PRIM&R recently submitted comments in response to the Food and Drug Administration (FDA)’s draft guidance “Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials,” which was published in the Federal Register on April 9, 2018.

The federal regulations covering pregnant women and neonates at 45 CFR 46 Subpart B, do not apply to FDA-regulated research. PRIM&R applauds the agency for taking this important step to fill current regulatory gaps around the inclusion of pregnant women in FDA-regulated clinical trials. Such gaps that have historically hindered pregnant women’s access to the benefits of clinical research—namely, safe and effective medications. At the same time, the guidance thoughtfully articulates the very real tension between the need for more information about how to appropriately treat pregnant women who get sick, or sick women who get pregnant, and the scientific and ethical complexity involved in including pregnant women in clinical trials.

PRIM&R also suggests a few areas for further clarification. Subpart B includes the following as one of 10 conditions that must be met for acceptable inclusion of pregnant women in research: “The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit  to the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means” (emphasis added). While the guidance generally recommends that FDA-regulated clinical research abide by Subpart B, in section III.C, titled “General Guidelines for Including Pregnant Women in Clinical Trials,” the guidance lists only two conditions under which it is ethically justifiable to include pregnant women with a disease or medical condition in premarketing studies of investigational drugs:

1. When adequate nonclinical studies have been completed; and
2. When “the clinical trial holds out the prospect of direct benefit to the pregnant woman and/or fetus that is not otherwise available outside the research setting or cannot be obtained by any other means.”

This language seems more restrictive than the corresponding language of Subpart B. We thus recommend FDA revisit section III.C to ensure it is not inadvertently limiting the inclusion of pregnant women in investigational drug studies in ways that are in tension with the rest of the guidance.

The draft guidance also wisely recognizes the complex issues that must be addressed when a woman becomes pregnant during the course of a clinical trial, but we suggest adding a few additional details. PRIM&R endorses the general recommendation that if a woman becomes pregnant while enrolled in a clinical trial, she should not automatically be unenrolled, but rather that the risks and benefits of continuing or leaving the trial should first be examined. We also suggest that ethics oversight bodies, such as IRBs, be involved in decisions about whether unblinding should occur in such cases. Furthermore, the draft guidance should clarify that, if a decision is made to allow a pregnant woman to continue on an investigational drug outside of a trial, just as in the case of continuing on the trial unblinded, she should undergo a separate informed consent process explaining that researchers will continue to collect data related to the investigational drug.

PRIM&R ultimately believes that the draft guidance will be of great benefit to relevant stakeholders, including industry, IRBs, and research subjects. The FDA’s support for the “judicious inclusion” of pregnant women in clinical trials is another welcome sign, along with the pending revisions to the Common Rule, that we are moving past the outdated notion that women who are or become pregnant are a vulnerable population that must be protected from the risks of clinical research. This is welcome progress.