In 1988, the Food and Drug Administration approved zidovudine (AZT) for the treatment of AIDS.1 It was momentous. Around the world, activists, researchers, and people living with HIV celebrated the possibility of life amid the carnage of AIDS.
Reality, however, soon set in. AZT was a powerful drug with harsh side effects, and not everyone could tolerate the medication. As researchers began experimenting with these new drugs, it wasn’t long before feminists identified a troubling aspect of drug development on HIV: Women were being excluded from clinical trials that could help them survive out of concerns that the drugs could harm a potential fetus.
Take the case of Irene. In 1991, Irene fell deeply ill with AIDS. Her CD4 count had dropped below 100, indicating severe HIV infection allowing for an AIDS diagnosis.2 Like many others living with HIV, the side effects of AZT were unbearable to her. Sick and in need of intervention, Irene’s physician advised her to enroll in a clinical trial to access some of the potentially lifesaving medications being tested on people living with HIV. But when Irene went to enroll in a new drug trial being conducted by Johns Hopkins University and Hoffmann-La Roche Company, she was told she could not enroll unless she was surgically sterilized. Irene was willing to take regular pregnancy tests and contraception but was unwilling to get surgical sterilization. She was excluded from the trial.3
As more women were diagnosed with HIV, cases like Irene’s multiplied. The root cause of these exclusions was 1977 Food and Drug Administration (FDA) guidance that specifically recommended excluding women of childbearing age from clinical trials. Denying women participation in clinical trials had immediate downstream consequences. Not only could women not access the possible experimental drugs for HIV, but the lack of women’s participation in clinical trials produced uncertainty for researchers and physicians who were treating women and wanted to know how sex or pregnancy might impact the use of the medication before they were willing to prescribe it. Together, these dynamics meant that women could not access experimental or approved medications.
Recognizing that progress would come from working in the knotty interactions between legal institutions and science, feminists fought to help women access AIDS clinical trials and drugs. This chapter highlights how feminist AIDS activists contributed to a larger push to force the FDA to transform how the agency regulates sex and gender in scientific research. Their efforts would lead to a profound shift in the study of women in drug development, both in and outside the context of AIDS.
While prior chapters focused on the coproduction of law and epidemiology, this chapter examines how feminists demanded more clinical trial research on women to alter the knowledge environment about women, HIV, and treatment. Feminists asserted at every step that it was women who should decide whether or not to bear the risk of harm through the drug development and rollout process – pregnant or not. These feminist arguments were successful, at least in part, due to the broader shifting legal sensibility that women ought to have more autonomy over their bodily choices developed in a series of constitutional US Supreme Court decisions which drove forward the idea that women ought to have privacy and autonomy over aspects of their reproductive decision-making. AIDS activists built on the momentum of the moment to help move the FDA to lift guidance that undermined a woman of childbearing years from participating in clinical trials.
The feminist struggle around AIDS was central to the change in the FDA rules. Though the feminist women’s health movement had long identified the FDA rules on clinical trials as an issue, it was the fight for AIDS drug treatment that helped propel forward the movement’s goal of altering FDA guidance. This chapter focuses in on several crucial dynamics of this fight. First, it looks at how AIDS activists sought to disrupt the regulatory frames around scientific research to force the production of better information about women. They did this in service of redistributive goals: to get women medical care and treatment. Second, the chapter highlights the role of pregnancy. Much to the chagrin of feminist AIDS activists, the hesitancy to enroll women in clinical trials vanished when it came to experimentation for the benefit of the fetus. This was a key concern in the ACTG 076 trial that set out to prove that AZT could stop mother-to-child transmission of HIV. While the success of the trial, and the new ability to prevent mother-to-child transmission, ended political controversy around ACTG 076, feminist concerns about autonomy and consent raised in the context of the trial continued to be salient over the coming decades. Finally, this chapter tracks how the legal ideas of choice and autonomy, pushed by feminists and increasingly a part of constitutional jurisprudence, becomes integral to achieving women’s participation in clinical trials.
Exclusions from Clinical Trials
Long before AIDS, the feminist women’s health movement raised concerns about how women were receiving care and treatment for a host of health issues. The largely male medical establishment discounted women’s health concerns and denied them research to substantiate their claims. The reticence about including women in clinical trials and a lack of funding for research extended to women’s health issues, including menstruation, menopause, pregnancy, and breast cancer.4 As has been widely documented by feminist historians, legal scholars, and sociologists of medicine, feminist advocates took up the cause of increasing and improving knowledge about women’s health by working to get this guidance altered. They began a long struggle to fight for what medical sociologist Steven Epstein has called, in his foundational work on AIDS and clinical trials, “inclusion”, a struggle for representation in clinical trials based on one’s sex, gender, and racial identity.5 They claimed that the white male body at the center of all research needed to be unseated, and a more diverse range of individuals should be included in clinical trials.6 As Epstein showed, advocacy by community groups would bring questions of identity directly into the realm of knowledge production.
Chapters 1 and 2 document how feminist women’s health and AIDS activism converged to change the Centers for Disease Control and Prevention (CDC) definition of AIDS. Building on the work of scholars and advocates, this chapter shows how these two movements, with many shared actors, mobilized legal tools to demand more inclusive research.7
From the start of the AIDS epidemic, AIDS activists were interested in treatment. Patients longed for a cure. Treatment activism, “drugs into bodies,” became a core and central feature of AIDS activism.8 People were dying, and advocates were pushing forward.9 Scientists, too, were searching for a solution.
AIDS activists felt that AIDS treatments should be developed and approved faster to ensure that people could receive lifesaving treatments quickly. To understand the history of this period and the activism directed at the FDA, it is necessary to first understand the drug approval process, which became a central target of AIDS activists and feminist advocates.
The FDA, situated within the Department of Health and Human Services, was and continues to be the agency responsible for protecting the health of the public by regulating the “safety, efficacy, and security” of “human and veterinary drugs, biological products, and medical devices.”10 The agency plays a powerful role in the governance of medicine and healthcare: It approves all drugs before they can be marketed and sold in the United States. The process for drug manufacturers begins by filing a new drug application (NDA).
To get an NDA, the FDA requires that data be presented for drug approval. Based on proof of efficaciousness, the FDA will approve the medication. Each drug requires a three-phase trial before a sponsor submits a NDA for FDA approval. The NDA is required for marketing approval. In Phase I, the sponsor studies the drug in humans. Generally, small numbers of healthy volunteers or patients are treated over a short period of time. Phase I is designed to look into individual tolerance for a drug and dosing. It also allows for an exploration of pharmacokinetics, the way the drug is processed in the body.11 Phase II studies are early-stage control trials often involving small population samples. They demonstrate effectiveness and relative safety. Phase III trials are large trials in which the drug developer will study several thousand people. This is the last step before approval. Sometimes, before a Phase I trial, an animal trial will be rolled out. These animal trials might be able to show the risks of the drugs before humans are involved.
In 1977, the FDA created a guidance document titled General Considerations for the Clinical Evaluation of Drugs.12 In this guidance, the FDA stated that women of childbearing potential should be excluded from Phase I trials and only be included in clinical trials if enough information had been amassed in Phase I and II trials (as well as animal reproduction studies) on efficacy and relative safety of the drug being tested for women of reproductive age. The 1977 guidance defined “women of childbearing potential” as “premenopausal females capable of becoming pregnant.” The definition included women who are single, actively trying not to get pregnant, and using “oral, injectable, or mechanical contraception; women whose husbands have been vasectomized or whose husbands have received or are using medical contraceptive devices.”
The guidance was developed in response to what is now known as the thalidomide tragedy. Thalidomide was prescribed to pregnant women in Germany to help address morning sickness. Due to the use of the drug, thousands of children were born with physical disabilities. The drug was not widely used in the United States, but it led to the 1962 drug amendments, which increased the FDA’s authority to approve drugs.13 It also precipitated concerns for pregnant women as research subjects. The result was the 1977 FDA guidance.14
The thalidomide tragedy also fed fears in the pharmaceutical industry that drug trials on pregnant women could lead to tort claims.15 Lawsuits following the use of thalidomide, costing companies millions, were invoked by both the FDA and pharmaceutical companies to caution against enrolling women in trials, feminist scholars feminist scholars were skeptical about this claim. After all, an untested and harmful drug could also result in lawsuits.
These factors – the thalidomide scandal, the 1970s guidance which followed, and fear of tort liability – justified the exclusion of women from trials and produced downstream effects.16 Pharmaceutical companies could not say with certainty that a drug would not be dangerous for a woman of childbearing potential or in pregnancy. The lack of inclusion meant very little was known about how drugs might impact women differently than men.
Experimental Treatments for Women
By the late 1980s, scientists sought to find treatments for AIDS. With death rates soaring among those infected with the virus, time was of the essence. But for activists, scientists were not moving fast enough. The AIDS Coalition to Unleash Power (ACT UP) began a series of demonstrations that would make it famous: “die-ins,” protests, and arrests at administrative agencies. Activists disrupted conferences and demanded meetings with leading agency heads and scientists.17
Partly in response to this pressure, the National Institute of Allergy and Infectious Diseases (NIAID) created the AIDS Clinical Trials Group (ACTG) in 1986.18 Located within the NIAID headed by Anthony Fauci, the ACTG would focus its attention on AIDS research and treatment. Despite this major step, the new group did not escape the scrutiny and critique of AIDS activists. They felt drug trials being conducted by the ACTG were too slow. Even worse, the trials contained placebo groups. This meant that some portion of the trial participants living with AIDS were receiving “sugar pills” with no possibility of benefiting from participating in the drug trial. AIDS activists felt that this turned desperate patients into guinea pigs. AIDS activists demanded that there be no placebos in AIDS-related clinical trials. Including people in AIDS clinical trials was a way to give some treatment, any treatment, even experimentally, to people who were dying.
By 1987, the FDA approved AZT to treat HIV. Despite the celebration of AZT, new problems emerged: The drug was hard to tolerate. And for feminists, another issue arose: It was necessary to get women enrolled in clinical trials so that they could access experimental medications. Women were being excluded because of the 1977 guidance, despite the exception that allowed for enrolling women in clinical trials if they faced life-threatening illnesses.19
The broader feminist women’s health movement and feminist AIDS activists knew that to get women access to treatment they also had to demand their inclusion in clinical trials.20 Shifts in the law laid new groundwork for this feminist fight for reforming clinical trials. Though 1973 marked a major shift in the idea of bodily autonomy for women with Roe v. Wade decriminalizing abortion, cases in the following decades challenged, and often won, a right to continued access to abortion and birth control. Implicitly and explicitly, these cases reinforced the idea that women ought to be able to make their own reproductive choices.
Law was not the only field experiencing a shift in understanding and thinking about the role of women in society. Sex and gender had an increasingly centered role in the field of public health.21 At least since the 1980s, critical strands of epidemiology gave rise to the new field of feminist epidemiology. Leading epidemiologist Nancy Krieger and public health expert and activist Glen Margo, for example, pushed for the need to focus on women in the AIDS response.22 Feminists were not alone in raising questions about identity in clinical trials. Racial justice advocates and public health scholars (many of whom were also feminists) were raising questions about the use and role of race and racial categories in scientific and public health research. This debate was contested and complicated: Biomedical research often (though not always) cemented ideas of sex and racial difference. At the same time, social scientists and public health practitioners often leaned into the idea that race is socially constructed and that racial disparities in health ought not to be conflated with biological race differences.
The FDA was paying attention to the new debates on identity in scientific research.23 By the mid 1980s, the presence of AIDS and the activists outside its doors motivated the FDA to understand if and how women were excluded from clinical trials and the impact this was having on health outcomes. The FDA began to investigate the impact of its 1977 guidance. In 1983 and 1988, the FDA conducted investigations into clinical trial practice. Its research reinforced what feminists had been arguing. There were significant disparities in the enrollment of women in some categories of disease studies, making it hard to unpack the thorny relationship between sex and pharmaceuticals.
A broad coalition of ACT UP members joined feminists in decrying the lack of inclusion of women in clinical trials.24 A 1988 ACT UP booklet titled FDA Action Handbook illustrates the issues activists were concerned about. Prominent ACT UP advocates Jim Eigo, Mark Harrington, Stephen Spinella, and Margaret McCarthy criticized the FDA for its exclusion of women:
For years, women have been systematically excluded from almost all drug trials … The reason given for excluding women from drug trials is usually that the studies on the effects of the drug on a fetus have not been done. Researchers will argue that you can’t trust women not to get pregnant. Researchers sometimes only allow women into trials, including AIDS trials, only if they agree to be sterilized. Some researchers may allow women into trials if they show them that they are using birth control and have repeated negative pregnancy tests.
Researchers have a “moral” problem with allowing women into studies if a fetus may be harmed. But they do not have a problem with any birth defects that may be caused if a man in a study is sexually active, causing the birth of a child with birth defects.25
The booklet calls out the FDA for its lack of inclusion of women and others who were being excluded, such as people of color and intravenous drug users.
The FDA has exacerbated this by discouraging researchers from including women in trials and by approving drugs that have only been tried in white, middle-class, educated urban men for years and years. The FDA has the power to make regulations to require that trials include women, people of color, IV drug users, etc. If the FDA stated that they would no longer accept data that was not representative of the population with the disease, then drug manufacturers would have to do what they said.26
According to advocates, the need for clinical trial access was partly driven by lack of ability to pay for access to AZT.
Even if they had a private doctor, the one drug which has been approved for treatment through prescription is AZT, which costs $8000–10,000 per year, more money than 50% of the women in the United States earn per year if they are in the paid labor force. For these reasons, for women in particular, participating in a clinical drug trial will be their only access to traditional medical treatment for AIDS. Yet women are hardly represented in government-sponsored drug trials which are being conducted.27
Informal barriers also blocked access to clinical trials, according to advocates. Women, for example, often had to pay for any preliminary exams to qualify for the trial, or a lack of support services, including childcare, made it so that women couldn’t attend the trial.28 Women did not know about trials as activists noted that most were not advertised in low-income neighborhoods.
To AIDS activists, these exclusions were murderous: “By not making participation in drug trials an option for women, either through intended exclusion or de-facto exclusion, the FDA, government-sponsored ACTGs, local governments and health care institutions and officials, are actively responsible for women’s deaths.”29
Agitation on the question of clinical trials and AIDs had also reached the national stage. In January of 1988, the New York Times Science Section declared in a headline that “AIDS Research on New Drugs Bypasses Addicts and Women.” The article describes how “findings on homosexual men may not apply to other groups” leaving open questions as to whether these life-extending drugs will benefit “drug users, nonwhite, and women.”30
In response to its internal research and increasing public pressure, the FDA issued a new guideline in July 1988 that called for researchers to provide drug safety and efficacy data by gender, age, and race.31 Together, the FDA and the General Accountability Office focused inwards on the agency called for taking up the issue of sex and gender in drug trials.32
As the agency evaluation continued, advocates pressed for further action. Feminist activists of the ACT UP Women’s Issues Committee wanted a Women’s Health Committee of the ACTG and made these demands in letters to Dan Hoth, Director of the Division of AIDS at the National Institutes of Health (NIH), and Anthony Fauci, Director of the NIAID. In keeping with the ACT UP activist model, they also disrupted scientific conferences with banners that said: “NIAID: Form a Women’s Committee Now.”
Activists also targeted researchers directly. For one action, organizers attended a meeting for a drug called foscarnet, a new antiviral being developed for the treatment of HIV. During the meeting, advocates managed to insert a slide into the projector to broadcast a message: “This drug is not for IDUs [injecting drug users], women, people of color, or poor people.”33 At another event, ACT UP advocates made fortune cookies and placed them on the tables for the coffee break. Upon opening them, researchers were met with ACT UP slogans: “Congratulations, your research has not saved the life of one PWA [person with AIDS]”; “It’s 1991. Is there a gynecologist on your team?”; and “Can you say Vagina?” The fortunes even reminded researchers that “large randomized trials will never tell us anything about women.”34
In a book published by activists on women and AIDS, leaders in ACT UP Maxine Wolfe and Iris Long, key players in the fight to change the CDC definition described in Chapters 1 and 2, wrote an essay, “Through the Eye of a Needle: Women’s Access to Drug Treatments through Clinical Trials.” Their chapter describes an epidemic among women who are Black and Latina, often use drugs, are often likely to be poor, have no medical coverage, and must rely on public services for health. Their inability to access medications through the formal or underground market grounded their argument: “For these reasons, women’s participation in a clinical drug trial will be their only access to traditional medical treatment for AIDS.”35
Though this chapter focuses on the FDA, AIDS advocates also frequently targeted the NIH, the agency responsible for funding research on public health issues. For feminists, actions at the NIH and FDA were deeply related. They both were meant to push scientists to understand that the epidemic was not only impacting women but that the lack of knowledge about women’s bodies and the lack of inclusion in clinical trials were leading women to be excluded from the AIDS treatment response.36 During one of the most famous ACT UP protests in 1990, ACT UP NY/ACT UP DC lesbian and gay affinity group stormed the NIH and Dan Hoth’s office. Activists raised signs that said “NIH, You Can’t Hide, We Charge You With Genocide.” Speaking at the protest, Phyllis Sharpe, a prominent Black feminist AIDS activist told the Los Angeles Times that the NIH does not “want to save me or my child.” The protest resulted in the arrest of sixty people.
As activists pushed outside the agencies, within government change was also afoot. There was a growing concern that “a failure to include sufficiently diverse populations could erroneously lead to treatment protocols skewed toward a norm of middle-aged, white males.”37 Leadership in Congress and in the agencies mobilized to push for better research and funding on women’s health. With the George W. Bush administration, David Kessler became head of the FDA in 1990. And Bernadine Healy became the first woman to head the NIH in 1991. Both Kessler and Healy were interested in raising awareness about issues of women’s health. The NIH had joined the call to improve women’s involvement in clinical trial research and Healy would launch the first NIH Women’s Health Initiative. Kessler hired Ruth Merkatz to become the first director of the FDA’s Office of Women’s Health. Others, like Congresswoman Barbara Mikulski, a Democrat from Maryland, led the charge from within Congress proposing laws to ensure clinical trial inclusion and launching congressional and public debate and discussion on the topic.38 Merkatz would later credit AIDS activists who she attributed as pushing forward the agenda to include women in clinical trials noting that the push came from feminist advocates.39
In 1992, the Government Accountability Office (GAO) released its report on women’s health. Focusing on new drug approvals between 1988 and 1991, the GAO report found that – despite the change in the guidelines – only 50 percent of these trials were pursuing an analysis of the drug based on sex.40 The report highlights the low enrollment of women in many clinical trials and the rationale being the FDA’s own policy precluding women of childbearing potential from participating in Phase I and early Phase II trials. The report also provides evidence that gender differences impact drug usage and effects, with several examples, including drugs for hypertension and anesthesia.41 These differences are attributed to differences in women’s size and body fat, and the presence of naturally occurring and ingested hormones.42 The report was an important step forward in the agency’s acknowledgment of the importance of studying sex and gender in the context of drug trials.
Experimenting with Pregnancy: ACTG 076
As advocacy and internal investigations continued at the FDA, by the early 1990s, a new set of concerns had emerged around the issue of pregnant women who would give birth to children with HIV. The issue of infants and children with AIDS had become one that could engender public attention and sympathy in a way in which prior rhetorical strategies on AIDS could not. Headlines featured the faces of infants dying of AIDS around the world. Infants known as Boarder Babies were often left to the care of hospitals, some living for years among patients in unstable housing. Compelling accounts appeared in national newspapers about the uncertain future for children with HIV and their parents.43
At the time, an infant born to a woman with HIV had a 30 percent chance of having HIV and a very high chance of dying within a few years of being born. Several pathways for HIV transmission from mother to child had been identified. HIV might travel through the placenta; it could be transmitted during birth via exposure from blood and vaginal secretions or through breast milk and breastfeeding. Transmission from mother to infant could occur during pregnancy and early in childbirth.44 The infants who contracted HIV before treatment was available most often succumbed to the virus.
By 1991, scientists were beginning to consider the possibility that providing antiretroviral drugs to pregnant women could help stop transmission to the child. However, understanding how to save infants required enrolling pregnant women in clinical trials.
This frustrated feminists who had been fighting to include HIV-positive women in clinical trials: Were women not worth studying for the sake of studying women? Why were women only a point of intervention when it came to pregnancy? Even while feminists had held onto the idea of choice and autonomy as the cornerstone of women’s participation in clinical trials, they were suspicious of the government’s sudden interest in pregnant women.
Researchers charged ahead: Could there be a drug that prevented mother-to-child transmission? In 1991, a new study was launched: the AIDS Clinical Trial Group 076 (ACTG 076). The name represented its status as the 76th trial performed by the ACTG. The trial enrolled 180 women who were given AZT and 183 who were given a placebo. The women who participated met several criteria: They had low T-Cell counts, were only experiencing mild symptoms, and had never taken AZT before.45 The medication was given to women during pregnancy and then again during labor.46
Advocates were concerned about several dimensions of ACTG 076. Drawing on interviews with advocates from the time period, scholar and activist Sarah Schulman outlined some of the primary concerns of feminist AIDS advocates. First was the idea that the trial design itself was flawed. If the only available medication to potentially treat mother-to-child transmission of HIV was being tested, was there a need for a control group? Feminist advocates did not think so – all women in the study should have the opportunity to potentially benefit from the drug.47 Second, because these trials, unlike many of the others, were being conducted in hospitals with a greater representation of poor women and women of color, the denial of a life-saving treatment raised questions of unethical testing on racial minorities. This idea was echoed in the media. A Newsday article from this period quotes Dr. Carol Levine, Executive Director of the New York City Commission on AIDS: “People ought to be very clear about what they are doing here … I think it’s very troubling since the majority of these women and children are members of poor minorities.” Levine goes on to note that there are consent issues in a trial that is “unprecedented” given that AZT, known for its inability to be tolerated due to high toxicity, could be given to “healthy fetuses and newborns.”48 In other words, pressure to take the experimental medication to save one’s child would undermine the ability of a woman to meaningfully consent.
Finally, and perhaps above all else, was the idea that women were being used for the sake of the potential life of the child,49 but they were not being given adequate attention in clinical trials as patients themselves.
Complicating things further, the ACTG trial generated tensions within ACT UP and between activists and scientists.50 Feminists who raised concerns, perceived to be HIV-negative and white, sought to stop the trial and distrusted community engagement mechanisms that had been set up by NIAID that would allow experimentation on pregnant women to continue when the experiments were only for the sake of the fetus.51
While some in ACT UP wanted to stop the trial, others felt that the trial should continue forward.52 Activist and scholarly accounts suggest that these tensions came to a head at a meeting of the ACTG in which community members were able to ask questions.53 Here, women in ACT UP, primarily white women, protested the research study. This seemed to upset one physician in particular, a member of the ACTG, who felt that this was an opportunity for Black women to get access to medication.54 Some of the men of ACT UP also felt that the protest stepped on the feet of the activists in ACT UP who had developed expertise in clinical trials.55 Despite protest and internal activist debate the ACTG 076 trial continued.56
The Citizen’s Petition and a New Rule: Let Women Choose
Like in previous moments, legal advocacy comprised a core piece of the advocacy around altering the study and acknowledgment of women and AIDS by scientists. In 1992, the year the GAO released its report, three lawyers, Terry McGovern from the HIV Law Project, Martha Davis from the National Organization of Women (NOW) Legal Defense Fund, and Alma Gomez from the American Civil Liberties Union’s AIDS project, utilized a mechanism at the FDA that allows citizens to petition the agency. As noted in Chapters 1 and 2, McGovern’s legal advocacy was central to the CDC changing the AIDS definition to be more inclusive of gynecological conditions associated with AIDS with the result of more diagnoses for women (at this time, most AIDS diagnoses were based on symptoms due to a lack of availability of tests). Her advocacy had now taken her in a new direction. Identifying women as having HIV meant that they needed treatment. The three lawyers wrote a citizen’s petition critiquing the FDA for not having gone far enough to ensure women were participating in clinical trials. They wrote it not only as representatives of their organizations but also for the ACT UP Women’s FDA Working Group and for AIDS Counseling and Education for Women in Transition from Correctional Facilities (ACE OUT). The citizen’s petition sought to ensure that women would be enrolled in clinical trials.
Their target was the 1977 guidance excluding women of childbearing potential from clinical trials. The 1977 guidance was having a negative impact on AIDS care. The petition noted that as of January 1992, “women’s enrollment in the ACTG studies reached 1,151, including 154 pregnant women. Men’s enrollment for the same period numbered 13,628.”
Now self-made experts in clinical trials,57 the lawyers and advocates made a range of arguments and recommendations regarding how and why women should be included in drug research. The petition reflects a set of legal arguments that were gaining momentum at the time in a range of cases on abortion and pregnancy: that women ought to have full bodily autonomy and choice. Here, the petition reflects the idea that women should be able to choose their own risks as they navigate life-and-death situations. It made a strong and clear appeal to the FDA: that women ought to be included in clinical trials – even at the earliest stages.
The authors of the citizen’s petition sought to allow women to use experimental drugs. This would require allowing women to determine their own risk-tolerance while ensuring oversight. They offered possibilities on how to ensure that decision-making both protected choice and autonomy while ensuring safety. They argued, for example, for the need for animal reproduction studies to be completed alongside Phase I testing of a drug. Animal reproduction studies could help establish whether there was a threat of reproductive harm caused by the drug. Based on the outcomes of animal reproduction studies and Phase I trials, women could be best informed about the possible risks of participating in a clinical trial. Where reproduction studies demonstrate significant harm to the fetus, and there is no life-threatening illness at stake, drug sponsors and investigators can require that pregnant women be included with full and informed consent. Feminists advocated for a more robust informed consent that would include the long- and short-term and/or potential risks but would ultimately leave the decision on whether or how to participate to women.58
Equality arguments also feature prominently in the citizen’s petition. Men were able to participate in clinical trials regardless of the possibility of intergenerational harm while women were excluded. Feminists sought that male and female participants be treated identically with regard to access to trials. In addition to including women in the trials, this would mean assuming that men, too, could play a role in transmitting potential issues – dislodging the focus on women.
Drawing on legal frameworks, the citizen’s petition states that the 1977 guidance fails to meet the two-part test for equal protection. It discriminates against women and, therefore, can only be sustained if the party seeking to uphold the policy shows by “exceedingly persuasive justification” that the classification serves “important governmental objectives and that the discriminatory means employed are substantially related to the achievement of those objectives.”59 The authors note that even if one assumed that fetal protection is an important governmental objective, the exclusion of women is not substantially related to that objective because it is overbroad and underinclusive. It supports the exclusion of all women of childbearing potential, and there is no comparable guideline for men.
The petition tapped into the line of constitutional changes that enabled this argument, including two cases decided by the Supreme Court the year prior: United Automobile Workers v. Johnson Controls and Casey v. Planned Parenthood. In United Auto Workers, an employer had barred women from working in an area of a plant where their lead exposure would have caused possible fetal harm. To work in this location, women would have to show proof of sterilization. The Supreme Court held that this proof of sterilization was facially discriminatory because it did not apply to men as well as women.
Despite the contextual differences – United Auto Workers is about work, not clinical trials – the case was important in emphasizing the evolving set of ideas around the risks women ought to be able to take with their reproductive choices. This idea of bodily autonomy was bolstered by a decision that came out only months before the petition was filed: Casey v. Planned Parenthood. The decision, known for its reworking of legal standards in the abortion context, was deployed by the authors of the citizen’s petition to make the point that the court had spoken about the idea of privacy and autonomy. Taken together, these cases helped the feminist authors make a controversial point: that women ought to be able to choose their own risks, even when pregnancy and a potential fetus are at stake. Pushing back against the paternalism of the state, the petition authors argued that privacy and autonomy outweigh “any generalized governmental interest in avoiding fetal toxicity.” The petition argued that the “exclusion which extends to women with life-threatening diseases or who are seeking treatment places an undue burden on these women’s exercise of reproductive choice.” (Though there were exceptions to life-threatening illnesses when it came to women’s participation in clinical trials, advocates pointed out that this was being ignored in the context of AIDS clinical trials.)
These themes also resonated broadly with a shift brought about at the FDA through ACT UP activism. Looking back on this moment, Lewis Grossman, in his book Choose Your Medicine, notes that this period would come to fundamentally shift the inner workings of the FDA – allowing drugs to be used by patients earlier in the clinical trials process – a shift that aligned with the deregulatory tendencies of the Reagan administration.60 It was a convergence of interests between progressive advocates for HIV treatment and the conservatives concerned with deregulation. Feminists, too, found a place inside this logic. Their fight for autonomy and choice was a part of the bigger movement that was changing how we should understand women’s risk-taking during pregnancy in law and in the regulation of clinical trials.61
New Guidance from the FDA
Ruth Merkatz came under specific pressure. In one instance, she heard a noise outside of her office and women’s AIDS activists were marching for women’s inclusion in clinical trials. They chanted “Get the facts, Ruth Merkatz.” At another event, feminist activists threw toilet paper at Merkatz while she spoke at a podium.62 She was sympathetic to their concerns seeking to root the agency shifts in the register of science while aware of the shifting sensibility that women ought to be able to choose to take risks, evidenced by the Supreme Court.63 She was working within the agency to transform the guidelines on clinical trials.
Growing pressure on the agency, alongside the FDA’s own internal investigations and support for transformation, resulted in new guidance. In July 1993, the agency published the Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs.
The new guidance acknowledged that it had been difficult to get early accumulation of research on women in the context of drug use because women were largely excluded from Phase I trials.64 Mirroring feminist claims, the language contextualizing the new guidance states that “the early exclusion may have perpetuated, in a subtle way, a view of the male as the primary focus of medicine and drug development, with women considered secondarily.”
The new 1993 (draft) guideline reflected the arguments in the citizen’s petition and the broader cultural shifts toward women’s autonomy and decision-making. As proof of this cultural shift, the 1993 guidance cited the Supreme Court’s contemporaneous opinion in United Automobile Workers v. Johnson Controls, raised initially in the citizen’s petition. Speaking directly to the issue of pregnant women in drug trials and comparing it to that of decision-making around employment, the supplementary material to the FDA guidance notes that:
While the purposes of clinical trials to develop safe and effective drugs are manifestly different from the purposes of private employment, FDA takes serious note of the Court’s position on the women’s right to participate in decisions about fetal risk and believes it is appropriate to consider the Court’s opinion in development policy on the inclusion of women in clinical trials.65
For the FDA, updating the guidance would mean modernizing the clinical trial guidelines to match the idea that women ought to be able to take risks during pregnancy.
The guidance, however, stops short of requiring drug companies to include women of childbearing potential. Instead, it articulates that the FDA expects a “careful characterization of drug effects by gender.” By this, the agency wants gender-disaggregated data on the pharmacokinetic differences (differences in the way a drug is “absorbed, excreted, metabolized, or distributed) as well as pharmacodynamic differences (“differences in the pharmacologic or clinical response to a given concentration of the drug in blood or other tissue”) by sex.
At the same time that the proposed guideline was released, Ruth Merkatz published an article in the New England Journal of Medicine arguing that gender matters in research. Clearly supporting the feminist arguments surrounding the expansion of the FDA effort to include women, Merkatz noted that “responses to drugs are influenced by many factors, including age, sex, ethnic background, metabolic phenotype, body-fat content and distribution, and body size.”66 She states that if these differences are recognized and adjusted for “in the dose or dose interval, choice of drug, monitoring procedures, or other aspects of drug administration [this] can improve outcomes for patients.”67 According to Merkatz, because of the GAO report, the FDA would now review all new drug applications to make sure they appropriately analyze for sex. “If such analyses are lacking, the FDA will call for their submission and may consider refusing to initiate review of the application if sex-specific analyses are not provided within a reasonable period.”68 Like the rule, she stops short of asserting that women should always be required in relevant clinical trials.69
Merkatz also acknowledged the alchemy between law and science that produced the new guidance. The Supreme Court’s decision United Automobile Workers v. Johnson Controls was “very much a factor in convincing everyone that … the restriction at FDA needed to be reconsidered.” Merkatz stated that “Although the purposes of clinical trials are manifestly different from the purposes of employment, the court’s emphasis on the woman’s right to participate in decisions about fetal risk underscored the principles of autonomy and informed consent.”70
Activists did not believe the FDA had gone far enough in its new guidance. On October 18, 1993, Terry McGovern and Martha Jones of the HIV Law Project and Martha Davis of the NOW wrote a memo critiquing the draft guidance. In their critique, McGovern, Jones, and Davis argued that the guidance should mandate the inclusion of women in clinical trials and noted that the guidance does not eliminate gender-based restrictions on accessing clinical trials (or require analysis of drug responses in light of potential gender differences). They stated their complaint:71
The closest the FDA comes to requiring that women be included in clinical trials is in a vague passage which states that “in some cases, there may be a basis for requiring participation of women in early studies.” The disease under study must be “serious and affect women,” and “especially when a promised drug for the disease is being developed and made rapidly under the FDA’s accelerated approval or early access procedures, a case can be made for requiring that women participate in clinical trials at the early stages.” The 1993 Guideline does not define these provisions and it does not commit the FDA to monitoring the IND [Investigational New Drug Application] process to ensure that trials meeting the vague criteria enumerated will include women.72
Alongside their frustration with what they felt was weak language in the guidance document, feminist advocates were also concerned that some of their points were simply ignored by the FDA. In their response to the revised guidance, they once again noted that animal reproduction studies were key to showing whether a drug could cause fetal abnormalities or had potential long-term reproductive effects. They argued that if the FDA mandated the animal reproduction studies, it would enable the agency to determine whether persons of “child-producing” potential who wish to participate in a clinical trial were at risk of experiencing reproductive effects.73 But, as the advocates point out, the FDA does not require these animal studies often due to worries of delaying the actual clinical trials from the beginning. For feminist advocates, a delay, which they estimated to be between 41 and 136 weeks, was worth it for the possibility of safely enrolling women.
Second, feminist advocates were frustrated that any generational male-mediated effects of drugs were ignored. They argued that women are either excluded from the study or asked to use contraception and be tested for pregnancy, but the FDA “does not recommend restricting men of child-producing capacity in the same manner” even though men included in studies lack the knowledge about risks to childbearing.74
For feminists, the draft 1993 guidance was not an adequate response to the citizen’s petition.75 The clear message from advocates was that the agency can force drug companies to include women and ensure women’s autonomy through informed consent.76 Where uncertainty persists in drug development, it should be up to the woman to decide whether or not to participate.
As they awaited a response, a National Task Force on AIDS Drug Development convened in November 1993 to expedite the search for new therapies against AIDS and HIV. One goal was identifying and removing any barriers or obstacles to developing effective treatments. Terry McGovern, now a member of the National Task Force on AIDS Drug Development given her advocacy in this space, was tasked with making recommendations to Donna Shalala, the secretary of health and human services. In keeping with her prior advocacy, McGovern advocated that the Department of Health and Human Services remove specific barriers to the participation of women of childbearing potential in clinical trials.77
As McGovern pushed the agency from within for greater inclusion, activism outside of the agency also continued. In September 1994, for example the national ACT UP Women’s Caucus met with Merkatz and Theresa Toigo, the deputy director of the Office of AIDS and Special Health Issues. In the meeting, members of the ACT UP Women’s Caucus, including Mary Lucey, expressed concerns about the lack of inclusion of women living with HIV in administrative processes at the FDA and in clinical trials.
In response to the concerns raised at the meeting, the FDA sent a letter to Mary Lucey on October 12, 1994. The letter defended the 1993 guidance, stating that it makes clear that “a gender analysis is expected in new drug applications and identifies specific pharmacokinetic issues in women that should be addressed, including effects of the menstrual cycle, effects of exogenous hormonal therapy including oral contraceptives, and the effects of the drug on the pharmacokinetics of oral contraceptives.”
Yet, even as the FDA restated its commitment to the inclusion of women in clinical trial research, the agency washed its hands of responsibility when it came to the lack of inclusion of women living with HIV in relevant drug trials – arguing that it wasn’t the FDA’s fault there was always an exception for life-threatening illnesses.78
Two weeks later, on October 27, 1994, McGovern, Davis, and Gomez received a formal response from the FDA to their citizen’s petition filed in December 1992. The 1992 petition predated the interim 1993 guidance, and the FDA treated the guidance as a partial response to the complaints lodged by McGovern, Davis, and Gomez.
In the formal FDA response to the citizen’s petition, authored by Interim Deputy Commissioner for Operations Linda Suydam, the agency recognized that the 1977 guidance looks “outdated”; ideas in it appear “rigid and paternalistic.”79 This is particularly true, the response notes, given the transformations in Supreme Court jurisprudence. Noting that it is not a case about clinical trials, Suydam acknowledges that the FDA still “took particular note of the Supreme Court’s position as articulated in United Automobile v. Johnson Controls on a woman’s right to participate in decisions about fetal risk.”
Though Suydam stated in her response that the FDA granted the petition in part by publishing a new guideline,80 in reality, the updated guidance failed to address many of the concerns raised by the team of feminist lawyers.
Keeping with prior assertions by the agency, Suydam, for example, disclaimed FDA responsibility for the lack of enrollment of women in clinical trials, stating that the agency never “recommended gender-based restrictions in clinical trials of drugs intended to treat life-threatening illnesses.”81 Second, she stated that where the studies do have barriers to participation, this is because study populations must be clearly delineated: “Thus, the desire to eliminate gender-based restrictions needs to be balanced against the need to answer specific scientific questions.” But, again, she noted that the agency had never said there should be an exclusion on the basis of gender from any trial in patients with immediate life-threatening diseases.82
Suydam pointed to the fact that researchers may be worried about tort liability. Sponsors, she said, may be “unwilling to administer the drug to women of childbearing potential without multiple protections against potential fetal exposure.” She asserted that the FDA would scrutinize any exclusions. The FDA would not, however, interfere in questions of contraception, she wrote. Decisions about contraception should be made on an individual basis by the woman and the study physician or other counselors.83
But what about during pregnancy? McGovern, Davis, and Gomez had argued that the FDA should prohibit the exclusion of pregnant women if the pregnant women if the pregnant women have given full informed consent to participate in drug trials. The FDA resisted this proposal. Suydam noted that early trials often do not offer any therapeutic benefit and that the “deliberate exposure of a fetus to an experimental drug raises serious ethical questions.” The FDA further argued that animal toxicity studies would reveal potential harms.84 But, again, the FDA noted that it does not recommend against access to clinical trials in the context of life-threatening emergencies.85
Feminist advocates inside ACT UP also resisted the new guidelines. A document produced by the ACT UP Women’s Caucus criticized the agency for stopping short of requiring inclusion. Under the banner “Say It: Women Get AIDS,” it criticized the guidelines for falling short of the goal of including women and demanded “guidelines that require inclusion of women on all levels of clinical AIDS drug trials.” The flyer considers various actions including an encampment and street theatre in front of the federal agency.
In September 1994, advocates made good on their promise, issuing flyers produced by members of ACT UP. The flyers, some printed on pink and blue paper, demanded a “public trial” and a “public spanking” and called to “convict the FDA.” The goal was to “demand the inclusion of women in all clinical trials.” Organizers also met with David Kessler, head of the FDA, to make presentations about the issue of women and clinical trials and ensure that there be increased meetings with women living with HIV.86
A year after the guidance was issued, the ACTG 076 trial showed that AZT could virtually stop the transmission of HIV from mother to child.87 The study was so successful that researchers ended the trial so that there would no longer be a control group and all enrolled could access the medications. There was a new standard of care that would decrease the number of infants born with HIV.
Feminists stopped their protests of ACTG 076, ceding to the reality that the drug was having a positive impact. But their suspicions of the potential harms of drugs developed for the fetus weren’t misplaced nor were their fears that pregnant women might bear the brunt of potentially coercive public health policies to better infant outcomes. These critiques would shape the discourse of feminist activism around pregnancy and AIDS in the decades to come.
The Struggle Continues: Still No FDA Mandate to Include Women in Clinical Trials
At the heart of the feminist fight to remake knowledge about women is a redistributive goal: better healthcare. The deaths of women living with HIV made this fight urgent. Feminists sought to alter the regulatory environment around clinical trial research with the specific goal of allowing women to access to drug trials and medications that would serve women better. Their fight embodied the feminist ideals of the 1990s – autonomy and choice – in this case, enabling women to take risks necessary to best treat their own health conditions.88 The 1993 guidance produced a shift in the inclusion of women in clinical trials, but the lack of a mandate, and the ongoing exclusion of women from trials, motivates activism still today.89
