More Inclusion of Pregnant and Breastfeeding Women in Clinical Research Needed

Global Regulators Envision Paradigm Shift Toward Inclusion of Pregnant and Breastfeeding Women in Clinical Research

Concerned about the dearth of information available on the safety and effectiveness of medical products for pregnant and breastfeeding women, the U.S. Food and Drug Administration and many of its regulatory counterparts around the world say it is time to address inadequacies in research through a paradigm shift in the approach to studying medical products in these populations.

Stories are all too common about pregnant women who are calling their doctors and scouring social media and the internet for advice on whether or not they should take a medicine, even for serious conditions like asthma, epilepsy, depression—or COVID-19. What they find instead are anecdotes and opinions, but little to no actual data about the safety or effectiveness of medications used during pregnancy.

Historically, pregnant and breastfeeding women have been excluded from clinical trials, especially pre-approval, primarily due to concern about the real or perceived potential risk to the fetus or child. Take the case of COVID-19, where pregnant women suffer increased risks for severe illness—including illness that results in ICU admission, mechanical ventilation, and death—leading to worse outcomes for the pregnant woman and fetus compared to nonpregnant women. Pregnant women with COVID-19 are at increased risk for serious adverse obstetrical outcomes, such as preterm birth. Nonetheless, even though they were not specifically excluded, no pregnant women were enrolled in clinical trials of remdesivir, a COVID-19 treatment. And even though the FDA encouraged developers to consider the inclusion of pregnant women in prelicensure COVID-19 vaccine trials, none were enrolled for any of the pivotal clinical trials of the Pfizer-BioNTech, Moderna, or Janssen (Johnson & Johnson) COVID-19 vaccines.

Even before COVID-19 shined a spotlight on this important issue, an escalating drumbeat of interest emerged from the FDA and other regulators to address information gaps that leave pregnant and breastfeeding women, along with their health care providers, to make important clinical decisions on the basis of scant data. We believe it is time for a change so that pregnant women and their doctors will not be tasked with weighing the benefits and risks of treatment in the absence of information.

US Activities

The FDA kicked off efforts to improve information on the safe use of medicines in pregnancy and during breastfeeding with the Pregnancy and Lactation Labeling Rule, finalized in 2014, requiring companies to keep product labeling up to date with any data relevant to these populations. The rule stops short, though, of requiring the collection of such data through clinical trials or studies. In response, the FDA has been involved in many activities to address this, too numerous to list here, but highlights include the issuance of three draft guidance documents and one final guidance document to help encourage the inclusion of pregnant and breastfeeding women in clinical trials:

• “Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials” (April 2018) (draft guidance) explores general guidelines for inclusion, research-related risks, and ethical considerations. The document also explores other important considerations: disease type and availability of therapeutic options, the timing of enrollment, pharmacokinetic data, safety data collection and monitoring, and stopping a clinical trial when finding out a participant is pregnant.
• “Postapproval Pregnancy Safety Studies” (May 2019) (draft guidance) addresses how to design investigations to assess the outcomes of pregnancies in women exposed to drugs and biological products regulated by the FDA; registry design considerations; and use of complementary studies and secondary data.
• “Clinical Lactation Studies, Considerations for Study Design” (May 2019) (draft guidance) examines ethical considerations, study design, milk sampling, estimation of infant dosage, and infant safety.
• “Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs” (November 2020) (final guidance) includes a discussion, in the context of enhancing diversity in clinical trials, of the continued inclusion of women who become pregnant during a clinical trial.

The FDA has been actively engaged in the Task Force on Research Specific to Pregnant and Lactating Women (PRGLAC), a multi-party effort established under the US Department of Health and Human Services. In 2018, the PRGLAC task force issued an extensive report to the Secretary of the Department of Health and Human Services and Congress with 15 recommendations on the research and development of safe therapeutics for pregnant and breastfeeding women. This was followed in 2020 with an implementation plan.

Further, the FDA’s Office of Women’s Health (OWH) funds research to expand our knowledge on medication use during pregnancy and breastfeeding. Recently funded projects include the development of an artificially intelligent virtual pregnant woman modeling suite to support regulatory decisions; model-informed drug passage into breast milk; and assessment of real-world use of pharmaceuticals among pregnant and lactating women.

In addition, OWH is funding the development of a pregnancy treatment repository as part of CURE ID. Health care providers from all over the world can access the platform via the web or mobile app to share and communicate real-world information about the use of existing drugs in new ways—including in pregnant patients to treat cancer and infectious diseases such as COVID-19. OWH also provides a public listing of active pregnancy exposure registries to bring awareness of opportunities to participate in research for pregnant individuals who may be taking medications or received a vaccine.

Across the Atlantic

In Europe, the public-private partnership Innovative Medicines Initiative established the Continuum of Evidence from Pregnancy Exposures, Reproductive Toxicology, and Breastfeeding to Improve Outcomes Now (ConcePTION) program in 2019, which recognizes that decision-making is extremely challenging for health care providers and pregnant or breastfeeding women needing medicines to treat serious illness. The initiative estimates that as few as five percent of available medications have been adequately monitored, tested, and labeled with safety information for use in this population. Moreover, they found that European product labeling lacks clear information to inform decision-making and often simply notes pregnancy as a contraindication, leading to risk avoidance that results in women choosing not to use a treatment. ConcePTION has called for more data, in part by improving and unifying existing approaches to traditional pregnancy registries, and is approaching the information gaps as an ecosystem issue that must also address societal and ethical issues and sustainability in addition to data, evidence generation, and evidence dissemination.

In 2020 the European Medicines Agency (EMA) highlighted their intent to foster clinical trial innovations that meet the needs of all patients, including neglected populations such as pregnant women, as one of the core recommendations in their five-year strategic plan. EMA also recently released draft guidance aimed at strengthening pharmacovigilance, including risk management and considerations for pregnant and breastfeeding women within the applicable structures and processes already in place for pharmacovigilance overall.

Cooperative Outreach

Despite these recent efforts around the world, there’s more to do. FDA experts from the Office of Global Policy and Strategy’s Europe Office and the FDA’s medical product centers, along with international colleagues at the EMA and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA), coauthored the journal article “Assuring Access to Safe Medicines in Pregnancy and Breastfeeding,” which was published online in the journal Clinical Pharmacology & Therapeutics in February 2021. The article puts forth a united call-to-action for how medical researchers should approach pregnant and breastfeeding women when conducting clinical trials and goes on to outline opportunities for change in the nonclinical, clinical, and post-marketing collection and use of data.

As for COVID-19, the International Coalition of Medicines Regulatory Authorities hosted a pregnancy and lactation workshop in February 2021, led by the FDA, EMA, MHRA, and others. The meeting supported international collaboration and explored how experiences with providing COVID-19 therapies and vaccines to pregnant and breastfeeding women can be leveraged to support a global strategy for collecting systemic data for this patient population. It was another example of how leadership in the international regulatory community is primed for moving the science forward to the benefit of patients and providers.

Next Steps

A major paradigm shift is necessary from the systemic exclusion to the inclusion of pregnant and breastfeeding women in clinical studies. This is essential to ensure the availability of information that is critical for informed decision-making when patients who are pregnant or breastfeeding an infant need medicines. Developing a roadmap for change, through international cooperation and harmonization, will take much care, consideration, and communication between all stakeholders. Despite persistent challenges, there is strong interest from the international regulatory community to continue the momentum in this important area of women’s health. The FDA intends to display leadership in such efforts with women, health care professionals, industry, and public health experts. We hope to be met with enthusiastic engagement by partners around the globe.