July 20, 1998
Director, Center for Drug Evaluation and Research
FDAMA - Women and Minorities Guidance Requirements
Michael A. Friedman, M.D., Acting Commissioner
Under the Food and Drug Administration Modernization Act of 1997 (FDAMA) Sec. 115
Clinical Investigations. (b) Women and Minorities. -- Section 505(b)(1) 21 U.S.C.
355(b)(1) was amended by adding at the end the following: The Secretary shall, in
consultation with the Director of the National Institutes of Health and with
representatives of the drug manufacturing industry, review and develop guidance, as
appropriate, on the inclusion of women and minorities in clinical trials . . .    
The Center for Drug Evaluation and Research (CDER) has been assigned the responsibility
for reviewing and implementing this section for the Agency.  To accomplish this task,
CDER established an ad hoc working group, FDAMA Women and Minorities Working
Group with representation from the Agency and the National Institutes of Health.  (A
complete membership listing is contained in Attachment 1 to the enclosed report.)  
The Center is submitting for your review and consideration the recommendations of the
FDAMA Working Group, which have the concurrence of CDERs Medical Policy
Coordinating Committee (MPCC) and are contained in the enclosed report.  These
recommendations also were discussed with representatives of the pharmaceutical
manufacturing industry, as required by section 115(b) of FDAMA. They are in agreement
that no additional guidance is needed at this time and offered to confer with the Agency
if this should change in the future. The Working Group recommends that this report be
made widely available, perhaps by posting it on an appropriate Web site.
I would like to emphasize that although we have concluded that additional guidance is
not needed at this time, the Agency will continue to implement procedures that will
enhance our ability to gather, search, and evaluate demographic data.  These processes
will make it possible to determine trends or indicate deficiencies, and decide whether
additional guidance should be developed in the future.  
Janet Woodcock, M.D.
Enclosure
cc: 
William Schultz, HF-22
Diane Thompson, HFW-1 (Enclosure)
FDAMA Women and Minorities Working Group Report
Under the Food and Drug Administration Modernization Act of 1997 (FDAMA)
Sec. 115 Clinical Investigations. (b) Women and Minorities. -- Section 505(b)(1) 21
U.S.C. 355(b)(1) was amended by adding at the end the following: The Secretary
shall, in consultation with the Director of the National Institutes of Health and with
representatives of the drug manufacturing industry, review and develop guidance,
as appropriate, on the inclusion of women and minorities in clinical trials . . .    
Overview
The process of implementing this section of FDAMA was logically divided into two
stages.  During the first stage, existing guidance was identified and evaluated to
assess whether it was adequate, whether additional guidance was needed or
whether there was insufficient information at this time to make such a
determination.  The outcome of this first stage would dictate whether another
stage, which might include gathering additional data and drafting additional
guidance, would be needed. 
Process
The FDAMA Women and Minorities Working Group conducted a series of three
meetings (2/23/98, 3/11/98, and 4/6/98) at which they accomplished the
following. (See Attachment 1 for listing of members)
C Assessed the scope of its task as outlined in FDAMA, supporting
documents, and legislative history.
C Compiled and evaluated existing FDA guidance on enrollment of
women and minorities in clinical trials.  A summary of guidance
currently in effect is contained in Attachment 2.
C Evaluated available pertinent databases and reports, including the
October 1992 GAO Report to Congressional Requestors, Womens
Health, FDA Needs to Ensure More Study of Gender Differences in
Prescription Drug Testing (Attachment 3).
C Evaluated pertinent companion PHS documents listed in Attachment
2.
1 Summary of existing guidance 
The 1988 "Guideline for the Format and Content of the Clinical and Statistical
Sections of New Drug Applications" emphasized the importance of including
analyses of demographic data in NDA applications.  The 1998 regulation, "Final
Rule on Investigational New Drug Applications and New Drug Applications,"
requires that analyses of effectiveness and safety data for important demographic
subgroups, including gender and racial subgroups, be submitted to NDAs and that
enrollment of subjects into clinical studies for drug and biological products be
tabulated by important demographic subgroups in investigational new drug (IND)
annual reports, i.e., age group, gender, and race.  This final rule allows the
Agency to refuse to file any NDA that does not analyze safety and efficacy
information appropriately by gender. 
The critical importance of including all appropriate subsets of the population in
product development was most clearly articulated in the 1993 "Guideline for the
Study and Evaluation of Gender Differences in Clinical Evaluation of Drugs, which
states: 
In general, drugs should be studied prior to approval in subjects representing
a full range of patients likely to receive the drug once it is marketed. 
Although in most cases, drugs behave qualitatively similarly in demographic
(age, gender, race) and other (concomitant illness, concomitant drugs)
subsets of the population, there are many quantitative differences, for
example, in dose-response, maximum size of effect, or in the risk of an
adverse effect.  Recognition of these differences can allow safer and more
effective use of drugs.  Rarely, there may be qualitative differences as well. 
It is very difficult to evaluate subsets of the overall population as thoroughly
as the entire population, but sponsors are expected to include a full range of
patients in their studies, carry out appropriate analyses to evaluate potential
subset differences in the patients they have studied, study possible
pharmacokinetic differences in patient subsets, and carry out targeted
studies to look for subset pharmacodynamic differences that are especially
probable, are suggested by existing data, or that would be particularly
important if present.
That guidance also makes clear the Agency position that women should be
included in all phases of clinical drug development.  The 1998 proposed clinical
hold rule, "Investigational New Drug Applications; Proposed Amendment to Clinical
2 Hold Regulations for Products Intended for Life-Threatening Diseases,"1 expands
upon this guidance because it would allow FDA to place an IND, or specific
protocols under an IND, on clinical hold if a sponsor proposes to exclude from
study women or men with reproductive potential because of a risk, or a potential
risk, of reproductive or developmental toxicity from the use of an investigational
drug product.  
Conclusions and Recommendations
The 1993 Gender Guideline, which is a comprehensive discussion of enrollment of
women in clinical trials, was promulgated to reverse a previous FDA policy that
resulted in the exclusion of women with childbearing potential from early drug
studies that did not target serious or life threatening diseases.  Because of the
specificity of this guidance, the Working Group has chosen to report on women
and minorities separately.
C Women
In the last five years, FDA has issued critical guidance and regulation aimed at
ensuring that women are included appropriately in clinical trials and that data are
analyzed to ensure that gender information is available and understood.  At
present, FDA believes that exclusionary policies regarding the participation of
women with childbearing potential in clinical trials will be addressed by the 1998
clinical hold proposed rule, if it is finalized.  Therefore, additional guidance is not
indicated, and would not be useful, at this time.  
The Tracking Subcommittee of the Agency Gender Effects Steering Committee
identified various Center mechanisms that have been used to track eligibility and/or
enrollment of women in clinical trials but these were all finite projects.  The
Working Group recommends that the Centers consider instituting a permanent
tracking system to monitor effectiveness and safety data for gender and racial
subgroups submitted under the new final rule.  The design and implementation of
such a tracking system are currently under discussion by members of the FDA
Office of Womens Health, Gender Effects Steering Committee, CDER senior
management team, and CDERs Womens Health Subcommittee of the Medical
Policy Coordination Committee.  The Office of Womens Health has recently
funded a CDER project that will develop tools to search large databases for
adverse events reported by gender and race.  In addition, the Centers should also
consider developing a program to educate reviewers on the new rule. 
1The comment period for this proposed rule closed on December 23, 1997.
The comments that were received are being reviewed by a special working group.
3 C Minorities
The 1993 Gender Guideline was promulgated specifically to reverse a long-
standing regulatory barrier to the participation of women with childbearing
potential in clinical trials.  Unlike women with childbearing potential, there has
never been a regulatory barrier to the inclusion of minorities in clinical trials and
there does not exist a guidance that addresses only the issue of minority
enrollment in clinical trials.  The portion of the 1993 Gender Guideline cited above
clearly articulates the expectation of FDA that all appropriate demographic
subgroups should be included in product development, but the fact that this
statement is found in the Gender Guideline conceivably might diminish its impact
on minority recruitment. 
There has been no recent methodical evaluation of minority enrollment patterns in
clinical trials.  The GAO report (see Attachment 3) supports the conclusion that
minorities are being enrolled in proportions appropriate to their relative disease
prevalence.  However, that report is not current.   More recently, the Office of
Special Health Issues has initiated a project to review demographic data from the
applications for new molecular entities (NMEs) approved by CDER during
1995-1996.  The project will gather data on the participation of racial/ethnic
minorities in clinical trials of the NMEs and the extent to which these populations
were discussed in labeling for these drugs.   It is anticipated that preliminary data
will be available in the fall of this year.  In addition, CDER is launching various
initiatives to ensure that the Agency will have the ability to track enrollment
trends.  For example, under the 1998 final rule, safety and effectiveness data on
racial subgroups will be required in NDAs and IND annual reports.  CDER is
developing a subset page that will be included in each NDA package where the
results, and adequacy, of such analysis can be summarized in an easily accessible
format.  Moreover, guidance is under development that will direct industry and
reviewers to ensure that appropriate mention of subset differences are included in
the adverse reaction and clinical trials sections of package inserts, or that
important gaps in knowledge be noted.
Certainly there are many societal and socioeconomic factors that affect the
composition of study populations and there are also clear examples of products
where the efficacy or safety profiles differ by racial subgroups.  However, the
Working Group does not find evidence of barriers to the enrollment of minorities in
clinical trials that are regulatory in nature or could be addressed by regulatory
guidance.  The Agency will continue to evaluate available data pertaining to the
enrollment of minorities in clinical trials. 
4 Attachment 1
Representatives of the FDAMA
Women & Minorities Working Group
Marietta Anthony - OC, Office of Womens Health
Rachel Behrman (lead) - Center for Drug Evaluation and Research
Julie Beitz - Center for Drug Evaluation and Research
Jonca Bull - OC, Office of Operations
Julie Carlston - OC, Office of Management Systems
Rose Cunningham (exec sec) - Center for Drug Evaluation and Research
Elaine Esber - Center for Biologics Evaluation and Research
Kathryn Hudson - OC, Office of Legislative Affairs
Diane Maloney - OC, General Counsel
Vivian W. Pinn - National Institutes of Health, Office of Research on 
Womens Health
Gene Hayunga - National Institutes of Health, Office of Research on 
Womens Health
Kimber Richter - Center for Devices and Radiological Health
Joy Samuels-Reid - Center for Devices and Radiological Health
Terry Toigo - OC, Office of Special Health Issues Attachment 2
SUMMARY OF AVAILABLE GUIDANCE & REPORTS
WOMEN ONLY:
(cid:130) FDA -  7/88 Guideline for the Format and Content of the Clinical and
Statistical  Sections of New Drug Applications 
(cid:130) FDA - 7/22/93 Guideline for the Study and Evaluation of Gender Differences
in Clinical Evaluation of Drugs
(cid:130) FDA - 9/24/97 Proposed Rule on Investigational New Drug Applications;
Proposed Amendment to Clinical Hold Regulations for Products Intended for
Life-Threatening Diseases
WOMEN AND MINORITIES:
(cid:130) 21 CFR 314.101(d)(2)
(cid:130) FDA - 2/11/98 Final Rule on Investigational New Drug Applications and New
Drug Applications  - 21 CFR Parts 312 and 314
RELATED GUIDANCE:
(cid:130) NIH - Recruitment and Retention of Women in Clinical Studies - a Report of
the Workshop Sponsored by the Office of Research on Womens Health 
(cid:130) NIH - 3/28/94 NIH Guidelines on Inclusion of Women and Minorities as
Subjects in Clinical Research
(cid:130) NIH - Informational document presenting excerpts from above guideline: 
Inclusion of Women and Minorities as Subjects in Clinical Research - 96-04
(cid:130) NIH - Outreach Notebook for the NIH Guidelines on Inclusion of Women and
Minorities as Subjects in Clinical Research - 97-4160 
RELATED REPORTS:
(cid:130) GAO - Womens Health - FDA Needs to Ensure More Study of Gender
Differences in Prescription Drug Testing