Drug developers often face a Catch-22 regarding clinical trials and pregnancy. How feasible is it to establish a drug’s safety for use in a population that may be unwilling or unable to participate in clinical trials? We look at the outcome of a recent Food and Drug Administration meeting and their draft guidance for more information.
Experts at a November 2021 Food and Drug Administration (FDA) meeting also wrestled with this theme of clinical trials and pregnancy.
The Antimicrobial Drugs Advisory Committee voted narrowly in favor of the safety and efficacy of Merck’s molnupiravir for treatment of mild-to-moderate COVID-19 in adults who are at risk for progressing to severe COVID-19 and/or hospitalization. Ahead of the meeting, the FDA highlighted nonclinical findings (i.e., animal studies) for molnupiravir that included mutagenicity, embryo-fetal toxicity, and impaired bone and cartilage growth. Panelists were asked to discuss the potential use of the drug during pregnancy.
At the November meeting, FDA reviewers stated that one risk mitigation strategy for such drugs would be not to authorize them for use during pregnancy. This approach would be appropriate, the agency said, if there are no clinical scenarios in which the benefits are thought to outweigh the risks during pregnancy.
A less restrictive approach would be to not recommend the drug for use during pregnancy, but pregnancy would not be considered a limitation of authorized use. The product could be prescribed during pregnancy at prescribers’ discretion in certain clinical scenarios where benefits were thought to outweigh the risks.
Medicine use during pregnancy: balancing risks
Through recent actions, the FDA has signaled its commitment to advancing research in pregnant and lactating people, recognizing that data are needed to inform labeling and benefit-risk determinations. To this end, the agency collaborated with the Duke University Robert J. Margolis Center for Health Policy to convene a February 2021 public meeting about scientific and ethical issues associated with enrolling pregnant individuals in clinical trials for drug development.
The U.S. Department of Health and Human Services has removed a reference to pregnant people as “vulnerable” from its Federal Policy for Protection of Human Research Subjects—also called the Common Rule. The FDA is working to harmonize its regulations with the Common Rule, as noted in the October 2018 Guidance for Sponsors, Investigators, and Institutional Review Boards: Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations (Final).
Labeling information for pregnant people typically is based on nonclinical data, “with or without limited human safety data,” the FDA states in its April 2018 Draft Guidance for Industry: Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials. Lack of information based on clinical data can mean providers and patients decide against treating underlying conditions, “which in some cases may result in more harm” to the parent and the fetus than if they had received treatment. In other situations, individuals who use medically necessary drugs may do so without understanding the benefits and risks to themselves or their fetuses.
Pregnancy and clinical trials
The April 2018 Draft Guidance identifies several reasons that justify including pregnant people in clinical trials:
- The lack of accessible, safe, and effective treatment options for pregnant individuals is a significant public health issue.
- The health of pregnant people and their fetuses can be compromised if the dose/dosing regimen, safety, and efficacy of treatments used during pregnancy are not established.
- In some cases, pregnant people and their fetuses directly benefit from participation in clinical trials in ways not possible outside the research setting.
A section of the guidance, FDA Regulations That Govern Research in Pregnant Women, identifies several conditions that must be met in trials supported or conducted by HHS. Further, as noted in the July 2020 Draft Guidance for Industry, Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products—Content and Format (Revision 1), the pregnancy and lactation labeling rule requires inclusions of a risk summary, clinical considerations, human data (if available), and a summary of animal data. For females and males of reproductive potential, the guidance includes subsections about pregnancy testing, contraception, and infertility.
FDA speakers at the February meeting said that risk assessment and benefit considerations may vary depending on the setting. These considerations include the amount of data available to inform safety, efficacy, and dosing; gestational age; the seriousness of the disease; and the availability of treatment options. Trials in the post-market setting may be easier to conduct because investigators have more data to work with. Areas to address were identified, including:
- Whether the regulatory requirements have been met.
- “Opportunistic” pharmacokinetic studies can have minimal risk (e.g., blood samples from routine clinical care).
- Intervention trials may be appropriate if the benefit-risk is favorable.
The FDA has stated an intent to use input from the February 2021 meeting to inform the finalization of the April 2018 draft guidance. According to the guidance, the agency “supports an informed and balanced approach to gathering data on the use of drugs and biological products during pregnancy through judicious inclusion of pregnant women in clinical trials and careful attention to potential fetal risk.”
Related FDA publications for industry include the November 2020 final guidance, Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs, as well as two May 2019 draft guidances: Postapproval Pregnancy Safety Studies and Clinical Lactation Studies: Considerations for Study Design.
Portions of this blog post first appeared in Volume 13 (Issue 5) of the Journal for Clinical Studies.