studies on healthy adults), phase 2 (somewhat larger studies focused on safety and early efficacy results), and phase 3 (larger efficacy studies). Reproductive toxicology studies on animals will have been conducted, usually in parallel with phase 1 and phase 2 studies. Many analyses have concluded that more research needs to be conducted after a product comes on the market (known as phase 4), particularly during pregnancy when physiologic changes can alter pharmacokinetics and pharmacodynamics. Many questions remain about the effects of medication on the fetus and the effect of pregnancy on the uptake and metabolism of medications in pregnancy. Because of lack of data, counseling pregnant patients about risks and benefits of most medications is limited. Health care providers may choose not to prescribe a necessary medication or to substitute a drug that is possibly less efficacious or has a greater side effect profile because the drug is believed to be safe in pregnancy. Even when medications are used routinely during pregnancy and lactation, we often lack evidence on effective dosages.4 For most medications used in pregnancy, the dose is usually extrapolated from studies in nonpregnant individuals or empirically adjusted to pregnancy. Recent postmarket studies sponsored by the FDA and evaluating the use of antiviral, antihyperglycemic, asthma, antiepileptic, and antipsychotic medications have shown that the use of these drugs has increased over time in the pregnant population and cite the need for further investigation.5–9 Lack of information leads to confusion among patients and prescribers and can lead to discontinuation of drugs such as antidepressants in pregnant or breastfeeding women, which may adversely affect women’s mental or physical health and ultimately the

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health of their fetus and neonate.10–12 With more information, a woman could potentially stay on important medications that improve her short-term and long-term health and quality of life while pregnant or nursing without causing harm to herself or her fetus. Additionally, she may be able to sustain breastfeeding for longer, as is recommended by the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics as a result of its beneficial health effect on mothers and their children.13 Currently, the FDA does not have a mechanism to promote studies of drugs in pregnancy and lactation. Given the perceived difficulties in conducting studies in pregnancy, and the fear of litigation, drug companies lack adequate incentives to conduct drug trials to evaluate efficacy and safety of their treatments in the pregnant and breastfeeding population. However, the FDA has taken multiple actions to improve availability of information on the use of medications during pregnancy. In 2002, the FDA distributed guidance to industry on the establishment of pregnancy registries for new and existing medications.14 A key goal of this guidance was to promote the collection of data on the clinical outcomes of pregnancies in which the women had been prescribed medication for conditions such as asthma, cancer, or human immunodeficiency virus and acquired immunodeficiency syndrome. The FDA Office on Women’s Health maintains a web site where both patients and health care providers can access these registries and information on how to participate: http://www.fda.gov/ScienceResearch/SpecialTopics/ WomensHealthResearch/ucm251314.htm.15 In 2004, additional FDA guidance was issued on how to conduct pharmacokinetic and pharmacodynamics studies in pregnant women for already approved antihypertensive and antibiotic medications. The goal was to inform drug dosing recommendations across the duration of pregnancy.16 In May 2008, the FDA proposed major revisions to prescription drug labeling that would provide greater information on the use of medicines during pregnancy and breastfeeding. The goal of the proposed changes to prescription labeling was to give health care providers more information for counseling childbearing-aged, pregnant, or breastfeeding women and to guide prescribing decisions. The proposed strategy would eliminate the historical ABCDX system familiar to many physicians, which unfortunately has not provided much clinically useful information that could be used to assess risk and benefit. This is because the categories can mislead pregnant women and health care providers to assume that risk increases from A with the highest risk at X. This is not the case

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because categories C, D, and X are based not only on risk, but also on the weighed benefits. Therefore, a drug in categories C or D may pose similar risk to one in category X or category B. In addition, the categories do not discriminate between risk based on human data and risk based on animal data or describe the nature of the risk or anomaly of concern. Under the proposed strategy, labeling would contain two subsections: one on pregnancy and one on lactation. The pregnancy and lactation subsections would both have three main components: a risk summary, clinical considerations, and a data section.17 After publication of the 2008 Proposed Rule, there was a 90-day open comment period. The FDA received more than 70 comments from private citizens, health care practitioners, the academic and scientific communities (including teratology experts), professional organizations, the pharmaceutical industry, and other stakeholders. Many of these comments provided detailed feedback and suggestions on how to further improve the proposed regulations. In 2008, the American College of Obstetricians and Gynecologists issued a statement on the proposed rule supporting a number of the changes listed previously and recommending action by the FDA: “Despite the proposed rule’s many advances, ACOG is disappointed in the delay of the implementation process given that there are 6 million pregnancies each year. Although manufacturing new labels is costly and companies can most efficiently revise labels as research yields new updates, this slow process delays the delivery of complete information. ACOG recommends that the FDA implement a public education campaign for health care providers concurrent with the implementation of the new requirements.”18 As of late 2013, the rule remains in draft format and has not yet been finalized. However, the Office of Management and Budget reported in Spring 2013 that it will be finalized by January 2014.19 The role of the FDA-approved label, as a resource of information for physicians, is critical, whether through accurate “black box warnings” for identified safety concerns or through the pregnancy section of the label to provide important data and clinical approaches.

PROPOSALS FOR FUTURE CONSIDERATION Facing similar issues in the pediatric population, the American Academy of Pediatrics has advocated the authorization of programs that provide incentives for drug companies to conduct pediatric drug trials for medications that are used in children but are developed for and tested in adult populations. Congress passed, and the President signed into law, the Best

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Pharmaceuticals for Children Act in 1997. The Act was expanded in 2002 and permanently reauthorized in 2012 as part of a larger FDA package.20 The Best Pharmaceuticals for Children Act serves as a “carrot” for drug companies to do research on pediatric populations by providing an additional 6 months of market exclusivity for a drug if the developer voluntarily engages in pediatric trials. The Best Pharmaceuticals for Children Act’s companion legislation, the Pediatric Research Equity Act—the “stick”—requires drug developers to conduct these trials for new drug applications driven by new indications or the need for different dosages and also allows the FDA to require a pediatric assessment of some approved drugs or biologic products for certain indications. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through its Obstetric and Pediatric Pharmacology and Therapeutics Branch, has the authority under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act to identify and prioritize drugs needing study, develop study requests, and conduct studies on priority drugs after manufacturers decline to do so.21 In 2011, the U.S. Government Accountability Office concluded that the Best Pharmaceuticals for Children Act was a successful program, finding that “at least 130 products have been studied for use in children” since the law’s expansion in 2007.13,22 To address similar challenges in determining whether drugs are safe and effective during pregnancy and lactation, Congress could authorize the use of a program similar to that of the Best Pharmaceuticals for Children Act in the pregnant and breastfeeding population. In the meantime, finalizing the Pregnancy Labeling Rule, and creating incentives for more research and collection of data through pregnancy registries, would expand the information available that we have for the benefit of women’s health. With more than 6 million pregnancies per year and 62 million women of childbearing age in the United States, this issue affects a large proportion of our nation’s population. The insufficient data to characterize fetal risk or effects on women’s health limit the opportunity to make informed clinical decisions about optimum management of acute and chronic disease during pregnancy.23 The benefit of better information regarding medications in pregnancy also extends from the pregnant woman to the fetus and newborn, making any initiative in this area a perfect extension to the Best Pharmaceuticals for Children Act. The controversial history of the FDA in regard to women’s health does not diminish the imperative for information regarding the safety and efficacy of drugs and devices in all stages of women’s lives. Several

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steps should be taken, the first of which being for the FDA to release a final rule on labeling, which has been stalled for unclear reasons for 5 years. The Best Pharmaceuticals for Children Act provides a model for how to begin to focus on the issue of trials in pregnancy and lactation. In fact, the Best Pharmaceuticals for Children Act’s infrastructure could be built on to include pregnant and breastfeeding women if the FDA’s Office of Women’s Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Obstetric and Pediatric Pharmacology and Therapeutics Branch were given legislative authority to identify and prioritize clinical trials in pregnant and breastfeeding women. Of course, such authority requires funding for both the FDA and the National Institutes of Health to implement such a program. Obstetrician–gynecologists, the American Congress of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine can play a greater role in advocating for funding for pharmaceutical and device research on products that will be used at all stages of a woman’s life, including during pregnancy. Clinician engagement in advocacy at the national level for additional patient registries, enhanced funding for research at the National Institutes of Health, and further postmarket studies supported by manufacturers would be beneficial to advancing this important agenda. REFERENCES 1. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971;284:878–81. 2. Dieckmann WJ, Davis ME, Rynkiewicz LM, Pottinger RE. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol 1953;66:1062–81. 3. Associated Press. Company news; Robins Plan is approved. Available at: http://www.nytimes.com/1989/06/17/business/ company-news-robins-plan-is-approved.html. Retrieved September 17, 2013. 4. Akus M, Bartick M. Lactation safety recommendations and reliability compared in 10 medication resources. Ann Pharmacother 2007;41:1352–60. 5. Avalos LA, Chen H, Yang C, Andrade SE, Cooper WO, Cheetham CT, et al. The prevalence and trends of antiviral medication use during pregnancy in the US: a population-based study of 664,297 deliveries in 2001–2007. Matern Child Health J 2013 Feb 19 [Epub ahead of print]. 6. Lawrence JM, Andrade SE, Avalos LA, Beaton SJ, Chiu VY, Davis RL, et al; Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) Study Group. Prevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001–2007. Obstet Gynecol 2013;121:106–14. 7. Hansen C, Joski P, Freiman H, Andrade S, Toh S, Dublin S, et al. Medication exposure in pregnancy risk evaluation program: the prevalence of asthma medication use during pregnancy. Matern Child Health J 2012 Oct 30 [Epub ahead of print].

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8. Bobo WV, Davis RL, Toh S, Li DK, Andrade SE, Cheetham TC, et al. Trends in the use of antiepileptic drugs among pregnant women in the US, 2001–2007: a medication exposure in pregnancy risk evaluation program study. Paediatr Perinat Epidemiol 2012;26:578–88. 9. Toh S, Li Q, Cheetham TC, Cooper WO, Davis RL, Dublin S, et al. Prevalence and trends in the use of antipsychotic medications during pregnancy in the U.S., 2001–2007: a populationbased study of 585,615 deliveries. Arch Womens Ment Health 2013;16:149–57. 10. Enriquez R, Wu P, Griffin MR, Gebretsadik T, Shintai A, Mitchel E, et al. Cessation of asthma medication in early pregnancy. Am J Obstet Gynecol 2006;195:149–53. 11. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment [published erratum appears in JAMA 2006;296:170]. JAMA 2006;295:499–507. 12. Marcus SM, Flynn HA, Blow F, Barry K. A screening study of antidepressant treatment rates and mood symptoms in pregnancy. Arch Womens Ment Health 2005;8:25–7. 13. American Academy of Pediatrics. Pediatric drug testing legislative and regulatory history. Available at: http://www.aap. org/en-us/advocacy-and-policy/federal-advocacy/Documents/ bpcapreahistory.pdf. Retrieved October 22, 2013. 14. Kennedy DL, Uhl K, Kweder SL. Pregnancy exposure registries. Drug Saf 2004;27:215–28. 15. U.S. Food and Drug Administration. List of pregnancy exposure registries. Available at: http://www.fda.gov/ScienceResearch/ SpecialTopics/WomensHealthResearch/ucm134848.htm. Retrieved September 18, 2013. 16. U.S. Department of Health and Human Services, Food and Drug Administration. 2004 guidance for industry phar-

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macokinetics in pregnancy: study design, data analysis and impact on dosing and labeling. Fed Regist 210: 63402–3. 17. U.S. Food and Drug Administration. Summary of proposed rule on pregnancy and lactation labeling. Available at: http://www.fda.gov/ Drugs/DevelopmentApprovalProcess/DevelopmentResources/ Labeling/ucm093310.htm. Retrieved September 18, 2013. 18. U.S. Food and Drug Administration. American College of Obstetricians and Gynecologists—comment. Available at: http://www. regulations.gov/#!documentDetail;D5FDA-2006-N-0515-0048. Retrieved September 18, 2013. 19. Content and format of labeling for human prescription drugs and biologics; requirements for pregnancy and lactation labeling. Available at: http://resources.regulations.gov/public/component/ main?main5UnifiedAgenda. Retrieved September 19, 2013. 20. U.S. Food and Drug Administration. Best Pharmaceuticals for Children Act. Available at: http://www.fda.gov/ RegulatoryInformation/Legislation/FederalFoodDrugand CosmeticActFDCAct/SignificantAmendmentstotheFDCAct/ ucm148011.htm. Retrieved August 11, 2013. 21. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Background of the Best Pharmaceuticals for Children Act (BPCA). Available at http://bpca.nichd.nih. gov/about/. Retrieved September 17, 2013. 22. U.S. Government Accountability Office. Pediatric research: products studied under two related laws, but improved tracking needed by FDA. Available at: http://www.gao.gov/new. items/d11457.pdf. Retrieved September 18, 2013. 23. Thorpe PG, Gilboa SM, Hernandez-Diaz S, Lind J, Cragan JD, Briggs G, et al. Medications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk. Pharmacoepidemiol Drug Saf 2013; 22:1013–8.

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Women's health, pregnancy, and the U.S. Food and Drug Administration.

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