                   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.

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