Feature Article
Beyond the Pregnancy Test: When
Can Pregnant Women Participate in Research?
May 2007 Issue
Stacey Hess Pino, MS
Senior IRB Analyst II - Purple Panel
Author has nothing to disclose with regards
to commercial support.
- Introduction
- Historical Context
- Inclusion of Pregnant Women
- Exclusion of Pregnant Women
- Pregnancy Testing
- Contraception
- Minors
- Consent
- Finally, a Few Words about Men
- Summary
- Quiz
Women
comprise 49.6
percent of the total world population. Approximately 52 percent of
these women are of childbearing age (ages 15 to 49). Special consideration
must be given to these 1.7 billion potential subjects before enrolling
them in research studies that present potential harm to mother or fetus.
How can the research design ensure that pregnant women and women of childbearing
potential are appropriately included in clinical research studies, yet
at the same time protect them and their fetuses from being harmed by the
research? This article addresses some key points regarding the inclusion
and exclusion of pregnant women in clinical research including pregnancy
testing, contraceptive use, inclusion of minors and consent language.
Historically,
women were excluded from participating in early clinical research studies
due to the potential risk of fetal harm should a woman become pregnant.
This concern resulted in the 1977 FDA guideline entitled, “General
Consideration for the Clinical Evaluation of Drugs,” which noted
that women of childbearing potential should be excluded from Phase I and
early Phase 2 studies until adequate information about the relative safety
and efficacy had been amassed, and only once preclinical data on teratogenicity
and female fertility in animals had been obtained. Although this guideline
was established to protect a woman and her fetus from the risks associated
with early clinical trials, it resulted in significant gaps in scientific
knowledge.
In 1993, the FDA revised its 1977 guideline acknowledging that the ban on women’s participation in early clinical trials no longer seemed reasonable as (1) important gender differences can be identified in all phases of research, thereby allowing later Phase 2 and 3 trials to be more suitably designed to further the clinical understanding of the appropriate use of drugs in women; (2) the 1977 restriction implied a lack of respect for a woman’s autonomy and decision-making capacity; and (3) it was possible to reduce the risk of fetal exposure with appropriate protocol design (Merkatz et al, 1993).
In this guideline, the FDA emphasized the need to minimize the risk of
pregnancy in women by providing contraceptive counseling, by performing
pregnancy testing, and by informing subjects about the potential risks
to their fertility and/or fetuses as a potential consequence of the study
intervention (FDA, 1993). This guideline underscored that while the FDA
remains involved in general risk/benefit determinations for subjects entering
various phases of clinical trials, initial determinations about whether
fetal risk is adequately addressed are properly left to patients, physicians,
local IRBs and sponsors (Stanford Policy, 1995).
The decision as to whether pregnant women can be specifically targeted for research, or merely not excluded from the study, depends on the identification of all the potential risks to mother and fetus. Investigators must consider such questions as:
- Are there risks associated with the study drugs, the devices, or any interventions (i.e., fasting or excessive exercise) that could harm the mother or fetus?
- Does the drug or biological agent increase some of the risks (such as elevated blood pressure) which could harm the mother or fetus?
- Could the research cause birth defects, miscarriage or early delivery?
The
investigator must indicate in the IRB protocol (Section E2) that pregnant
women will be enrolled, and explain why research on pregnant women is
indicated or why they should not be excluded. Any real or potential risks
to the mother and the fetus must be described (Section H) along with an
explanation of how these risks will be minimized or eliminated.
The IRB reviews the study procedures, the investigator’s brochure and the description of the risks. The IRB scientists review the background information (including related animal studies) for information about fetal loss, malformations, problems with birth weight, and reduced survival. If the information available is inadequate, the IRB will not approve the enrollment of pregnant women. If enrollment of pregnant women is allowed, the IRB can decide whether any additional protections are necessary to further minimize the risks to mother and/or fetus (45 CFR 46.111). Additional protections might be: initiating drug therapy later in the pregnancy (when risk of damage to fetal development is lower), additional labwork, or requiring monitoring by an OB/GYN.
Federal Regulations, SUBPART
B , require that as part of the approval process, the IRB must make
certain findings when reviewing “all research involving pregnant
women, human fetuses, neonates of uncertain viability, or nonviable neonates”.
These findings are made by the IRB at the time of review and are recorded
in the IRB minutes.
Most
frequently, pregnant women are excluded from research because the risks
of harm to the woman, the fetus, or both are unknown. If pregnant women
are excluded, then consideration must also be given to women who might
not know they are pregnant or who might become pregnant during the course
of the study; therefore, a plan for pregnancy screening must be included
in the protocol. Usually the plan calls for either pregnancy testing prior
to enrollment or prior to the initiation of the “risky” study
interventions. Study designs may require only single, one-time pregnancy
testing; others may require more frequent pregnancy testing; and still
others may require both pregnancy testing and contraceptive use to ensure
that women are not pregnant during any “risky” study interventions.
If pregnant women are excluded from the research, then the protocol and
consent form must (1) indicate whether women who refuse pregnancy testing
are excluded [Sections F1 and Q]; (2) include a description of all required
pregnancy testing and contraception use [Sections F2 and Q]; and, (3)
include a description of the real and potential risks to mother and fetus
if the subjects become pregnant [Sections H and Q].
Pregnancy
testing may be done on either urine or blood samples. However, blood tests
are more accurate and provide an earlier indication of pregnancy. The
manner of pregnancy testing must be based on the risks, the subject population
and the other study interventions. With either type of testing, the timing
of the testing (for example, please refer to the
BUMC IRB Policies for the BUMC policy for pregnancy testing and research
MRIs), the frequency of the testing (i.e., prior to each MRI), and
who will perform the testing (i.e., “the study nurse”) must
be clearly described in the protocol. The usual requirement is for study
staff or clinical personnel to perform pregnancy testing, rather than
allowing the subject to do a home pregnancy test and to report the results.
With all pregnancy testing, an adequate plan
to protect the confidentiality of the subjects’ test results must
be in place.
If pregnancy testing is done for screening, either to identify pregnant
women to include in the study or to exclude women who are pregnant from
the study, then informed consent is required. In some instances, a separate
screening consent is done for the pregnancy testing alone; and in other
studies, subjects are consented to the full study which includes the pregnancy
testing.
Women
may have to agree to use an approved method of contraception in order
to participate in some studies involving pregnancy risks. Use of contraception
is only required for women of childbearing potential. Women who are surgically
sterile, menopausal women who have not had a menstrual period for at least
one year, and women who do not have sex with men are excluded from the
contraception requirement.
The following are considered to be “reliable” birth control options:
- Birth control drugs given by pills, shots, or placed on or under the skin
- Male or female condoms with or without a cream or gel that kills sperm
- Diaphragm or cervical cap with a cream or gel that kills sperm
- Intrauterine devices (IUD) and contraceptive rings
- Abstinence: While this is the most reliable form of birth control (when followed), most researchers do not list it as a “reliable” birth control option because people are frequently non-compliant.
- “Double” methods: In higher risk studies, subjects may be required to use “double” birth control methods (one being a barrier method).
The specific contraceptive requirements must be included in the protocol
and consent--including the timing of contraceptive use prior to study
interventions, and how long contraceptive use is required after completion
of the study interventions. Subjects must also be told in the consent
what to do if their birth control method fails or if they think they have
become pregnant during the study.
In
Massachusetts, minors are those persons under 18 years of age. In protocols involving minors, the investigator must explain how pregnancy
testing, results reporting, and contraception methods, will be addressed
with both the child and the parent. If the minor is found to be pregnant,
the researcher is not responsible for providing pregnancy counseling but
must provide a plan for how minor subjects will be referred for follow-up,
along with an explanation of how the confidentiality of the child’s
information will be protected. Unless waived
by the IRB, parental consent (permission) and child assent are required
for pregnancy testing of minors.
Massachusetts does not have specific laws regarding the enrollment of
pregnant minors (sometimes called “emancipated minors”) in
research. As a rule, the IRB bases its decision about whether parental
consent is required for pregnant minors on whether these young women currently
make their own healthcare decisions. It is presumed that if a pregnant
minor makes her own healthcare decisions, then she can make her own decision
regarding research participation; but if she still relies on a parent
to make her healthcare decisions, then the parent’s consent is required
for her to participate in the research.
All
research risks or potential risks to pregnant women or fetuses must be
disclosed in the consent document. The risks to the mother must be clearly
differentiated from the risks to the fetus. The known risks must be described,
as well as whether or not animal studies and reproductive toxicology studies
have been done. If pregnant women are excluded, then an explanation of
any required pregnancy testing or contraceptive use and a warning about
the risks of becoming pregnant must be in the consent. If the risks can
be minimized so that pregnant women are not excluded, then any special
precautions or monitoring that are needed must be described.
In Section Q of the INSPIR application, the investigator can opt for the templated “pregnancy risk language” to be automatically added to the consent form. However, this language is not appropriate for all studies. The pregnancy risk language is required when you want to warn women about the importance of not becoming pregnancy. Click here to view the templated pregnancy risk language, and for instructions on how and when to use this templated pregnancy.
Click
here for samples of other “pregnancy risk “consent language.
Finally, a Few Words about Men
Certain
study drugs, biologicals or devices, when used in male subjects, may have
the potential of causing harm to these subjects’ sex partners or
to their offspring if their partners become pregnant. Male subjects in
such studies must refrain from donating sperm, and must abstain from having
sex with women or must agree to use an appropriate method of contraception.
The requirements vary depending on the protocol and the level of risk
but, as with female subjects, all risks and requirements must be clearly
described in the protocol and consent.
Women of childbearing potential and pregnant women must not be excluded
from all clinical research. Instead, research protocols must be carefully
evaluated to determine whether the risks justify exclusion, or whether
additional protections can be added so that pregnant women can participate.
Works Cited:
- Food and Drug Administration. General Considerations for Clinical Evaluation of Drugs. Washington, D.C.: GPO, 1977. (Publication No. HEW (FDA) 77-3040).
- Food and Drug Administration. “Guideline for the Study and Evaluation of Gender Differences.” NIH Guide 22.31 (August 27, 1993).
- Merkatz, Ruth B., et al. “Women in Clinical Trials of New Drugs – A Change in Food and Drug Administration Policy.” New England Journal of Medicine July 1993: 329(4): 292-296.
- Stanford University. “Women as Subjects in Research.” Research Policy Handbook February 1995: Document 7.2.
Quiz
There are no quiz questions this month (and, therefore, no CME credits). Take a few minutes and check where you stand with quizzes that count towards Recertification. You need at least 51 correct answers in your My Account to be recertified to continue doing clinical research at BUMC. Click here for an explanation of who needs to be recertified and how to meet the requirements. If you have questions, please check the Frequently Asked Questions for certification and those for recertification. If you still have questions, please send them to crtimes@bu.edu.