Women
Historically, in order to avert harm to a developing fetus in
an unsuspected pregnancy, physicians and the lay community have
expressed concerns regarding the participation of women of
child-bearing potential in research. As a result, federal
agencies developed special guidelines ostensibly for the
protection of the developing fetus that excluded women of
child-bearing potential from participation in some research. In
1977, for example, the FDA published a guideline that excluded
most women of child-bearing potential from early phases of drug
trials. An exception was made for studies involving women with
serious and life-threatening diseases.
Over the past decade, questions raised by grass roots,
professional, consumer, and governmental groups regarding the
adequacy and fairness in the distribution of the benefits and
risks of research resulted in changes to the regulations for the
involvement of women in research. At the same time improved
pregnancy tests and methods of contraception became widely
available. In 1988, the FDA issued guidelines that called for
safety and efficacy profiles for women, elderly, and diverse
racial groups as part of new drug applications (NDAs). Then in
1993, following broad public discussion about participation of
women in clinical trials, the FDA issued a new guideline that
eliminated restrictions on women of child-bearing potential
participating in all phases of drug trials. The guideline
detailed procedures for minimizing the risks of pregnancy in
women participants, such as contraceptive counseling, pregnancy
tests, timing of short term studies in relation to the menstrual
cycle, and the process of informed consent. Though the FDA
emphasized the importance of risk/benefit determinations for
subjects entering various phases of clinical trials, they
underscored that initial determinations regarding whether risks
to a fetus were adequately addressed were best left to patients,
physicians, local HSPC’s, and study sponsors. The new
guideline also called for gender analysis with special attention
to factors affecting the role of the menstrual cycle and
exogenous hormone therapy in relation to the drug, as well as the
influence of the drug on oral contraceptives.
The DHHS has also carefully examined the issue of
participation of women in research. Since the primary aim of
clinical trials is to provide scientific evidence leading to a
change in health policy or a standard of care, it is imperative
to determine if the intervention or therapy being studied affects
men and women differently. As stated in its new guideline, NIH
Outreach Notebook of the Inclusion of Women and Minorities in
Biomedical and Behavioral Research (1994) (Please
see Appendix 8
for detailed information), the NIH has concluded that the
inclusion of women in research is sufficiently important that the
only justifiable reason to exclude non-pregnant women of
child-bearing potential from research is compelling evidence that
the proposed project would be inappropriate with respect to the
health of the subject or the purpose of the research.
The policy statement referenced above pertains primarily to
the inclusion of women as subjects in clinical trials, i.e.,
medical research testing new treatments. However, the inclusion
of women in behavioral research is also important and should be
accomplished unless there is a compelling rationale which
establishes that inclusion is inappropriate with respect to the
health of the subjects or the purpose of the research.
Significant portions of the text below are presented verbatim
as published in the Code of Federal Regulations and the Federal
Register.
Pregnant
Women as Human Research Subjects
Drug research using pregnant women as subjects is governed by
the federal regulations [45 CFR 46, Subpart
B].
In accordance with [45 CFR 46.207 (a)], "No
pregnant woman may be involved as a subject in a human clinical
research project unless: (1) the purpose of the activity is to
meet the health needs of the mother and the fetus will be placed
at risk only to the minimum extent necessary to meet such needs,
or (2) the risk to the fetus is minimal."
Research involving pregnant women is permitted only if the
mother and father are legally competent and both have given their
consent after having been fully informed regarding the possible
impact on the fetus, except that the father’s consent need
not be secured if (1) the purpose of the activity is to meet
the health needs of the mother; (2) his identity or whereabouts
cannot reasonably be ascertained; (3) he is not reasonably
available; or (4) the pregnancy resulted from rape (45 CFR 46.207(b)].
Women of
Childbearing Potential as Human Research Subjects
Non-pregnant women should not be excluded from any phase of
research unless the science of the project or the health of the
subject will be compromised. Regarding clinical drug research,
Phase I, II and III trials should have the proportion of women in
the study which at least reflects the proportion of women in the
population which will receive the drug when it is marketed, and
should enroll numbers adequate to detect clinically significant
sex differences in drug metabolism and response.
Risk to
Fertility
It is expected that both male and female subjects will be
informed about potential risks to their fertility including the
development of any abnormalities or abnormalities in function of
reproductive organs as a consequence of the proposed study
intervention.
"Where abnormalities of reproductive organs or their
function (spermatogenesis or ovulation) have been observed in
experimental animals as a consequence of the proposed study
intervention, 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 [subjects] 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." (Federal Register, Vol. 58, No. 139, p
39411, H, Thursday, July 22, 1993)
Risk to
Fetus and/or Infant
- General Guidelines: "Appropriate precautions
should be taken in research 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 [drug
information] 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 general
assessment of fetal toxicity in drugs with related
structures or pharmacological 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 child-bearing potential, i.e.,
usually by the end of Phase II and before any expanded access
program is implemented." (Federal Register, Vol. 58,
No. 139, p 39411, G, Thursday, July 22, 1993.)
- Minimizing the Possibility of Fetal Exposure:
"Pregnancy testing may be used to detect unsuspected
pregnancy prior to initiation of study treatment. Timing
of the start of the study to coincide with or immediately
follow the onset of menses is also an adequate indication
that the subject is not pregnant. The investigator should
ascertain that the subjects will responsibly employ a
reliable method of contraception or abstinence for the
duration of the drug or treatment exposure, which may
exceed the length of the study. If requested, the
investigator should be able to refer the subject to a
knowledgeable counselor or physician for contraceptive
advice."
- Inclusion of Women in Early Clinical Trials (Phase I
and Early Phase II): "In some cases, there may
be a basis for requiring [inclusion] 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 real access
procedures, a case can be made for requiring that women
[be allowed to] participate in clinical studies at an
early stage. When such a drug becomes available under
expanded access mechanism (for example, treatment IND or
parallel track) or is marketed rapidly under subpart E
procedures because an effect of 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 of
participation of women." (Federal Register, Vol. 58,
No. 139, p 39409, G, Thursday, July 22, 1993)
- Risk to Infant of Nursing Mother: The potential
for harm from exposure to a drug with unknown risks
exists for nursing infants as well as fetuses. Therefore,
this policy applies to breast feeding female subjects who
are potential subjects in a drug trial in the same manner
in which it applies to gestating women.
Active
Recruitment of Women
In order to assure that adequate numbers of women are
included, researchers are encouraged to actively recruit women
into clinical trials. For specific outreach methodologies,
researchers should refer to the NIH
Outreach Notebook of the Inclusion of Women and Minorities in
Biomedical and Behavioral Research (1994). (Please
see Appendix 8
for more information.)
Sample
Informed Consent Statement to be Included for a Potentially Toxic
Drug Study
The following language is recommended when women of
child-bearing potential (non-pregnant) will be enrolled into a
potentially toxic drug study:
"If you are a woman who is able to become pregnant, it is
expected that you will use a medically accepted method of birth
control [outline the recommended forms of birth control] to
prevent exposing a fetus to a potentially dangerous agent with
unknown risk. If you are pregnant or currently breast feeding,
you may not participate in this drug study. If you are
pregnant, if you become pregnant, or if you are breast-feeding
during this study, you or your child may be exposed to an unknown
risk. There are also known risks to you or your unborn baby,
including [state specific risks].
"To confirm to the extent medically possible that you are
not pregnant, you are required to agree [to have a pregnancy test
done before beginning this research study] [to begin the study
after the onset of your next menstrual period] [choose one]. You
must agree to avoid sexual intercourse or use a birth control
method judged to be effective by the investigator and which will
not interfere with the proposed investigation. Pregnancy could
still result despite the responsible use of a reliable method of
birth control while participating in this research study. You
agree to notify the investigator as soon as possible of any
failure of your birth control method, or if you become pregnant,
either of which may result in your being withdrawn from the
study." Prior to enrollment, investigators are required
to discuss with subjects what will happen if pregnancy occurs.
Contact OPRS
October 29, 2004
Contact Webmaster
|
