Urgent Action Needed from NIH, FDA, Congress, and HHS to Improve Inclusion of Pregnant and Lactating Women in Clinical Trials, Says New Report

WASHINGTON - Pregnant and lactating women are often excluded from clinical trials due to concerns about legal liability, but a new report finds limited evidence of such liability - and says the lack of evidence available to pregnant and lactating women and their clinicians with which to make decisions about using a drug or vaccine poses greater potential for harm than including them in research. The report from the National Academies of Sciences, Engineering, and Medicine recommends improving the safe and ethical inclusion of pregnant and lactating women in clinical research. The Food and Drug Administration should develop clearer guidance on including these populations in clinical trials, Congress should create incentives to encourage their inclusion, and the National Institutes of Health should develop a plan to prioritize research with these populations across its institutes and centers.

Each year, more than 3.5 million women give birth in the U.S., and some experience serious diseases or conditions that are unique to pregnancy - such as gestational diabetes, preeclampsia, and severe nausea. Pregnant and breastfeeding women also experience many of the same conditions that may require treatment as adults who are not pregnant do, such as depression, cancer, lupus, or HIV. Seventy percent of pregnant women take one or more prescription medications during pregnancy, and the same is true for at least half of all lactating women.

Pregnant and lactating women are excluded from most clinical studies, however, leaving a dearth of data about the appropriate dose, efficacy, and safety of most medical interventions for these populations. Pregnant and lactating patients and their clinicians are therefore forced to make decisions regarding drugs and vaccines without the benefit of high-quality evidence of a product's effects on the health of the patient, their fetus, or their children. This prompts some pregnant and lactating women to forgo necessary treatment, while others decide to use the medical product and face unknown likelihood of harm and uncertain benefits. Improved inclusion of pregnant and lactating women in clinical trials would generate the research and evidence that they and their health care providers need to make well-informed decisions, the report says.

A case law analysis commissioned by the committee that wrote the report found no claims of liability for injuries resulting from pregnant or lactating women participating in clinical trials since 1962, when the FDA began requiring trials to evaluate the safety and efficacy of drugs before they could be marketed. In contrast, the committee's analysis found many cases involving liability claims from pregnant women who used drugs that were already approved and on the market. The report says this analysis is the first of its kind, but it is not a complete picture of liability given the limited data available.

Clearer guidance from FDA, detailing expected study designs, safeguards, and product-specific monitoring, would equip investigators and research sponsors with crucial information for safely executing these trials and mitigate potential legal liability. The report recommends FDA revise its guidance to state that studies providing explicit support for drug safety, efficacy, and dosage in pregnant and lactating women should be initiated no later than the end of Phase III of a clinical trial. The guidance should be clear that the requirement to include pregnant and lactating women in a trial is dependent upon available clinical and preclinical safety and efficacy data. If a trial sponsor believes there is evidence that raises concerns about potential harm to pregnant and lactating women or their offspring, the sponsor can submit a justification to the FDA for not including them. FDA should also require that diversity action plans include pregnant and lactating women.

"The current reality facing many pregnant and lactating women who are deciding whether to use an approved drug or medical treatment is that they are essentially taking part in a large and uncontrolled safety experiment," said committee chair Margaret Foster Riley, professor of law and Dorothy Danforth Compton Professor at University of Virginia. "The status quo of not including pregnant and lactating women in research is not an acceptable path forward, and we recommend that regulatory agencies and policymakers work together to incentivize and improve the safe and ethical inclusion of these populations in clinical trials."

"Women deserve better evidence about the safety and efficacy of drugs during pregnancy or lactation, and I applaud the urgent action called for in this report to make that evidence available," said Victor J. Dzau, president of the National Academy of Medicine. "The National Academy of Medicine has long championed the ethical imperative for being inclusive in clinical trials and research and the benefits of doing so."

Congressional Action

The report recommends that Congress pass legislation to encourage and incentivize more studies to provide information about labeling medical products for pregnant and lactating women, modeled after legislation that successfully addressed evidence gaps for therapeutics intended for children. Importantly, Congress should authorize FDA to require research related to the use of drugs, biologics, vaccines, and medical devices in pregnant and lactating women.

Congress should also pass legislation that:

• Directs the secretary of the U.S. Department of Health and Human Services to require any entity that submits a new application for a medical product - or for a new dosage or regimen for an existing product - to include data on the dosage, administration, safety, and effectiveness of its use for pregnant and lactating women.
• Creates incentive programs, such as extended market exclusivity or tax breaks, to an approved application holder. These programs should be authorized for an initial five-year period.
• Asks the director of the NIH to annually publish a prioritization list of on- and off-patent drugs for which further studies are needed to assess the dosage, safety, and effectiveness for pregnant and lactating women.
• Directs the secretary of HHS to award contracts to conduct clinical studies in pregnant and lactating women for products that are no longer subject to patent exclusivity.
• Grants the secretary of HHS the authority to request that medical product patent holders conduct studies that include pregnant or lactating women.

Recommendations for Regulatory Agencies

HHS should form an interagency task force - including FDA, NIH, the Centers for Disease Control and Prevention, and other agencies - to maintain infrastructure and guidelines for pregnancy and lactation safety studies for medical products that have already been approved and are on the market, the report says. This task force should create a central repository for these research findings and study data, as well as create new standards so that women's electronic health records can be linked with their children's for research purposes.

NIH should develop a plan to prioritize research that includes pregnant and lactating women across its institutes and centers. Along with other federal agencies that fund clinical research, the report says, NIH should cover the cost of clinical trial insurance for clinical research grants that include pregnant and lactating women.

The Office for Human Research Protections within HHS should provide clear guidance on protections for pregnant and lactating women research subjects. The guidance documents should help clinical researchers, institutional review boards, and data and safety monitoring boards ensure that pregnant and lactating women who participate in clinical research are adequately protected without creating undue burdens, harmonizing this guidance with FDA's guidance.

The report says that following the 2022 Supreme Court decision in Dobbs v. Jackson Women's Health Organization, privacy issues for pregnant research participants may increase, and certificates of confidentiality can be a valuable tool to protect research participants' privacy and address concerns that their health information may be shared. Principal investigators of studies that include pregnant women or women who may become pregnant over the course of the study should apply to NIH for a certificate of confidentiality, if not automatically granted one by a federal funding agency.

Undertaken by the Committee on Developing a Framework to Address Legal, Ethical, Regulatory, and Policy Issues for Research Specific to Pregnant and Lactating Persons, the study was sponsored by U.S. Department of Health and Human Services.

The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, engineering, and medicine. They operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln.

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Megan Lowry, Media Relations Manager
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202-334-2138; email [email protected]

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