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Gender Studies in Product Development: Historical Overview

Women of Childbearing Potential and Early Clinical Trials

Ruth Merkatz, Ph.D., Director of FDA’s Office of Women's Health, brought an historical perspective to the Gender Workshop, including a review of the FDA’s 1977 guideline, "General Considerations for the Clinical Evaluation of Drugs," and the context in which it was issued. This guideline recommended excluding women with childbearing potential from participating in phase 1 and early phase 2 clinical studies until reproductive toxicity (segment 2) studies were conducted and some evidence of effectiveness had become available. The recommended exclusion was broadly applied to any "premenopausal female capable of becoming pregnant," but explicitly did not apply to women with life threatening diseases.

The policy was developed to reflect societal interests in protecting vulnerable populations and emerged in part from discoveries of birth defects resulting from fetal exposure to certain drugs, including thalidomide and DES. It also reflected the recognition that early clinical trials often take place prior to completion of preclinical reproductive toxicology studies, which include potential teratogenic effects on a developing fetus. With a possibility for fetal damage from experimental drugs and no clearly articulated medical benefit to the phase I and early phase 2 trials, women with childbearing potential were considered inappropriate subjects in early clinical trials. These considerations formed the basis of the exclusionary approach recommended in the 1977 guideline.

In later years, however, that recommendation began to raise important ethical and even legal questions about the appropriateness of assuming that women cannot take steps to avoid becoming pregnant, where appropriate, and of deciding for women that protecting the fetus outweighed other possible interests. Dr. Merkatz explored these questions in her talk and described the influence of the National Commission for the Protection for Human Subjects of Biomedical and Behavioral Research, which issued the Belmont Report in 1977, outlining the ethical principles expected to govern drug research. Subsequent interpretations of the report's emphasis on respect for persons, which encompasses the principle of autonomy, raised serious questions about the virtual ban participating in early clinical trials imposed on women with childbearing potential.

Further support for reconsidering the policy of excluding women with childbearing potential from clinical trials came from a number of women's health advocacy groups. These advocates argued that the policy had a chilling effect on access to later clinical trials, despite its focus on early phase trials. Despite the explicit exception for women with life-threatening diseases, there were also concerns that the 1977 guideline had an effect on this population as well. Because of accelerated approval and rapid development of experimental therapies to treat life-threatening diseases, it is important to include women earlier in these studies.

Policy Changes: The 1993 FDA Gender Guideline and NIH Initiatives

In 1993, FDA explicitly reversed the 1977 recommendation that women with childbearing potential be excluded from early clinical studies when it published "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs." The new guideline also called for data to be analyzed to assess gender effect. Issues surrounding implementation of this guideline represented an important element of workshop deliberations.

The new guideline is best understood as part of a continuing effort to enhance individualized pharmaceutical therapy. This is based on the growing recognition that pharmaceuticals may need to be administered differently in different population groups identified by one or more demographic or clinical characteristics, such as gender, ethnicity, age, body size, hepatic or renal function, disease state or enzyme activity. Several important FDA documents reflect the early recognition of the value of individualized therapy:

  • The 1985 New Drug Application (NDA) rewrite noted the need to consider dosing in relevant population subsets, specifically citing older patients, children and patients with renal failure.
  • The 1988 implementing guidance document for the NDA rewrite, entitled "Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications," advised sponsors to include dose modifications and to analyze pooled safety, effectiveness and dose-response data in the integrated summaries of safety and effectiveness. One of the goals of the guideline was to identify differences in drug response associated with age, race and gender among subset groups within the overall study population.
  • The "Guideline for the Study of Drugs Likely to be Used in the Elderly," published in 1989, called for including older patients in drug studies, understanding age-related differences in pharmacokinetics, and analyzing safety and effectiveness results by age.

Robert Temple, M.D., Associate Director for Medical Policy in the Center for Drug Evaluation and Research at FDA, explained how the new guideline was structured to promote individualization of drug therapy. Like the guideline focused on the elderly, the gender guideline states FDA's expectation that the data supporting an NDA will include a reasonable representation of the population that will receive the drug, and that safety and effectiveness data will be examined to identify significant differences by demographic groups, such as gender and age. Dr. Temple explained that the 1993 Guideline focuses on data needed for approval and marketing, with only limited reference to the details of development or when and how a sponsor should study both genders. He emphasized that rigid gender quotas are not expected in clinical trials but that the guideline does express a preference for including both genders in the same studies, rather than in separate single-gender studies. It also suggests that FDA might require the inclusion of both genders in early safety, efficacy, and dose-finding studies where drugs for serious or life-threatening diseases are likely to be made widely available prior to approval, or are Rely to be approved on the basis on phase 2 data.

The 1993 Guideline emphasizes the process of informed consent so that trial participants understand what is known and unknown about experimental agents. It stresses the need, where appropriate, for women with childbearing potential to use contraception or abstinence while participating in early trials. It recognizes as well that under certain circumstances pregnancy tests may be an important part of protocol design in order to guard against the potential for fetal damage. The 1993 Guideline thus reflects the FDA’s continued interest in protecting the fetus from unanticipated exposure to potentially harmful drugs, while bringing renewed attention to the benefits that may accrue to women when they are able to participate in all phases of drug development.

More specifically, the new Guideline describes the importance of pharmacokinetic studies, the possible contribution of factors other than gender to an apparent gender difference (such as body size, smoking, and concomitant illness), the value, and sometimes the difficulty, of conducting relevant pharmacodynamic studies, the value of population pharmacokinetic and pharmacodynamic analysis (a pharmacokinetic screen, in FDA parlance) and the importance of conducting relevant subset analyses. In addition, the Guideline indicates that the influence of menstrual status, that is, whether women are pre-or post-menopausal, and menstrual cycle on the pharmacokinetics of an investigational drug should be explored, as should the effects of concomitant supplementary estrogen treatment or systemic contraceptives. Finally, the Guidance suggests that the influence of the investigational drug itself on the pharmacokinetics of selected oral contraceptives should be explored.

A primary focus of the Guideline is to recommend that analyses be performed to assess differences in drug action due to gender in controlled clinical trials conducted to establish safety and efficacy in the total population. Such analyses may be presented as integrated summaries, which are essentially meta-analyses, in which data from multiple trials in a clinical trial base are combined and subjected to statistical analysis for gender effects. Because of their post-hoc character, these analyses do not test a hypothesis but instead are descriptive, a characteristic they share with most analyses of safety data. Clearly, such analyses can support further studies but if the information from these analyses is consistent, it can also be incorporated into product labeling and be useful to patients and practitioners even without further studies.

Although current FDA regulations do not require the participation of specific patient subsets in particular trials, a proposed new rule requires that the NDA format and content include presentations of safety and effectiveness data for important subgroups, specifically gender, age, and racial subgroups and, when appropriate, other demographic subgroups. These proposed new rules will also request that the IND annual report include information about the total number of subjects enrolled into clinical trials, categorized by gender, age, and race. [Docket 95N-00101]

Several workshop speakers emphasized that FDA’s 1993 Guideline has had a clear impact on clinical drug trials. Janice Bush, M.D., Vice President of Janssen Research Foundation, said that since its publication, pharmaceutical sponsors have enrolled more women and included them earlier in the drug development process. Dr. Merkatz also emphasized the progress that had been made in articulating the guideline principles to FDA staff, as well as to sponsors of research, scientific and academic groups, health advocacy groups, and other constituencies. She noted that special attention has been focused on the Institutional Review Boards, which review protocols, and appropriate inclusion and exclusion criteria and informed consent procedures have been emphasized.

Significantly, as issues of access to clinical trials. were being debated at the FDA, initiatives at the National Institutes of Health (NIH) were moving in a similar direction. Eugene Hayunga, Ph.D., Research Policy Officer at the Office of Research on Women's Health (ORWH), described NIH policy to workshop participants. While NIH has required that women and minorities be included in clinical research since 1986, a series of policy revisions in the early 1990s strengthened this mandate. The NIH Revitalization Act of 1993 then gave these policies the force of law. A year later, a new guideline was issued jointly by ORWH and NIH's Office of Research on Minority Health.

The guideline requires the NIH to ensure that women and members of minority groups and their sub-populations are included in all NIH-supported human subjects research and in phase 3 clinical trials in numbers sufficient to allow a valid analysis of differences in intervention effect. Researchers are not allowed to use cost as an acceptable reason for excluding these groups. Also, the NIH must initiate programs and support for outreach efforts to recruit these groups into clinical trials.

Together, the 1993 FDA guideline and the NIH initiatives point the way for greater analysis of the gender-related effects of medical products. Nonetheless, the Guideline continues to generate comment and debate as scientific, ethical and liability exposure issues are considered. Dr. Bush commented that industry needed to make better use of the data on potential gender effects that is now being collected. She noted that the workshop could make a useful contribution by offering practical proposals that did not impede clinical research or impose data requirements without sound scientific justification. Also essential to the ongoing dialogue is a frank discussion of liability, said Dr. Bush. While there is little record of substantial liability claims by clinical trial participants, children adversely affected by the medical decisions of a parent have the right to pursue litigation when they reach the age of majority in many states and this is a cause for concern.

Some patient advocacy groups continue to claim that legal and medical obstacles to trial participation are still imposed on women with childbearing potential, despite the guideline changes. In her workshop presentation, Theresa McGovern, Executive Director and counsel to the HIV Law Project, suggested that the obstacles may be particularly great for HIV-positive women. Ms. McGovern offered specific examples of clinical trials from which this population had been excluded, as well as instances in which the side effects of approved drugs were poorly understood in HIV-positive women. That perspective was echoed by a patient spokesperson, Ms. Claudette Bain, who described her concerns about various AIDS therapies that had been minimally tested in women. Jeanne DeJoseph, Ph.D., another patient spokesperson, discussed the relative lack of safety and efficacy drug profiles for premenopausal women who had suffered a myocardial infarction.

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