In this document, FDA is publishing a new guideline on FDA'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
conduct of specific additional studies in women, where indicated.
This guideline revises the section of the 1977 guideline, entitled
"General Considerations for the Clinical Evaluation of Drugs,"
that excluded women of childbearing potential from participation
in early studies of drugs. For the purpose of this document. the
agency will refer to the "General Considerations for the
Clinical Evaluation of Drugs" as the "1977 guideline."
Although the new guideline outlines in some detail the specific
considerations related to the evaluation of gender differences
during evaluation of drug products, the agency views the principles
of inclusion of women in product development programs and analysis
of subgroup differences as being broader standards which apply
equally to the clinical development of biological products and
medical devices.
The new guideline reflects good drug development practice implicit
in the law and regulations. Certain requirements, such as inclusion
of adequate numbers of women and by-gender analyses, have been
emphasized in the past. However, as with any new guideline, where
sponsors have developed drugs in good faith relying on existing
guidelines, they will have an opportunity to satisfy newly appreciated
data needs after approval where this is compatible with the public
health and the law. This new guideline does not change FDA's commitment
to safe development of drugs but gives more flexibility to institutional
review boards (IRB's), investigators, and patients in determining
how best to ensure safety.
II. Background
A. Participation of Women in Clinical Studies
Over the past decade there has been growing concern that the drug
development process does not produce adequate information about
the effects of drugs in women. This concern arises from a number
of sources.
Analyses of published clinical trials in certain therapeutic areas
(notably cardiovascular disease) have indicated that there had
been little or no participation of women in many of the studies.
Certain major studies of the role of aspirin in cardiovascular
and cerebrovascular disease, for example, did not include women,
and this omission left the scientific community with doubts about
whether aspirin was, in fact, effective in women for these indications.
Similarly, published studies of anti-anginal drugs often had few
or no women in them. It has been suggested that a similar situation
might exist for the studies intended to support marketing approval
of new drugs.
In addition, FDA notes that there has been little study of the
effects of such aspects of female physiology as the menstrual
cycle and menopause, or of the effects of drugs widely used in
women such as oral contraceptives and systemic progestins and
estrogens, on drug action and pharmacokinetics.
Concern has also been expressed that the 1977 policy excluding
women of childbearing potential from early drug studies may have
led to a more general lack of participation of women in drug development
studies, and thus to a paucity of information about the effects
of drugs in women. In addition to concerns about whether the policy
interfered with development of adequate data on drug therapy in
women, the 1977 guideline, seen from the viewpoint of the 1990's,
has appeared rigid and paternalistic, leaving virtually no room
for the exercise of judgment by responsible female research subjects,
physician investigators, and IRB's.
Concerns about the adequacy of data on the effects of drugs in
women have arisen at a time when FDA, drug developers, and the
scientific community have focused increasingly on the need to
individualize treatment in the face of the wide variety of demographic,
disease-related, and individual patient-related factors that can
lead to different responses to drugs in subsets of the population.
Optimal use of drugs requires identification of these factors
so that appropriate adjustments in dose, concomitant therapy,
or monitoring can be made.
Subgroup-specific differences in response can arise because of
variation in a drug's pharmacokinetics (i.e., the drug's concentration
in plasma or elsewhere as a function of time) or pharmacodynamics
(the body's response to a given concentration of the drug).
B. Pharmacokinetic and Pharmacodynamic Differences Among Patients
Important variations in pharmacokinetics can arise from many factors:
1. A number of demographic characteristics may affect pharmacokinetics:
Older people are more likely to have decreased renal function,
which may cause drugs excreted by the kidney to accumulate; younger
people metabolize theophylline more rapidly; ethnic groups differ
in the prevalence of metabolic abnormalities such as slow acetylation
and G6PD deficiency; women metabolize certain substances at rates
different from men (for example, they metabolize alcohol and ondansetron
more slowly).
2. Diseases other than the one being studied may alter the pharmacokinetics,
of many drugs: Kidney disease may decrease the ability to excrete
drugs in the urine; liver disease can interfere with the metabolism
of drugs or with their excretion into the bile.
3. The presence of other drugs may lead to pharmacokinetic interactions:
Quinidine and fluoxetine inhibit the metabolism of imipramine
and desipramine, as well as that of many other drugs metabolized
by cytochrome P450 2D6 (debrisoquin hydroxylase); ketoconazole
and erythromycin inhibit the metabolism of terfenadine. In such
cases, toxic blood concentrations of the drug whose metabolism
is inhibited can occur even while a constant dose of the drug
is maintained.
4. In addition, other differences between individual subjects
may affect pharmacokinetics. For example, small body size or muscle
mass may lead to higher blood concentrations after a given dose.
Documented subgroup pharmacokinetics differences are fewer, but
have been observed, including increased sensitivity to beta-blockers
in Asians, decreased sensitivity to beta-blockers in the elderly,
decreased responsiveness to the blood pressure lowering effects
of adrenocortical extract (ACE) inhibitors and betablockers in
African-Americans, and increased sensitivity to the central nervous
system effects of midazolam in older people.
Despite the many examples of pharmacokinetic and pharmacodynamic
differences in population subsets, there has often been insufficient
attention in the course of drug development to looking for such
differences among individuals in responses to drugs, including
differences related to gender. In the case of gender, some have
suggested the lack of information may have resulted from the exclusion
of women from clinical trials. A number of studies have evaluated
this possibility.
In 1983 and 1989, FDA examined the relative numbers of individuals
from two important demographic groups, women and the elderly,
in the data bases of new drug applications (NDA's). FDA found,
in general, that the proportions of women and men included in
the clinical trials were similar to the respective proportions
of women and men who had the diseases for which the drugs were
being studied, taking into account the age range of the population
studied. The General Accounting Office (GAO) conducted a larger
study of drugs approved during the period 1988 through 1991, with
generally similar findings. Thus, women typically represent a
majority of patients in NDA data bases of drugs used to treat
conditions more common (or more commonly treated) in women (e.g.,
arthritis and depression) and a minority, although usually a sizable
one of about 30 percent or more, in conditions that occur predominantly
in males in the age ranges usually included in clinical trials
(e.g., angina pectoris). Appendix I of the guideline includes
additional details of these surveys.
Although women have been included in the later phases of clinical
trials, inclusion alone is not sufficient for adequate assessment
of potential gender differences. There must an effort to use the
data to discover such differences. An FDA guideline issued in
1988 ("Guideline for the Format and Content of the Clinical
and Statistical Sections of New Drug Applications") called
for analyses of gender-related differences in response. FDA and
GAO examined NDA's to see whether analyses of this kind were being
conducted and submitted. Both examinations found that in many
cases (about half) the data bases were not being analyzed to determine
whether there were gender, age, or race differences in response
to drugs.
A further reason for the lack of information about potential gender
differences in drug response is the lack of specific studies of
pharmacokinetics in women, even where gender-related differences
in pharmacokinetics might be expected or important. There are
a variety of potential differences of this type, including differences
due to menopause or the menstrual cycle, or to concomitant oral
contraceptive or estrogen use, as well as differences based on
different body fat proportion, and differences in weight or muscle
mass.
C. FDA Guidance on Individualization of Treatment
Since 1988, FDA has taken several major steps to encourage development
of data that support informed individualization of treatment:
1. The agency's 1988 guideline entitled, "'Guideline for
the Format and Content of the Clinical and Statistical Sections
of Now Drug Applications," calls for analyses of NDA data
to identify variations among population subsets in favorable responses
(effectiveness) and unfavorable responses (adverse reactions)
to drugs. The population subsets that should be evaluated routinely
include demographic subsets, such as different genders, age groups
and races, people receiving other drug therapy, and people with
concomitant illness.
2. The agency has addressed specifically the need to develop information
on a particular demographic subset, the elderly, in the 1989 guideline
entitled, "Guideline for the Study of Drugs Likely to be
Used in the Elderly."
3. In the Federal Register of November 1, 1990 (55 FR 46134),
the agency proposed to amend the labeling regulation (21 CFR 201.57)
to require a "Geriatric Use" section that would contain
available information on experience with the drug in the elderly
and describe any needed modifications in the use of the drug in
that population. In the Federal Register of October 16, 1992 (57
FR 47423), the agency proposed to amend the same regulation to
facilitate inclusion of information on the use of drugs in children.
D. Changes in the Guideline
The new guideline discusses FDA'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, where appropriate, assessment of pharmacodynamic
differences and the conduct of specific additional studies in
women. The policy applies to all drug or disease specific clinical
guidelines based on the 1977 guideline, that exclude women of
childbearing potential from participation in early studies of
drugs.
III. Revised Policy on
Inclusion of Women of Childbearing Potential in Clinical Trials
A. The 1977 Guideline-"General Considerations for the
Clinical Evaluation of Drugs"
The 1977 guideline set forth a policy on, among other things,
the inclusion of women of childbearing potential in clinical trials.
The policy stated that, in general, women of childbearing potential
should be excluded from the earliest studies of a new drug, that
is, phase 1 and early phase 2 studies. Phase 1 refers to the first
introduction of a new drug into humans, who are often, but not
always, healthy volunteers, to study the basic tolerability of
the drug, its metabolism, and its short term pharmacokinetics.
With the exception of some early studies in life-threatening diseases,
phase 1 studies usually do not have therapeutic intent. Phase
2 refers to the initial controlled trials of a drug to study its
effectiveness. Before the first such study, there is generally
no evidence that the drug is of therapeutic value in humans.
If adequate information on effectiveness and relative safety were
amassed during phase 1 and early phase 2, the guideline stated
that women of childbearing potential could be included in subsequent
studies of effectiveness, that is, later phase 2 and phase 3 studies,
so long as animal teratogenicity and the female part of animal fertility
studies had been completed. The policy did not specifically address
the manner in which the early human evidence of safety and effectiveness
and the results of animal reproduction studies should be used
to make decisions about participation of women. In later trials,
leaving these considerations to the usual risk-benefit assessment
made by the patient, physician, and IRB, with subsequent FDA review.
In the 1977 guideline, the term "women of childbearing potential"
was defined very strictly, essentially referring to all premenopausal
women physiologically capable of becoming pregnant, including
women on oral, injectable, or mechanical contraceptives, single
women, celibate women, and women whose partners had been sterilized
by vasectomy. There was no provision for the use of pregnancy
testing to identify women who could participate in studies without
a risk of fetal exposure. The 1977 guideline also noted, however,
that women of childbearing potential could receive investigational
drugs in the earliest phases of testing even in the absence of
adequate reproduction studies in animals, when the drugs were
intended for life-saving or life-prolonging treatment.
The effect of the 1977 guideline has been that women generally
have not been included in phase 1 nontherapeutic studies or in
the earliest controlled effectiveness studies (i.e., early phase
2), except for studies of life-threatening illnesses, such as
acquired immune deficiency syndrome (AIDS) and cancer.
B. Reasons for Revising the 1977 Policy
The policy set forth in the 1977 guideline has been under discussion
for several years within and outside the agency, and there has
been increasing sentiment that it should be revised. For example,
in October 1992, FDA and the Food and Drug Law Institute cosponsored
a meeting on women in clinical trials of FDA-regulated products
at which many speakers described the current restrictions as paternalistic
and overprotective, denying young women the opportunity available
to men and older women to participate in early drug development
research.
Although the 1977 guideline has not resulted in a failure to include
adequate numbers of women in the later phases of clinical trials,
it has restricted the early accumulation of information about
response to drugs in women that could be utilized in designing
phase 2 and 3 trials, and perhaps delayed appreciation of gender-related
variation in drug effects. The early exclusion also 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. There
is reason to believe that earlier participation of women in studies
would increase the likelihood that gender-specific data might
be used to make appropriate adjustments in larger clinical studies
(e.g., different doses in women or weight adjusted (milligram
per kilogram) dosing instead of fixed doses).
The agency believes that removal of the prohibition on participation
of women of childbearing potential in phase 1 and early phase
2 trials is consistent with congressional efforts to prevent unwarranted
discrimination against such women. For example, in the employment
context, the Pregnancy Discrimination Act, as interpreted by the
U.S. Supreme Court in the landmark case of International Union,
United Automobile, Aerospace and Agricultural Implement Workers,
UAW v. Johnson Controls, Inc., 111 S.Ct. 1196 (1991), prohibits
the blanket exclusion of pregnant women from jobs they are qualified
to perform solely because the working conditions of those jobs
pose potential risks to exposed fetuses. The Court emphasized
that "decisions about the welfare of future children must
be left to the parents who conceive, bear, support, and raise
them, rather than to the employers who hire those parents."
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 a woman's right
to participate in decisions about fetal risk and believes it is
appropriate to consider the Court's opinion in developing policy
on the inclusion of women in clinical trials.
C. Current FDA Position on Participation of Women of Childbearing
Potential in Early Clinical Studies
The
agency has reconsidered the 1977 guideline and has concluded that
it should be revised. This does not reflect a lack of concern
for potential fetal exposure or indifference to potential fetal
damage, but rather the agency's opinion that (1) exclusion of
women from early trials is not medically necessary because the
risk of fetal exposure can be minimized by patient behavior and
laboratory testing, and (2) initial determinations about whether
that risk is adequately addressed are properly left to patients,
physicians, local IRBs, and sponsors, with appropriate review
and guidance by FDA, as are all other aspects of the safety of
proposed investigations.
The agency is, therefore, withdrawing the restriction on the participation
of women of childbearing potential in early clinical trials, including
clinical pharmacology studies (e.g., dose tolerance, bioavailability,
and mechanism of action studies), and early therapeutic studies.
It is expected that, in accordance with good medical practice,
appropriate precautions against becoming pregnant and exposing
a fetus to a potentially dangerous agent during the course of
study will be taken by women participating in clinical trials.
It is also expected that women will receive adequate counseling
about the importance of such precautions, that efforts will be
made to be sure that a woman entering a trial is not pregnant
at the time the trial begins (i.e., a pregnancy test detecting
the beta subunit of the hCG molecule is negative), and that the
woman participant is fully informed about the current state of
the animal reproduction studies and any other information about
the teratogenic potential of the drug. As is the case for all
studies carried out under an investigational new drug application
(IND), the adequacy of the precautions taken will be considered
by FDA in its review of protocols. In situations where enrollment
continues over a prolonged period (unlikely for early clinical
studies) and significant new information about teratogenicity
becomes available, the sponsor has the responsibility to transmit
this information quickly to the investigator and to current as
well as potential study participants in the informed consent process.
The agency recognizes that this change in FDA's policy will not,
by itself, cause drug companies or IRBs to alter restrictions
they might impose on the participation of women of childbearing
potential. We do not at this time perceive a regulatory basis
for requiring routinely that women in general or women of childbearing
potential be included in particular trials, such as phase 1 studies.
However, as this guideline delineates, careful characterization
of drug effects by gender is expected by the agency, and FDA is
determined to remove the unnecessary Federal impediment to inclusion
of women in the earliest stages of drug development. The agency
is confident that the interplay of ethical, social, medical, legal
and political forces will allow greater participation of women
in the early stages of clinical trials.
In some cases, there may be a basis for requiring participation
of women in early studies. When the disease under study is serious
and affects women, and especially when a promising drug for the
disease is being developed and made available rapidly under FDA's
accelerated approval or early access procedures, a case can be
made for requiring that women participate in clinical studies
at an early stage. When such a drug becomes available under expanded
access mechanisms (for example, treatment IND or parallel track)
or is marketed rapidly under subpart E procedures (because an
effect on survival or irreversible morbidity has been shown in
the earliest controlled trials), it is medically important that
a representative sample of the entire population likely to receive
the drug has been studied, including representatives of both genders.
Under these circumstances, clinical protocols should not place
unwarranted restrictions on the participation of women.
The agency advises that this guideline represents its current
position on the clinical evaluation of drugs in humans. This guideline
does not bind the agency, and it does not create or confer any
rights, privileges, or benefits for or on any person.
IV. Comments
Interested persons may, on or before November 19, 1993, submit
to the Dockets Management Branch (address above) written comments
regarding this guideline. Two copies of any comments should be
submitted, except that individuals may submit one copy. Comments
are to be identified with the docket number found in brackets
in the heading of this document. Received comments may be seen
in the office above between 9 a.m. and 4 p.m., Monday through
Friday. These comments will be considered in determining whether
further amendments to, or revisions of, the guideline are warranted.
The new guideline replaces that portion of the 1977 guideline
that dealt with women of childbearing potential. The text of the
new guideline on gender differences follows:
Guideline for the Study and Evaluation of Gender Differences
in the Clinical Evaluation of Drugs
I. Introduction
The Food and Drug Administration (FDA) advises that this guideline
represents its current position on the clinical evaluation of
drugs in humans. This guideline does not bind the agency, and
it does not create or confer any rights, privileges, or benefits
for or on any person.
The principles of inclusion of women in product development programs
and analysis of subgroup differences outlined in this guideline
also apply to the clinical development of biological products
and medical devices.
A. Abstract
In general, drugs should be studied prior to approval in subjects
representing the 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. Study protocols
are also expected to provide appropriate precautions against exposure
of fetuses to potentially dangerous agents. Where animal data
suggest possible effects on fertility, such as decreased sperm
production, special studies in humans may be needed to evaluate
this potential toxicity.
B. Underlying Observations
The following general observations and conclusions underlie the
recommendations set forth in this guideline:
1. Variations in response to drugs, including gender-related differences,
can arise from pharmacokinetic differences (that is, differences
in the way a drug is absorbed, excreted, metabolized, or distributed)
or pharmacodynamic differences (i.e., differences in the pharmacologic
or clinical response to a given concentration of the drug in blood
or other tissue).
2. Gender-related variations in drug effects may arise from a
variety of sources. Some of these are specifically associated
with gender, e.g., effects of endogenous and exogenous hormones.
Gender-related differences could also arise, however, not because
of gender itself, but because the frequency of a particular characteristic
(for example, small size, concomitant hepatic disease or concomitant
drug treatment, or habits such as smoking or alcohol use) is different
in one gender, even if the characteristic could occur in either
gender. Proper management of patients of both genders thus requires
that physicians know all the factors that influence the pharmacokinetics
of a drug. An approach is needed that will identify, better than
is done at present, all such factors. Understanding how various
factors may influence pharmacokinetics will greatly enhance our
ability to treat people of both genders appropriately.
3. For a number of practical and theoretical reasons, the evaluation
of possible gender-related differences in response should focus
initially on the evaluation of potential pharmacokinetic differences.
Such differences are known to occur and have, at least to date,
been documented much more commonly than documented pharmacodynamic
differences. Moreover, pharmacokinetic differences are relatively
easy to discover. Once reliable assays are developed for a drug
and its metabolites (such assays are now almost always available
early in the development of the drug), techniques exist for readily
assessing gender-related or other subgroup-related pharmacokinetic
differences.
Formal pharmacokinetic
studies are one means of answering questions about specific subgroups.
Another approach is use of a screening procedure, a "pharmacokinetic
screen" (see "Guideline for the Study of Drugs Likely
To Be Used in the Elderly"). Carried out in phase 2 and 3
study populations, the pharmacokinetic screen can greatly increase
the ability to detect pharmacokinetic differences in subpopulations
and individuals, even when these differences are not anticipated.
By obtaining a small number of blood concentration determinations
in most or all phase 2 and 3 patients, it is possible to detect
markedly atypical pharmacokinetic behavior in individuals, such
as that seen in slow metabolizers of debrisoquin, and pharmacokinetic
differences in population subsets, such as patient populations
of different gender, age, or race, or patients with particular
underlying diseases or concomitant therapy. The screen may also
detect interactions of two factors, e.g., gender and age. The
relative ease with which pharmacokinetic differences among population
subsets can be assessed contrasts with the difficulty of developing
precise relationships of most clinical responses to drug dose
or to the drug concentration in blood, which usually would be
necessary when attempting to observe pharmacodynamic differences
between two subgroups.
A final reason to emphasize pharmacokinetic evaluation is that
it must be carried out to allow relevant assessment of pharmacodynamic
differences or relationships. Assessing pharmacodynamic differences
between groups or establishing blood concentration-response relationships
is possible only when groups are reasonably well matched for blood
concentrations. Enough pharmacokinetic data must therefore be
available to permit the investigator to administer doses that
will produce comparable blood concentrations in the subsets to
be compared or, alternatively, to compare subsets that have been
titrated to similar blood concentrations.
4. The number of documented gender-related pharmacodynamic differences
of clinical consequence is at this time small, and conducting
formal pharmacodynarnic/effectiveness studies to detect them may
be difficult, depending on the clinical endpoint. Such studies
are therefore not routinely necessary. The by-gender analyses
of clinical trials that include both men and women, however, which
are specified in the 1988 guideline entitled "Guideline for
the Format and Content of the Clinical and Statistical Sections
of New Drug Applications" are not difficult to carry out.
Particularly if these analyses are accompanied by blood concentration
data for each patient, they can detect important pharmacodynamic/effectiveness
differences related to gender.
C. Inclusion of Both Genders in Clinical Studies
The patients included in clinical studies should, in general,
reflect the population that will receive the drug when it is marketed.
For most drugs, therefore, representatives of both genders should
be included in clinical trials in numbers adequate to allow detection
of clinically significant gender-related differences in drug response.
Although it may be reasonable to exclude certain patients at early
stages because of characteristics that might make evaluation of
therapy more difficult (e.g., patients on concomitant therapy),
such exclusions should usually be abandoned as soon as possible
in later development so that possible drug-drug and drug-disease
interactions can be detected. Thus, for example, there is ordinarily
no good reason to exclude women using oral contraceptives or estrogen
replacement from trials. Rather, they should be included and differences
in responses between them and patients not on such therapy examined.
Pharmacokinetic interaction studies (or screening approaches)
to look at the interactions resulting from concomitant treatment
are also useful.
Ordinarily, patients of both genders should be included in the
same trials. This permits direct comparisons of genders within
the studies. In some cases, however, it may be appropriate to
conduct studies in a single gender, e.g., to evaluate the effects
of phases of the menstrual cycle on drug response.
Although clinical or pharmacokinetic data collected during phase
3 may provide evidence of gender-related differences, these data
may become available too late to affect the design and dose-selection
of the pivotal controlled trials. Inclusion of women in the earliest
phases of clinical development, particularly in early pharmacokinetic
studies, is, therefore, encouraged so that information on gender
differences may be used to refine the design of later trials.
Note that the strict limitation on the participation of women
of childbearing potential in phase 1 and early phase 2 trials
that was imposed by the 1977 guideline entitled, "General
Considerations for the Clinical Evaluation of Drugs," has
been eliminated.
There is no regulatory or scientific basis for routine exclusion
of women from bioequivalence trials. For certain drugs, however,
it is possible that changes during the menstrual cycle may lead
to increases in intra-subject variability. Such variability could
be related to hormonally-mediated differences in metabolism or
changes in fluid balance. Sponsors of bioequivalence trials are
encouraged to examine available information on the pharmacokinetics
and metabolism of the test drugs and related drugs to determine
whether there is a basis for concern about variability in pharmacokinetics
during the menstrual cycle. Where the available information does
raise such concern, measures could be taken to reduce or adjust
for variability, e.g.. administration of each drug at the same
phase of the menstrual cycle, or inclusion of larger numbers of
subjects. Sponsors are encouraged to collect data that will contribute
to the understanding of the relationship between hormonal variations
and pharmacokinetics.
D. Analysis of Effectiveness and Adverse Effects by Gender
FDA's guideline on the clinical and statistical sections of NDAs
calls for analyses of effectiveness, adverse effects, dose-response,
and, if available, blood concentration-response, to look for the
influence of: (1) Demographic features, such as age, gender, race;
and (2) other patient characteristics, such as body size (body
weight, lean body mass, fat mass), renal, cardiac, and hepatic
status, the presence of concomitant illness, and concomitant use
of drugs, including ethanol and nicotine. Analyses to detect the
influence of gender should be carried out both for individual
studies and in the overall integrated analyses of effectiveness
and safety. Such analyses of subsets with particular characteristics
can be expected to detect only relatively large gender-related
differences, but in general, small differences are not likely
to be clinically important. The results of these analyses may
suggest the need for more formal dose-response or blood concentration-response
studies in men or women or in other patient subsets. Depending
on the magnitude of the findings, or their potential importance
(e.g., they would be more important for drugs with low therapeutic
indices), these additional studies might be carried out before
or after marketing.
E. Defining the Pharmacokinetics of the Drug in Both Genders
The factors most commonly having a major influence on pharmacokinetics
are renal function, for drugs excreted by the kidney, and hepatic
function, for drugs that are metabolized or excreted by the liver;
these should be assessed directly as part of the ordinary development
of drugs. The pharmacokinetic effects of other subgroup characteristics
such as gender can be assessed either by a
pharmacokinetic screening approach, described in the 1989 guideline
entitled, "Guideline for the Study of Drugs Likely to Be
Used in the Elderly," or by formal pharmacokinetic studies
in specific gender or age groups. Using either a specific pharmacokinetic
study or a pharmacokinetic screen, the pharmacokinetics of a drug
should be defined for both genders. In general, it is prudent
to at least carry out pilot studies to look for major pharmacokinetic
differences before conducting definitive controlled trials, so
that differences that might lead to the need for different dosing
regimens can be detected. Such studies are particularly important
for drugs with low therapeutic indices, where the smaller average
size of women alone might be sufficient to require modified dosing,
and for drugs with nonlinear kinetics, where the somewhat higher
milligram per kilogram dose caused by a woman's smaller size could
lead to much larger differences in blood concentrations of drug.
Gender may interact with other factors, such as age. The potential
for such interactions should be explored.
Three pharmacokinetic issues related specifically to women that
should be considered during drug development are: (1) The influence
of menstrual status on the drug's pharmacokinetics, including
both comparisons of premenopausal and postmenopausal patients
and examination of within cycle changes; (2) the influence of
concomitant supplementary estrogen treatment or systemic contraceptives
(oral contraceptives, long-acting progesterone) on the drug's
pharmacokinetics; and (3) the influence of the drug on the pharmacokinetics
of oral contraceptives. Which of these influences should be studied
in a given case would depend on the drug's excretion, metabolism,
and other pharmacokinetic properties, and on the steepness of
the dose-response curve.
Hormonal status during the menstrual cycle may affect plasma volume
and the volume of distribution (and thus clearance) of drugs.
The activity of certain cytochrome P450 enzymes may be influenced
by estrogen levels and, in addition, microsomal oxidation by these
enzymes may decline in the elderly more in men than women. Oral
contraceptives can cause decreased clearance of drugs (e.g., imipramine,
diazepam, chlordiazepoxide, phenytoin, caffeine, and cyclosporine),
apparently by inhibiting hepatic metabolism. They can also increase
clearance by inducing drug metabolism (e.g., of acetaminophen,
salicylic acid, morphine, lorazepam, temazepam, oxazepam, and
clofibrate). Certain anticonvulsants (carbamazepine, phenytoin)
and antibiotics (rifampin) can reduce the effectiveness of oral
contraceptives. Many of the potential interactions of gender and
gender related characteristics (e.g., use of oral contraceptives)
can be evaluated with the pharmacokinetic screen. In some cases,
specific studies will be needed.
F. Gender-Specific Pharmacodynamic Studies
Because documented demographic differences in pharmacodynamics
appear to be relatively uncommon, it is not necessary to carry
out separate pharmacodynamic/effectiveness studies in each gender
routinely. Evidence of such differences should be sought, however,
in the data from clinical trials by carrying out the by-gender
analyses suggested in the guideline on the clinical and statistical
sections of NDA's. These analyses of controlled trials involving
both genders are probably more likely to detect differences than
studies carried out entirely in one gender. Experience has shown
that gender differences can be detected with such approaches.
If the by-gender analyses suggest gender-related differences,
or if such differences would be particularly important, e.g.,
because of a low therapeutic index, additional formal studies
to seek such differences between the blood level-response curves
of men and women should be conducted. Even in the absence of a
particular concern based on the by-gender analyses, if there is
a readily measured pharmacodynamic endpoint, such as blood pressure
or rate of ventricular premature beats, and if there are good
dose-response data for the overall population, it should be feasible
to develop dose response data from population subsets (e.g., both
genders) in the critical clinical trials.
G. Precautions in Clinical Trials Including Women of Childbearing
Potential
Appropriate precautions should be taken in clinical studies to
guard against inadvertent exposure of fetuses to potentially toxic
agents and to inform subjects and patients of potential risk and
the need for precautions. In all cases, the informed consent document
and investigator's brochure should include all available information
regarding the potential risk of fetal toxicity. If animal reproductive
toxicity studies are complete, the results should be presented,
with some explanation of their significance in humans. If these
studies have not been completed, other pertinent information should
be provided, such as a general assessment of fetal toxicity in
drugs with related structures or pharmacologic effects. If no
relevant information is available, the informed consent should
explicitly note the potential for fetal risk.
In general, it is expected that reproductive toxicity studies
will be completed before there is large-scale exposure of women
of childbearing potential, i.e., usually by the end of phase 2
and before any expanded access program is implemented.
Except in the case of trials intended for the study of drug effects
during pregnancy, clinical protocols should also include measures
that will minimize the possibility of fetal exposure to the investigational
drug. These would ordinarily include providing for the use of
a reliable method of contraception (or abstinence) for the duration
of drug exposure (which may exceed the length of the study), use
of pregnancy testing (beta HCG) to detect unsuspected pregnancy
prior to initiation of study treatment, and timing of studies
(easier with studies of short duration) to coincide with, or immediately
follow, menstruation. Female subjects should be referred to a
study physician or other counselor knowledgeable in the selection
and use of contraceptive approaches.
H. Potential Effects on Fertility
Where abnormalities of reproductive organs or their function (spermatogenesis
or ovulation) have been observed in experimental animals, the
decision to include patients of reproductive age in a clinical
study should be based on a careful risk-benefit evaluation, taking
into account the nature of the abnormalities, the dosage needed
to induce them, the consistency of findings in different species,
the severity of the illness being treated, the potential importance
of the drug, the availability of alternative treatment, and the
duration of therapy. Where patients of reproductive potential
are included in studies of drugs showing reproductive toxicity
in animals, the clinical studies should include appropriate monitoring
and/or laboratory studies to allow detection of these effects.
Long-term follow up will usually be needed to evaluate the effects
of such drugs in humans.
Appendix I
I. Surveys of Participation of Women in Clinical Trials in
New Drug Applications (NDA's)
The extent of participation of women in the data bases of NDA's
has been examined several times in recent years, by FDA in 1983
and 1989, and by the General Accounting Office (GAO) in 1992.
In general, the genders were represented to approximately the
extent one would predict from the gender prevalence of the condition
treated by the drug in the age group studied. The relative disease
prevalence in men and women can vary with age. Consider, for example,
the participation of women in studies of anti-anginal drugs. Almost
all patients in angina studies, which require vigorous treadmill
exercise tests, are under 75 years old and the large majority
are under 65. Although eventually women develop symptomatic coronary
artery disease in their 60's, 70's, and 80's, and become similar
to men in the prevalence of this condition, they are much less
likely than men to be affected in their 40's, 50's, and early
60's. The overall NDA data base for an anti-anginal drug, made
up primarily of people 50 to 65, will therefore include a significantly
greater proportion of men than women. Efforts to include more
very old patients in trials, i.e., patients in their 70's and
80's, should lead to a greater proportion of women in trials of
anti-anginal drugs.
Results of
the FDA and GAO surveys are described below. Also included is
an analysis of gender distribution in recently approved or submitted
NDA's for antidepressant drugs. This analysis was conducted to
evaluate the frequently heard claim that this class of drugs is
studied predominantly (or even exclusively) in males despite the
wide use of antidepressants in women.
A. The 1983 Survey
Primarily carried out to assess the inclusion of the elderly in
NDA's, the 1983 survey looked at the age and gender prevalence
of patients included in 11 pending NDA's. The NDA's were chosen
because they were readily available and did not need to be retrieved
from storage; figures were taken by FDA staff from the pending
applications. In one case (ranitidine), the values represent only
domestic patients for only one claim, leading to a small number
of patients; many more patients (those included in foreign studies,
or in studies of other claims) were available for safety evaluation.
Table 1 shows the results of the survey. As expected, the non-steroidal
anti-inflammatory drugs (NSAID's) were studied predominantly in
women, because arthritis, especially rheumatoid arthritis, is
more common in women. This predominance was slightly less prominent
in the case of zomepirac, which was studied extensively for pain
(gender-neutral), in addition to arthritis. The hypnotic drug
(triazolam) and the antibiotics (cefoperazone and netilmycin)
were studied in approximately equal proportions of men and women.
The patient populations included in the NDAs for verapamil, for
angina, and bumetanide, for heart failure, were about two-thirds
male, and about two-thirds of the patients were less than 60 years
old, an age group in which angina and heart failure are more prevalent
in men than in women. In the patients over age 70, representing
10 percent of the bumetanide patients and 7 percent of verapamil
patients, the gender distribution was about equal (49 percent
women in the verapamil studies and 45 percent women in the bumetanide
studies). Studies of ranitidine for duodenal ulcer, a predominantly
male disease, included about 75 percent males. Other indications
for this drug, such as gastric ulcer, would be expected to have
a different gender distribution. The two anti-cancer drugs in
this survey were studied principally for exclusively male conditions,
cancer of the prostate and testis.
B. The 1989 Survey
In an effort to avoid possible selection bias, all drugs approved
in 1988 were surveyed; this time the sponsors provided the data.
FDA asked them to provide data reflecting "the principal
data base used for safety review"' in the latest safety update
and asked that phase 1 subjects/patients be excluded. Sponsors
gave either data on all patients or only patients given the test
drug; the estimates of gender exposure should not be greatly affected
by this difference.
Table 2 shows the results of the 1989 survey for 12 of the 20
drugs approved in 1988. Because sponsors had little control over
gender distributions in the small populations available for study,
four orphan drugs were omitted from the survey (tiopronin for
prevention of cystine stones; ethanolamine oleate for esophageal
varices; ifosfamide, third-line therapy for testicular cancer;
and mesna, a prophylactic agent for ifosfamide-induced hemorrhagic
cystitis). Also omitted were three contrast agents for single
dose uses (but these agents are in the 1992 GAO survey), and a
topical product (oxiconazole cream) for which gender distribution
was not available.
Again, the anti-inflammatory drug (diclofenac) was studied predominantly
in women (more than two-thirds of the patients), as was nimodipine,
for prevention of vascular spasm after subarachnoid hemorrhage,
also a female-predominant condition. Pergolide, an anti-Parkinson's
disease drug; astemizole, an antihistamine; and octreotide, a
drug for symptoms of carcinoid tumor, were studied in about equal
numbers of men and women. The studies of the cardiovascular drugs
nicardipine (angina and hypertension) and carteolol (hypertension)
included 59 and 67 percent men, respectively, reflecting the male
gender predominance of angina, and perhaps hypertension, in the
relatively young (two-thirds of the patients were under the age
of 60) populations studied. Nizatidine and misoprostol were studied
extensively in duodenal ulcer, a predominantly male disease, with
about 70 percent of patients being male, although approval of
misoprostol was for a different claim. Cefotiam, an intravenous
antibiotic, was studied mainly in elderly patients (65 percent
over 60; 36 percent over 70); about two-thirds were male, for
unclear reasons. The topicals were studied in a predominantly
young population (about 90 percent under the age of 60), more
often in males. Certain tinea infections (tinea cruris and tinea
pedis) are more common in males, accounting for the high proportion
(72 percent) of males studies of naftifine. Why photoplex was
studied somewhat more in males (63 percent) is not clear.
C. The GAO Survey
In 1992, the GAO analyzed the gender, age, and race distribution
of all NDA's approved from January 1988 through June 1991. Data
were collected by means of a questionnaire sent to the sponsor
of each drug. The number of patients receiving the test drug during
drug development, domestic studies only, was requested, and patients
were broken down by gender, age (<15, 15 to 49, 50 to 64, >65),
and race. The age distribution data allow a separate analysis
of women of childbearing potential (taken here as women age 15
to 49). Data are available for 53 drugs (of 63 drugs a proved
during the 3 1/2-year period, 4 drugs intended for single gender
use and 6 whose sponsors provided no, or no usable, questionnaire
were omitted).
The results of the GAO survey are given in Tables 3A and 3B for
phase 2 and 3 patients. The tables show gender distribution overall
for the whole data base and for the 15 to 49 age group as well.
For anti-inflammatory, anti-infective, central nervous system/anesthetic,
topical, antihistamine, and cancer drugs, women constituted 40
percent or more of the patients studied, with occasional exceptions.
The most striking exception is mefloquine, where only 11 percent
of patients were women. This occurred because the primary studies
of mefloquine for treatment of malaria were conducted in Thai
military personnel. Women fairly consistently represented less
than 40 percent of the patients for anti-ulcer drugs (duodenal
ulcer, a male-predominant condition, was a principal disease studied
for nizatidine, omeprazole, and misoprostol) but accounted for
55 percent of the patients in studies of dipentum, a drug for
ulcerative colitis (ulcerative colitis is more common in women).
Women consistently made up less than 40 percent of the populations
studied for cardiovascular disease, including populations used
to evaluate agents used to diagnose or evaluate coronary artery
disease, except for nimodipine (for spasm after subarachnoid bleed)
and adenosine (for supraventricular tachycardia). For drugs to
treat ventricular arrhythmias and angina, both commonly the result
of coronary disease, the fraction of women ranged from 15 percent
(bepridil, for unresponsive angina) to 20 to 30 percent (propafenone,
moricizine, and indecainide), reflecting the lower rate of coronary
artery disease in younger women and the fact that most patients
in studies are under 60 years old. Studies of drugs for hypertension
(carteolol, doxazosin, nicardipine, isradipine, ramapril, pinacidil)
included 27 to 42 percent women. In some cases, these drugs were
being evaluated for other claims, such as angina or heart failure,
which are male predominant in the age groups studied. For all
of the antihypertensives, there were at least 290 women in the
domestic data base, enough to detect significant gender differences
in response.
Of interest is the observation that there was no tendency for
women to represent a lower percentage of patients in the 15 to
49 age group than in the overall population. There is thus no
suggestion in these data that the restriction on participation
of women of childbearing potential in early trials carries over
to later phase 2 or 3 trials.
D.
Antidepressants
By chance, none of the surveys included any antidepressant drugs,
a class of drug frequently cited as needing study in women, both
because women are frequently given antidepressants and because
of suspected interactions of the drugs with the menstrual cycle.
Table 4 shows gender participation for sertraline and paroxetine,
the two most recently approved antidepressants, as well as two
agents likely to be, approved within the next year. Women, as
expected based on past experience, represented 58 to 65 percent
of the patients.
II. Tables
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Anti-inflammatory: Benoxaproten (Oraflex) Ketoprofen (Orudis) Zomepirac (Zomax) |
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Cardiovascular: Verapamil (Isoptin) Burnetanide (Bumex) |
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Hypnotic: Triazolarn (Halcion) |
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Antibiotic: Cefoperazone (Cefobid) Netilmycin (Netromycin) |
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Anti-ulcer: Ranitidine (Zantac) |
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Anti-cancer (prostate, testes): Leuprolide(Lupron) Etoposide (Vepesid) |
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Anti-inflammatory : Diclofenac (Vottaren) |
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Cardiovascular/cerebrovascular: Nicarchpine (Cardene) Cartedol (Cartrol) Nimodipine (Nimotop) |
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Anti-ulcer: Nizatidine (Axid) Misoprostol (Cytotec) |
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Antibiotic: Cefotiam (Ceradon) |
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Anti-Parkinson: Pergolide (Permax) |
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Antihistamine: Astemizole (Hismanal) |
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Anti-carcinoid symptoms: Octreotide (Sandostatin) |
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Topical (tinea, sunscreen): Naftifine (Naftin) Photoplex |
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Anti-inflammatory/Analgesic: Dezocine (Dalgan) Diciofenac (Voltaren) Etodolac (Lodine) Ketoroiac (Toradol) |
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Ant-infectives: Ofloxacin (Floxin) Cefmetazole (Zefazone) Cefixime (Suprox) Fluconazole Diflucan) Naftifine (Naftin) Celpiramide Mefloquine (Lariam) Oxiconazole (Oxistat) |
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Central Nervous System/Anesthetic: Clomipramine (Anaframil) Propofol (Dipravan) Clozapine (Clozaril) Estazoiam (Prosan) Pipecuronium (Arduan) Doxacurium (Nuromax) Pergolide (Permax) |
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Cardiovascular: Nimodipine (Nimotop) Adenosine (Adenocard) Doxazosin (Cardura) Pinacidil (Pindac) Nicardipine (Cardene) Benazepril (Lotensin) Isradipine (Dynacirc) Propafenone (Rhythmol) Ramapril (Altace) Carteolol (Cartrol) Moricizine (Ethmozine) Indecainide (Decabid) Bepridil (Vascor) |
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Cancer: Octreotide (Sandostatin) Carboplatin (Paraplatin) Levamisole (Ergamisol) Ondansetron (Zofran) |
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Diagnostics Technescan Mag 3 loversol (Optiray) Gadopentetate (Magnevist) TC-99M Sestamibi (Cardolyte) TC-99M Exametazime (Ceretec) Iotralan (Osmovist) |
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Topicals: Photoplex Fluticasone (Cutivate) Halobetasol (Ultravate) Metipranolol (Optipranolol) Cefotiam (Ceradon) Rev-Eyes |
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Gastrointestina 1: Olsalazine (Dipentum) Nizatidine (Axid) Misoprostol (Cytotec) Omeprazole (Losec) |
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Antihistamine: Astemizole (Hismanal) |
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Anti-inflammatory/Analgesic: Dezocine (Dalgan) Diciofenac (Voltaren) Etodolac (Lodine) Ketoroiac (Toradol) |
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Ant-infectives: Ofloxacin (Floxin) Cefmetazole (Zefazone) Cefixime (Suprox) Fluconazole Diflucan) Naftifine (Naftin) Celpiramide Mefloquine (Lariam) Oxiconazole (Oxistat) |
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Central Nervous System/Anesthetic: Clomipramine (Anaframil) Propofol (Dipravan) Clozapine (Clozaril) Estazoiam (Prosan) Pipecuronium (Arduan) Doxacurium (Nuromax) Pergolide (Permax) |
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Cardiovascular: Nimodipine (Nimotop) Adenosine (Adenocard) Doxazosin (Cardura) Pinacidil (Pindac) Nicardipine (Cardene) Benazepril (Lotensin) Isradipine (Dynacirc) Propafenone (Rhythmol) Ramapril (Altace) Carteolol (Cartrol) Moricizine (Ethmozine) Indecainide (Decabid) Bepridil (Vascor) |
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Cancer: Octreotide (Sandostatin) Carboplatin (Paraplatin) Levamisole (Ergamisol) Ondansetron (Zofran) |
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Diagnostics Technescan Mag 3 loversol (Optiray) Gadopentetate (Magnevist) TC-99M Sestamibi (Cardolyte) TC-99M Exametazime (Ceretec) lotraian (Osmovist) |
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Topicals: Photoplex Fluticasone (Cutivate) Halobetasol (Ultravate) Metipranolol (Optipranolol) Cefotiam (Ceradon) Rev-Eyes |
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Gastrointestinal: Olsalazine (Dipentum) Nizatidine (Axid) Misoprostol (Cytotec) Omperazole (Losec) |
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Antihistamine: Astemizole (Hismanal) |
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Sertaline (Zoloft) Paroxetine (Paxil) Pending No. 1 Pending No.2 |
1991 |
2979 |
58 |
42 |
Dated:July 19, 1993.
David A Kessler,
Commissioner of Food and Drugs.
[FR Doc. 93-17411 Filed 7-21-93; 8:45 am]
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