AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 October 7, 1994 Women and HIV Infection (Part X) Women in Clinical Trials December, 1993 With its recent publication of "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs," FDA has taken two important steps to ensure that new drugs are properly evaluated in women. First, it has provided formal guidance to drug sponsors to emphasize the importance of appropriate gender enrollment in clinical studies and of analyses capable of identifying potential gender differences in drug efficacy and/or safety. Second, the agency has altered a 16-year- old policy that had excluded the participation of women with "childbearing potential" from the earliest phases of clinical trials. These changes have occurred in response to growing concerns that the drug development process does not produce adequate information about the effects of drugs in women. These concerns have arisen at a time when FDA, drug developers, and the scientific community have voiced a need to have available data on drug responses in the subsets of the population to receive the drug. Responses to drugs may be influenced by many factors, including age, gender, ethnic background, metabolic phenotype, body-fat content and distribution, and body size. Concurrent illnesses and concomitant medications can also influence the effects of a drug. All these factors, either singly or in combination, can influence a drug's pharmacokinetics (the concentration of the drug in the blood or body tissues over time) and/or its pharmacodynamics (the body's response to a given concentration of a drug). When such differences are recognized, appropriate therapeutic recommendations can be made so that overall benefit of the drug can be enhanced. Gender-related differences in pharmacokinetics have been identified for some drugs. For example, propranolol is metabolized more slowly in women than in men; this is thought to be due to the interaction of the sex hormones and the enzymes that metabolize this drug. Most differences in pharmacokinetics between men and women are probably related to body size, body composition, and hormonal influences. The hormonal environment may influence both pharmacokinetics and pharmacodynamic parameters of drugs. Four factors can be identified that might lead to hormonally mediated gender differences in drug effects: (1) variations in levels of gonadotropins and circulating steroidal hormones, notably estradiol and progesterone, during the menstrual cycle; (2) differences in the hormonal milieu between premenopausal and postmenopausal women, including the use of exogenous hormonal replacement therapy; (3) the effects of different hormonal levels during pregnancy and the metabolic consequences of pregnancy itself; and (4) the effects of steroidal contraceptives on the metabolism of drugs taken concomitantly and, conversely, the effects of other drugs on the efficacy of contraceptives. The influence of the variable levels of the sex hormones during the menstrual cycle on insulin binding is an example of a pharmacodynamic effect. In one study, it was shown that the binding of insulin to blood cells was higher in the follicular phase than in the luteal phase of the menstrual cycle. There appears to be an inverse relationship between the binding of insulin to certain blood cells and the levels of estradiol and progesterone. This relationship may result in episodes of hyperglycemia during the luteal phase of women with insulin-dependent diabetes mellitus. Since 1988, FDA has taken steps to encourage development of data that support informed individualization of treatment, including issuance in 1988 of the "Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications (NDAs)." Recognizing the importance of gender analysis, FDA conducted a retrospective study analysis of NDA data to identify variations in drug safety and effectiveness among population subsets, including subsets based on gender, age, race, concurrent therapies, and concomitant illnesses. In this analysis, it was determined that safety data had been examined according to gender only 54% of the time and that efficacy data had been examined in this manner only 43% of the time. In light of these findings, FDA will now review all new drug applications shortly after submission to determine if they include the appropriate analyses by gender. If they do not, the applicant will be instructed to submit these analyses promptly to allow the completion of the review of the application. In addition to the request for appropriate gender analyses for current and future new drug applications, FDA has issued new guidelines on the participation of women in drug evaluations. The guidelines urge that women be enrolled in studies of new drugs in numbers adequate to allow detection of clinically significant differences in drug response and stress the importance of assessing possible pharmacokinetic differences between women and men. Such pharmacokinetic differences could be particularly important in the case of a drug with a low therapeutic index, where the smaller average size of women might necessitate modified dosing. The guidelines emphasize three pharmacokinetic issues that should be considered during drug development: (1) the effects of the menstrual cycle and menopausal status on a drug's pharmacokinetics; (2) the effects of concomitant estrogen supplementation or use of systemic contraceptive agents, including both estrogen-progestin combinations and long-acting progesterones on a drug's pharmacokinetics; and (3) the influence of a drug on the effectiveness of oral contraceptives. In order to fully evaluate the potential for gender differences in drug effects, FDA urges that women of all ages be studied, including early in drug development. There is no longer any restriction on the enrollment of women of childbearing potential in even the earliest phase of clinical trials. Instead, the new guideline calls for appropriate measures for minimizing the risk of fetal exposure, such as pregnancy testing, contraception, and provision of full information about potential fetal risks to prospective study subjects. In addition, it places the responsibility for initial determinations about the adequacy of these precautions in the hands of patients, physicians, Institutional Review Boards, and drug sponsors, with review and guidance by FDA. FDA and the scientific community are also concerned about the lack of data on the effects of drugs and biological agents in pregnant women. The potential for teratogenicity and the fear of liability have often been cited for the paucity of studies in this population, but the result is that many drugs are ultimately administered during pregnancy without reliable data on their maternal and fetal effects. FDA intends to explore the difficult issues associated with the evaluation of the effects of new drugs and biological agents in pregnant women in a series of public workshops and conferences similar to those that led to the policy changes described in this article. To obtain a copy of "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs," published July 22, 1993, write to the Center for Drug Evaluation and Research (HFD-8), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855. Please send two self-addressed adhesive labels with your request. (Ruth B. Merkatz, Ph.D., R.N. Robert Temple, M.D. Women in Clinical Trials. FDA Medical Bulletin. 1993 Dec;23(3):2-4.) Women in Clinical Studies October, 1993 The FDA published new guidelines for the enrollment of women into clinical trials. The new guidelines, published in the Federal Register July 22, would replace earlier guidelines developed in the 1970's that excluded women from clinical trials. Garance Franke- Ruta, a New York-based AIDS activist, said that the new guidelines "were a step in the right direction, but didn't go far enough." She added that the FDA needs to develop guidelines specifically for women with life-threatening diseases. For more information, contact Patrick Savino at the FDA (301-295-8012). (David Gold. Gay Men's Health Crisis Treatment Issues, Volume 7, Number 9, October, 1993.) Women in Clinical Trials October, 1993 In July 1993, FDA published in the Federal Register proposed revisions to the agency's 1977 guideline, "General Considerations for the Clinical Evaluation of Drugs." The changes will help ensure that sponsors of trials for new drugs appropriately include women in their clinical studies and analyze data for differences in how men and women respond to the drugs, with particular attention to possible effects in women of the menstrual cycle, menopause, and use of birth control pills or estrogens. The agency also revised a policy that had excluded most women of childbearing potential with noncritical illnesses from the earliest phases of clinical trials. Dianne Murphy, M.D., assistant director for medical affairs in FDA's division of antiviral drug products, Center for Drug Evaluation and Research, says the issues surrounding these changes were brought to the forefront by the HIV epidemic. "The guidelines always provided that women with serious or life-threatening diseases could obtain an experimental drug in early phases of testing," says Murphy. "What's new is that now we're saying to drug manufacturers, 'Not only do we want you to study it in women, we are going to insist that you do so, if it's going to be used by women who have serious and life-threatening diseases.'" She explains that because of the urgent need, drug testing for HIV is on a fast track, with condensed stages of controlled studies and, frequently, fewer people in them. "Since the process moves so quickly, extensive clinical data collected over a long period of time often are not available," she says. "You need to know as soon as possible, for example, what adverse effects occur that might be dose-dependent, and work up those differences early in the drug development program. You don't want to wait for later stages of testing to begin to define dosage adjustments for men and women." Murphy stresses that the reason for including women in any phase 1 drug trial--regardless of the seriousness of the disease--should be to answer a question, not to fill a quota. She says, "The first question is: Do women in general absorb, metabolize or excrete this drug differently than men, or do they have different reactions to the drug? We want drug sponsors to include at least enough women to collect and analyze data on that question. Phase 1 testing will not likely detect subtle differences, but you might have some hints. The sponsor might want to better define in phase 2 any gender differences in absorption or excretion of the drug, for example, that might affect the dosing regimen." Very few women with HIV were included in studies early in the epidemic, but their numbers are increasing. According to the National Institute of Allergy and Infectious Diseases (NIAID), in 1992 women accounted for 23 percent of adult participants in the AIDS Clinical Trials Group, the institute's largest clinical trials network. That percentage is up from 6.7 percent in the years 1986 through 1990 and 14 percent in 1991. Some HIV studies include only women. Better information on the length of survival and quality of life in HIV-infected women are research goals of the Women's Interagency HIV Study, recently begun by CDC and NIAID. This large-scale study is designed to identify clinical signs of HIV infection in women, describe how the immune system declines, and look for factors that can affect the progression of the disease. It will also examine factors influencing women's access to health care. (Marian Segal. FDA Consumer. October 1993.) FDA Guideline on Women in Clinical Trials September, 1993 The FDA has published a new guideline on the agency's expectations regarding inclusion of patients of both genders in drug development, analyses of clinical data by gender, assessment of potential pharmacokinetic differences between genders, and the conducting of specific additional studies in women when indicated. The guideline also revises a 1977 policy that had excluded women of childbearing potential from the early studies of most drugs. The general principles of inclusion of both genders and analysis of gender differences are applicable to medical devices and biologic products as well as drugs. The new guideline explains that concerns about inadequate information concerning the effects of drugs in women have arisen concomitantly with an increasing recognition of the need to individualize medical treatment because a wise variety of demographic, disease-related, and individual patient factors can lead to different responses to drugs in subsets of the population. In most cases these differences are quantitative differences; for example, in dose-response, maximum size of effect, or in the risk of an adverse effect. In rare cases, there may be qualitative differences as well. A guideline on the study of drugs likely to be used in the elderly was issued previously (JAMA. 1991;265:182). The new guideline encourages sponsors of drug research to include patients of both sexes in all phases of drug development, and to analyze the effectiveness and safety databases to look for significant differences in response between men and women. A recent survey by the General Accounting Office and a survey by the FDA found that in many cases (about half) the databases in new drug applications were not being analyzed to determine whether there were gender, age, or race differences in response to drugs. The new guideline draws particular attention to the necessity for those directing drug development studies to consider the effects of such aspects of female physiology as the menstrual cycle and menopause, and the effects of drugs widely used in women, such as oral contraceptives and systemic progestins and estrogens, on drug action and pharmacokinetics. It explains that, for a number of practical and theoretical reasons, the evaluation of possible gender-related differences in drug response should focus initially on evaluation of potential pharmokinetic differences, i.e. differences in the way a drug is absorbed, excreted, metabolized, or distributed. The guideline's removal of the prior restriction on participation of women of childbearing potential in early clinical studies reflects the agency's view that institutional review boards, investigators, and subjects should play a greater role in determining whether participation of women in trials is appropriate and how best to minimize the likelihood of exposure of a fetus to potentially toxic agents. In its review of protocols, the FDA will continue to evaluate the adequacy of provisions providing for precautions against becoming pregnant and exposing a fetus to a potentially dangerous agent in the course of a trial. (Stuart L. Nightingale, MD, Associate Commissioner for Health Affairs. JAMA. 1993 Sept 15;270(11):1290. Editor's Note: Written inquiries may be directed to the Office of Health Affairs, FDA, Parklawn Building, 5600 Fishers Lane, Rockville, MD 20857.) FDA Guideline on Women in Clinical Trials July 21, 1993 The Food and Drug Administration is publishing a guideline calling for better assessment of possible gender differences in responses to new medications. The guideline will be published on July 22 in the Federal Register and is discussed in the current issue of The New England Journal of Medicine [Editor's Note: See, Merkatz RB. Temple R. Subel S. Feiden K. Kessler DA. Women in clinical trials of new drugs. A change in Food and Drug Administration policy. The Working Group on Women in Clinical Trials. N Engl J Med 1993 Jul 22;329(4):292-6. See also Comments in: N Engl J Med 1993 Jul 22;329(4): 271-2 and N Engl J Med 1993 Dec 9;329(24):1815-6]. At the same time, FDA revised a l977 policy that had excluded women of childbearing potential from the early studies of most drugs. As Ruth Merkatz, Ph.D., R.N., Special Assistant to the FDA Commissioner: Women's Health Issues, and co-authors point out in a Special Report of NEJM, the new "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs" will help "ensure that the safety and efficacy of drugs are adequately studied in the full range of patients who will receive therapy." The new guideline encourages companies to include patients of both sexes in drug development as, in general, they have in the past and to analyze the effectiveness and safety databases to look for significant differences in response between men and women. (For background, see Talk Paper below, April 5, l993.) The guideline directs particular attention to possible pharmacokinetic effects of the phases of the menstrual period, menopause and use of oral contraceptives or estrogens. Elimination of the l977 restriction on participation of women of childbearing potential in early clinical studies reflects the agency's view that institutional review boards, investigators and patients should play a greater role in determining whether participation of women in trials is appropriate and how best to make sure there is no exposure of a fetus to potentially toxic agents. In its review of the manufacturers' protocols, FDA will continue to evaluate the risks and benefits of drug studies in specific populations, including women. FDA and the authors of the Special Report in NEJM -- Dr. Merkatz, Robert Temple, M.D., Solomon Sobel, M.D., Karyn Feiden and FDA Commissioner David A. Kessler, M.D. -- believe that the new policy will encourage the collection of better information about the effects of drugs in women, and provide women with greater opportunities to participate in drug development and research. The general principles about inclusion of women and gender analysis outlined in the guideline also apply to biological products and medical devices. (Talk Paper, Department of Health and Human Services, July 21, l993.) [Editor's Note: See: Mohiuddin SM. Hilleman DE. Gender and Racial Bias in Clinical Pharmacology Trials [editorial]. Annals of Pharmacotherapy. 1993;27:972-3. See also, Current issues surrounding women and minorities in drug trials [review article] located in the same issue on pages 904-11.] FDA Plans Policy Change on Women in Clinical Trials April 5, 1993 A new FDA guideline will encourage companies both to include women in reasonable numbers in studies and provide the agency information about any significant differences found between men and women in their responses to drugs. It will also change a policy in effect since l977 that has resulted in the exclusion of most women capable of becoming pregnant from participating in the earliest phases of clinical trials. The agency believes that the new policy will permit earlier detection of gender differences that could lead to better selection of doses and monitoring procedures in later studies. The gender-specific data will also result in better labeling information for prescribing physicians. Based on several surveys of new drug applications, FDA found that women have generally participated in substantial numbers in clinical trials, usually reflecting the gender prevalence of the disease for which the drugs were being studied. However, women capable of becoming pregnant have been excluded in many cases from phase I trials, the earliest studies in humans intended to give a preliminary assessment of how well the drug is tolerated, and from early phase II trials, the first controlled studies of drug efficacy. In addition, results of animal reproduction studies have been required before women could be included in trials. This policy was intended to protect a fetus from any possibility of unnecessary exposure to potentially toxic agents. However, the policy has not excluded women capable of becoming pregnant from trials of drugs for life-threatening diseases such as AIDS and cancer. In recent years, the policy has been re-evaluated and there has been a growing belief that it should be changed. First, the policy has been viewed by some as being paternalistic because it denies women the right to make their own decisions on risks they wish to take. Second, while FDA still believes that protecting fetuses from potentially toxic agents is an important principle, the agency has concluded that fetal protection can be achieved by measures short of excluding women from early trials. The new guidelines call for precautions such as pre-enrollment pregnancy testing; use of contraception and behavioral measures that minimize the possibility of pregnancy; and providing women with appropriate information about potential risks. FDA is also planning to address the issue of the participation of pregnant women in clinical trials. (News Release, Department of Health and Human Services, Food and Drug Administration, April 5, l993.) Additional reading material: Women and HIV Clinical Trials is the special topic of the October 1993 issue of FOCUS: A Guide to AIDS Research and Counseling (Volume 8, Number 11). AIDS ALERT (September 1993, Volume 8, Number 9) is a special issue on women and AIDS. See, specifically, Drug trial changes should open doors for HIV-positive women, pp. 129-31. Recent information about the inclusion of women in clinical research can be found in Academic Medicine (1994 September, Volume 69, Number 9, pp. 693-715). Special articles include: Dubois MY. Burris JF. Introduction, p. 693-4. McCarthy CR. Historical Background of Clinical Trials Involving Women and Minorities, p. 695-8. Pinn VW. The Role of the NIH's Office of Research on Women's Health, p. 698-702. Merkatz RB. Junod SW. Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, p. 703- 707. Bush JK. The Industry Perspective on the Inclusion of Women in Clinical Trials, p. 708-15.