To Include or to Exclude? The Policy Question Plaguing Women's Role in Clinical Trials

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Acknowledgments

*Breanne Sergent is a second-year law student at Southern Illinois University at Carbondale. Address correspondence to Ms. Sergent at Southern Illinois University School of Law, Law Journal Office, 251 Lesar Law Building, Carbondale, Illinois, 62901, or via email at [email protected].

Notes

Nat’l Heart Lung & Blood Inst., How Does Heart Disease Affect Women? 1 (2011), available at http://www.nhlbi.nih.gov/health/health-topics/topics/hdw/[hereinafter NLB Article].

“Cardiovascular disease is the leading killer of women over age 25” and “kills nearly twice as many women in the United States as all types of cancer, including breast cancer.” Heart Disease and Women, N.Y. Times,June 22, 2012, http://health.nytimes.com/ health/guides/specialtopic/heart-disease-and-women/overview.html.

NLB Article, supra note 1.

Men typically have the more common, or “classic,” heart attack signs such as “tightness in the chest, arm pain, and shortness of breath.” On the contrary, the common symptoms that women display include “nausea, fatigue, indigestion, anxiety, and dizziness.” Heart Disease and Women, supra note 2.

Carol Joann Bess, Gender Bias in Health Care: A Life or Death Issue for Women with Coronary Heart Disease, 6 Hastings Women's L.J. 41, 41 (1995)(“growing evidence in medical research suggests a gender bias against women, particularly in the area of coronary heart disease (CHD)”).

To demonstrate the flawed nature of the exclusion of women from clinical trials, an extreme example is a documented study that focused on the impact of obesity on breast and uterine cancer and utilized only male participants. See Karen H. Rothenberg, Gender Matters: Implications for Clinical Research and Women's Health Care, 32 Hous. L. Rev. 1201, 1208 (1996).

Robyn Whipple Diaz & Katherine B. Steuer, Reforming Women's Health Research: A Renewed Focus on Sex Difference in Clinical Trials , ABA Health eSource (Mar. 2012), http://www.americanbar.org/newsletter/publications/aba_health_esource_home/aba_health_law_esource_0312_diaz.html.

U.S. Food & Drug Admin., Draft Guidance for Industry and Food and Drug Administration Staff: Evaluation of Sex Differences in Medical Device Clinical Studies 5 (Dec. 19, 2011), available at http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM283707.pdf [hereinafter 2011 FDA Guidance] (citing D.B. Kramer et al., Premarket Clinical Evaluation of Novel Cardiovascular Device: Quality Analysis of Premarket Clinical Studies Submitted to the Food and Drug Administration 2000–2007, 17 Am. J. Therapeutics 2 (2010)).

Nicole Ostrow, Women Underrepresented in Heart-Device Studies, Contradicting FDA Rules, Bloomberg, Mar. 1, 2011, http://www.bloomberg.com/news/2011-03-01/women-underrepresented-in-heart-device-studies-contradicting-fda-rules.html.

Id.

Barbara A. Noah, The Participation of Underrepresented Minorities in Clinical Research, 29 Am. J.L. & Med. 211 (2003) (discussing the exclusion of racial and ethnic minorities from the clinical trial process as analogous to the plight of women's exclusion and identifying similar policy concerns).

Cynthia Hathaway, A Patent Extension Proposal to End the Underrepresentation of Women in Clinical Trials and Secure Meaningful Drug Guidance for Women, 67 Food & Drug L.J. 143, 153–54 (2012). In her article, Hathaway contends that “taking women into account in drug development may be inevitable, because it represents a step along the path to personalized medicine, touted as the future of medical treatment.” With the completion of the Human Genome Project, the “natural first step” to harnessing this innovation would be to analyze genetic differences based on one of the most basic and readily identifiable characteristics—sex. Id.

2011 FDA Guidance, supra note 8.

U.S. Gen. Accounting Off., Women's Health: Women Sufficiently Represented in New Drug Testing, but FDA Oversight Needs Improvement 5 (2001), available at www.gao.gov/new.items/d01754.pdf [hereinafter GAO Oversight Report].

Id. at 5.

Id.

Id. The drug labeling indicates which “medical conditions and patient populations … the drug has been tested and approved as safe and effective.” Id.

Id.

Id. at 6. The investigational new drug (IND) application must “summarize the investigations conducted prior to trials in humans, lay out a plan for how the drug will be tested in humans, and provide assurances that appropriate measures will be taken to protect study participants.” Id.

Id. Within an IND, a drug manufacturer will also “demonstrate that the drug is reasonably safe for subsequent testing in humans based on laboratory and animal testing and exhibits enough potential effectiveness to justify its commercial development.” Id.

Id.

Id.

Id.

Id.

Because certain drugs for life-threatening diseases may not have an effective course of treatment for comparison purposes, researchers will instead utilize “historical information about patient outcomes.” Id.

Hathaway, supra note 12, at 144.

In its definition of “drugs,” the Act referred to “articles intended for use … in man or other animals.” Fed. Food, Drug, and Cosmetic Act, Pub. L. No. 75–717, § 505, 52 Stat. 1040, 1052–53 (1938); see also Hathaway, supra note 12, at 145.

In 1961, researchers discovered a significant increase in the number of birth defects that was attributable to pregnant mothers ingesting thalidomide for nausea or insomnia. The result was babies born with such deformities as absent or shortened limbs, giving the appearance of flipper hands and feet. See Hathaway, supra note 12, at 146; see also Phocomelia, PDR Medical Dictionary 1483 (3d ed. 2006).

Diethylstilbestrol (DES) was initially prescribed between 1940 and 1971 to pregnant women to prevent complications such as miscarriages or premature labor. However, its prevalence declined following studies conducted in the 1950s that demonstrated its ineffectiveness in addressing these problems. The adverse effects of DES use were not realized until 1971 when researchers linked in-utero exposure of DES with a specific type of cervical/vaginal cancer called clear cell adenocarcinoma in the daughters of women who had taken DES. Nat’l Cancer Inst., Diethylstilbestrol (DES) and Cancer (Oct. 5, 2011), http://www.cancer.gov/cancertopics/factsheet/Risk/DES.

Hathaway, supra note 12, at 145.

“Women of childbearing potential” were defined as “all pre-menopausal women capable of having children, including women on oral contraceptives, single women, celibate women, and even women whose partners had been sterilized.” Jillian Hemstock, Women in Clinical Trials—Where Are They?, 12 Buff. Women's L.J. 25, 27 (2004).

GAO Oversight Report, supra note 14, at 5.

Hemstock, supra note 31, at 26; see also FDA Guidelines on Women in Clinical Trials Do Not Mandate Inclusion, Guide to Good Clinical Prac. Newsl., Jan. 1994, at 4 [hereinafter FDA Newsletter](discussing that, with the exception of cancer or AIDS studies, the 1977 guidelines broadly excluded women from Phase I and II trials).

HIV Law Project and the NOW Legal Defense Fund, advocates for mandated inclusion of women in the clinical trial process, characterized the 1977 guidelines as creating a “status quo.” See FDA Newsletter, supra note 33.

Hemstock, supra note 31, at 27.

Karen L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice, 24 J. Health Pol. Pol’y, & L. 531, 534 (June 1999).

Id.

FDA guidance, as opposed to an FDA regulation, does not legally bind either the FDA or drug sponsors. Rather, the guidance is “intended to show how statutory and regulatory requirements may be met, but drug sponsors can choose alternative methods to fulfill regulatory requirements.” However, if a regulation is issued following a guidance, the FDA “applies the guidance in a manner consistent with the regulations.” GAO Oversight Report, supra note 14, at 10 (citing Federal Register, Vol. 62, No. 39, at 8961-72, Feb. 27, 1997).

Hemstock, supra note 31, at 27.

Baird, supra note 36, at 537.

Dep't of Health and Human Serv., Nat’l Inst. of Health Nat’l Heart Lung & Blood Inst., WHI Background and Overview, http://www.nhlbi.nih.gov/whi/background.htm. The Women's Health Initiative proved to be successful in raising awareness of the deficit in medical research of women; in 1993, President Clinton signed the NIH Revitalization Act into law, which authorized increased funding for female specific diseases such as breast, ovarian, and other reproductive cancers, as well as osteoporosis. Id.

GAO Oversight Report, supra note 14, at 1 (citing U.S. Gen. Accounting Office, Women's Health: FDA Needs to Ensure More Studies of Gender Differences in Prescription Drug Testing (1992)).

Guideline for the Study and Evaluation of Generic Differences in the Clinical Evaluation of Drugs, 58 Fed. Reg. 39406-01, 39406 (July 22, 1993).

Id. at 39411.

Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, §115(b).

GAO Oversight Report, supra note 14, at 3.

Id.

Id.

Id.

Id. at 4.

Id.

Women accounted for 52% of the entire enrollee population for the clinical trials observed. Id. at 3.

Id. at 3–4.

Hemstock, supra note 31, at 30–31.

U.S. Gen. Accounting Off., Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women 1–2 (Jan. 19, 2001).

Jesselyn Clair S. Pe, Gender Issues in Health Research and the Impact of the Women's Health Office Act of 2005 on Women's Health, 28 Women's Rts. L. Rep. 127, 131 (2007).

Statutorily mandated Offices on Women's Health were established within the Office of the Secretary of Health and Human Services, the Office of the Director of the Center for Disease Control and Prevention Offices, the Agency for Healthcare Research and Quality Activities, the Office of the Administrator of the Health Resources and Services Administration, and the Office of the Commission of the FDA. See Women's Health Office Act, H.R. 949, 109th Cong. (2005); see also Pe, supra note 56, at 140.

Pe, supra note 56, at 141.

Id. at 12.

Comm. on Women's Health Research, Inst. of Med., Women's Health Research: Progress, Pitfalls, and Promises 233 (Nat’l Academies Press 2010), available at http://www.nap.edu/catalog.php?record_id=12908.

Inst. Med., Executive Summary: Women's Health Research: Progress, Pitfalls, and Promises 2 (2010), available at http://www.nap.edu/catalogue.php?record_id=12908 (citing Consolidate Appropriations Act, Pub. L. No. 110–161, 121 Stat. 1844 (2008)).

2011 FDA Guidance, supra note 8.

GAO Oversight Report, supra note 14, at 1; see also Hathaway, supra note 12, at 144 (discussing how the “inadequate enforcement of recruitment of women and of reporting data by sex has fostered suboptimal analysis and reporting of data on women,” resulting in limited possibilities in the progression of medical research).

Men were seen as the norm, and women were regarded as possessing “unknown variables,” such as menstrual cycles, pregnancy, and menopause, which would confound clinical results and add unnecessary cost and labor to the experimentation process. See Rothenberg, supra note 6, at 1206; see also Hathaway, supra note 12, at 144.

Hathaway, supra note 12, at 149.

Id. at 149–50.

Id. at 150.

Id.

Christina Cole, Women and the FDA: Remedying the Past and Preserving the Future, 7 Hous. J. Health L. & Pol’y 127, 139 (2006).

Id. at 128–29.

Hathaway, supra note 12, at 145.

Advocacy groups, in support of their argument for mandated inclusion, asserted that apprehension about incurring legal liability and the possible costs in defending suits brought by women who presented with birth defects in their children would deter companies from including women if the choice were left up to their discretion. See FDA Newsletter, supra note 33; see also Anna C. Mastroianni, HIV, Women, and Access to Clinical Trials: Tort Liability and Lessons from DES, 5 Duke J. Gender L. & Pol’y 167, 168 (1998)(identifying “the potential exposure of drug trial sponsors to tort liability” as a frequently cited “primary reason for excluding women from trials”).

Hathaway, supra note 12, at 144.

Some factors that have been identified as “chang[ing] the climate for the inclusion of women in clinical trials include the feminization of medicine and increasing health care costs.” Additionally, an increase in the number of female practitioners in the medical field has been identified as raising awareness within the medical research community on matters affecting women's health. See FDA Newsletter, supra note 33.

Id.

2011 FDA Guidance, supra note 8, at 6.

Diaz & Steuer, supra note 7; 2011 FDA Guidance, supra note 8, at 7 (recommending that investigators “strive to enroll representative proportions of women and men (i.e., consistent with disease prevalence) to improve the quality and consistency of available sex-specific data” for the device being studied).

Hathaway, supra note 12, at 157.

Id. at 160; see also Comm. on Women's Health Research, Inst. of Med. of the Nat’l Acads., Women's Health Research: Progress, Pitfalls, and Promise 4–6 (Sept. 23, 2010)(prepublication copy), available at http://www.nap.edu/catalog/12908.html.

Hathaway, supra note 12, at 160.

Mastroianni, supra note 72, at 182.

Id. (citing West v. Johnson & Johnson Products, Inc., 174 Cal. App. 3d 831 (Cal. Ct. App. 1985), in which a woman was awarded damages for injuries incurred from tampon use because the “manufacturer failed to test the product adequately” and Taylor v. Wyeth Laboratories, Inc., 362 N.W. 2d 293 (Mich. Ct. App. 1984), in which the jury was allowed to determine an oral contraceptives manufacturer's potential negligence based on the manufacturer's failure to analyze a causal relationship between womens’ blood type and disproportional adverse reactions to the drug that had been suggested by a previous study).

Id.

Rothenberg, supra note 6, at 1242–43 (citing UAW v. Johnson Controls, 499 U.S. 187 (1991), which held that decisions about an unborn child belong within the discretion of “those who conceive and bear the children [and] not by employers or the courts.” The case involved a challenge to the company's “fetal protection policy [which] barred all fertile women from jobs involving lead exposure exceeding the standard set by the Occupational Safety and Health Administration for workers planning to have children.” Although the Court's holding was framed within the context of employment discrimination, it is still useful for policy considerations to support the notion that to exclude women from clinical trials because of their reproductive abilities/child bearing status is to discriminate against women on the basis of gender).

Id. at 1245–59 (explaining in detail the potential arguments under these theories and drawing on pertinent case law for sources of authority and policy considerations).

Hathaway, supra note 12, at 160.

Id.

Id. at 161.

Id. at 160.

Id. at 162–63.

Id. at 163.

Hathaway, supra note 12, at 172–73.

Id. at 172.

Id. at 170–72; see also Dep't Health & Hum. Servs., U.S. Food & Drug Admin., The Prediatric Exclusivity Provision: January 2001 Status Report to Congress 8, available at www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM049915.pdf.

Id. at 170–71.

Id. at 173–76.

2011 FDA Guidance, supra note 8, at 5.

Id.

Id.

Id.; see also Sarah K. Keitt, Sex & Gender: The Politics, Policy, and Practice of Medical Research, 3 Yale J. Health Pol’y, L. & Ethics 253, 266 (2003) (discussing what has been demonstrated to increase retention rates of women in clinical studies, including “paying close attention to women's needs and concerns” and forming meaningful relationships beyond the basic researcher and participant roles).

2011 FDA Guidance, supra note 8, at 9 (citing Jennifer Hays et al., The Women's Health Initiative Recruitment Methods and Results, Annals Epidemiology, Oct. 2003, at S18, S19).

2011 FDA Guidance, supra note 8, at 9.

Id.

Id.

Id. at 11.

Id. at 14.

Id. at 15.

Id.

See Hemstock, supra note 31, at 27; see also GAO Oversight Report, supra note 14, at 2–3.

Advocacy groups for women, such as the Society for Women's Health Research, have asked the FDA to finalize the guidance into a rule. Rochelle Green, Women Underrepresented in Trials of Many High Risk Medical Devices, The Day, June 8, 2012, www.theday.com/article/20120608/NWS13/306089924/1019&town.

Id.

“Industry is always most attentive to the bottom line,” said Christine Carter, vice president for scientific affairs at the Society for Women's Health Research (SWHR) in Washington. “So companies will continue to lament that trials are expensive and that recruiting more women is a problem.” Device makers will change their study protocols just enough to meet FDA requirements, Carter predicted, but protocols will be “less than ideal for those of us concerned with sex differences and women's health.”

Id.

White males dominated the participant pool of most clinical trials until the mid-1980s. During this time, researchers were content with such absurd study designs as having only male participants in the first randomized trial that studied the use of estrogen for heart disease prevention. Id.

Bess, supra note 5, at 49.

The FDA needs to work to strike a more compromising balance between the two competing interests of industry (wanting “faster approvals and ‘less burdensome’ regulation”) and health advocates (concerned about patient safety and new research development). Green, supra note 110.

Hathaway, supra note 12, at 144 (highlighting the lack of incentives presently available to drug companies that could encourage them “to have different dosing regimes or patient information sheets for men and women”).