In a recently issued draft guidance for industry, FDA encourages drug sponsors to consider the inclusion of pregnant subjects in clinical studies evaluating drugs and therapeutic biological products in some circumstances and examines the specific ethical and scientific considerations that may impact this decision. FDA states that they are addressing the challenges of including pregnant women in investigational research to promote maternal/fetal health and informed prescribing decisions during pregnancy.

Addressing a Public Health Issue

FDA points to several potential justifications for including pregnant women in clinical studies.

In some circumstances, inclusion may be appropriate to allow pregnant patients to access an experimental drug that may offer a direct benefit to the women and/or fetus and that is not available outside the research setting. By this, FDA explains that it means considering situations where no other treatment options are available to the pregnant patient, or where the patient has not responded to other available treatments.

Further, FDA frames accessible treatment options for pregnant patients as a significant public health issue. The extensive physiological changes associated with pregnancy may alter a drug’s pharmacokinetics and pharmacodynamics in ways that directly impact safety, efficacy, and appropriate dosing. As a result, pregnant women and their doctors often face a difficult decision about whether to start or continue to use a medication to manage chronic disease conditions or treat acute medical problems, armed with only limited data available about the use and effect of the product in pregnant patients. The Agency notes that almost 4 million births occur in the United States each year, and there are more than 60 million women in the United States in the age range that suggests childbearing potential.

When to Enroll Pregnant Patients

In the draft guidance, FDA states that FDA-regulated clinical trials in pregnant women must conform to all applicable FDA regulations, including those related to human subject protections (21 CFR part 56, Institutional Review Boards, and 21 CFR part 50, subpart B, Informed Consent of Human Subjects). FDA also notes that if the trial is supported or conducted by the Department of Health and Human Services, then 45 CFR part 46 may also apply, which would include subpart B, Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research. While FDA’s regulations do not contain language similar to that in 45 CFR part 46, subpart B, in this draft guidance, FDA recommends that these requirements be satisfied for FDA-regulated clinical research as well. Subpart B requires that trials supported or conducted by HHS meet ten conditions which the draft guidance lays out.

Among other considerations, the draft guidance suggests that the level of risk that trial participation poses to the fetus is an important variable in deciding whether including a pregnant patient is ethically justified. Where the research-related risk to the fetus is more than minimal, FDA advises that pregnant women should only be included in a clinical trial where doing so offers the potential of a direct clinical benefit to the enrolled pregnant women and/or the fetus, including access to a needed but otherwise unavailable therapy, or to a therapy that reduces the risk for acquiring a serious health condition. In contrast, where the research-related risk to the fetus is only minimal, enrolling pregnant women in clinical studies may be appropriate in order to develop important biomedical knowledge, such as pharmacokinetic data about a product, regardless of whether or not there are other treatment options available to the pregnant patient.

Before pregnant women are included in a clinical trial, the Agency recommends that the sponsor gather adequate preclinical studies, including studies of the drug in pregnant animals.

Further considerations are dependent in part on whether the trial is for an approved or investigational drug. Where a drug has not yet been approved, FDA recommends that inclusion be limited to situations where the trial offers a possible direct benefit to the women and/or fetus. In the postmarketing setting, however, inclusion of pregnant women should be predicated on the availability of an established safety database of non-pregnant women in clinical trials or preliminary safety data regarding the use of the drug in pregnant women, and on whether or not efficacy and safety of the product in pregnant women can be extrapolated through other means.

FDA also recommends that institutional review boards that regularly review research involving pregnant women should consider including at least one member with knowledge about and experience in working with such subjects, consistent with 21 CFR 56.107’s existing professional competency requirements. In addition to employing members equipped to evaluate the relative the risks and benefits of research to pregnant subjects and the adequacy of safeguards designed to protect the rights and welfare of such subjects, FDA indicates that institutional review boards should be familiar with the legal and ethical issues raised by pregnant minors, including whether, under applicable state law, a pregnant minor is considered a child, thus triggering applicable additional safeguards for children in clinical investigations provided at 21 CFR part 50, subpart D.

Trial Design Considerations

In conducting a clinical trial that includes pregnant women, or where a subject may become pregnant during the course of the trial, the draft guidance provides specific suggestions about trial design, including approaches to collection of pharmacokinetic and safety data, safety monitoring of the pregnant women as well as infants born to women who were pregnant while participating in a clinical trial, the timing of enrollment of pregnant women, informed consent considerations, and providing counseling for subjects who become pregnant during a clinical trial.

The draft guidance also recommends that sponsors consult with an ethicist during the planning stages of a drug development program. Where a clinical trial will include pregnant subjects, sponsors should also consider the use of researchers with an expertise in obstetrics and/or maternal/fetal medicine.