7

A Path Toward Inclusion

PROGRESS TOWARD IMPLEMENTING THE PRGLAC TASK FORCE RECOMMENDATIONS

Diana Bianchi, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, provided additional background on the work of the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC Task Force) and an update on progress toward implementing the PRGLAC Task Force recommendations.¹ The task force, led by the National Institute of Child Health and Human Development (NICHD), included members representing National Institutes of Health (NIH) institutes, the Centers for Disease Control and Prevention (CDC), the U.S. Food and Drug Administration (FDA), the Agency for Healthcare Research and Quality, the Health Resources and Services Administration, the U.S. Department of Health and Human Services (HHS), the Department of Veterans Affairs, multiple professional societies, industry, academia, and nonprofit organizations. In 2018 the PRGLAC Task Force issued its 15-recommendation report and in 2020 the PRGLAC Task Force issued guidance on implementing those recommendations. Bianchi said that, although the PRGLAC Task Force charter has now expired, implementation of the recommendations remains “a very high priority” for NICHD.

The mantra of the PRGLAC Task Force, Bianchi said, is “to protect pregnant [and lactating] people through research instead of from research.” A theme across the task force’s recommendations is the need to “change the existing culture that has limited scientific knowledge of therapeutic product safety, effectiveness, and dosing for pregnant and lactating people.” She highlighted several key recommendations including recommendations to remove pregnant persons as a vulnerable population under the Common Rule; expand the workforce of clinicians and researchers with expertise in obstetric and lactation pharmacology and therapeutics; remove the regulatory barriers; and referring participants to the PRGLAC Task Force website for the full set of recommendations and the implementation report.²

Implementation of PRGLAC Task Force Recommendations

Bianchi reviewed the progress made thus far in implementing the PRGLAC Task Force recommendations (summarized in Box 7-1). Recommendations 1, 2, 9, and 11 address different actions needed to ensure that pregnant and lactating persons are included in high-quality, timely clinical

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¹ For a full list of the PRGLAC Task Force recommendations, see https://www.nichd.nih.gov/sites/default/files/2018-09/PRGLAC_Report.pdf (accessed September 12, 2022).

² See https://www.nichd.nih.gov/about/advisory/PRGLAC (accessed September 6, 2022).

research, including studies of products for conditions specific to pregnant and lactating persons. One of the largest and most well-funded programs addressing the underrepresentation of pregnant persons in clinical trials is the Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub.³ The MPRINT Hub “serves as a national resource for expertise in maternal and pediatric therapeutics to conduct and foster therapeutics-focused research in obstetrics, lactation, and pediatrics, while enhancing inclusion of people with disabilities,” Bianchi said. The MPRINT Hub includes a knowledge core (with regulatory science, drug development, and other expertise) and two centers of excellence, one at the University of California San Diego, which is studying the effects of maternal antibiotics on breast milk and infant outcomes, and another at Vanderbilt University, which is studying maternal and pediatric precision therapeutics and neonatal opioid withdrawal syndrome. Another action, Bianchi said, in addressing these recommendations are studies of the efficacy of antiviral drugs to treat pregnant persons with COVID-19 that are under way by the Maternal Fetal Medicines Unit (MFMU) Network.⁴

Actions undertaken to expand the clinical research workforce with obstetric and lactation expertise (recommendation 3) include NICHD training and career development awards for research on pregnant and lactating persons, and educational resources, including webinars, that are available through the MPRINT Hub.

To address recommendation 7 regarding liability concerns, NICHD will sponsor a congressionally mandated study to be undertaken by a National Academies consensus committee to develop a framework for addressing liability issues associated with research that includes pregnant or lactating persons. She pointed out that this workshop also includes discussions of liability issues as called for in recommendation 7.

Recommendation 10, calling for the implementation of “a proactive approach to protocol development and study design to include pregnant women and lactating women in clinical research,” has resulted in several initiatives. As mentioned, the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) network⁵ is studying the efficacy of antiviral treatments for COVID-19 (e.g., remdesivir) in pregnant persons. MFMU has completed the study, Tranexamic Acid (TXA) for the Prevention of Obstetrical Hemorrhage after Cesarean Delivery.⁶ NICHD has partnered with the Bill & Melinda Gates Foundation to study the efficacy

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³ See https://mprint.org (accessed September 6, 2022).

⁴ See https://www.nichd.nih.gov/research/supported/mfmu (accessed September 12, 2022).

⁵ See https://www.impaactnetwork.org (accessed October 25, 2022).

⁶ See https://clinicaltrials.gov/ct2/show/NCT03364491 (accessed September 12, 2022).

of a single oral dose of azithromycin during labor in reducing maternal and infant infection and death in low- and middle-income countries.⁷ Bianchi added that NICHD also has open grant solicitations on translational research in maternal and pediatric pharmacology and therapeutics.⁸

Finally, there are a number of actions being taken to address recommendation 12, which calls for using and improving existing resources for data relevant to research in pregnant and lactating persons. Bianchi said that the Office of the Secretary’s Patient-Centered Outcomes Research Trust Fund (OS-PCORTF) has funded several projects on using electronic health record (EHR) infrastructure and data for research on maternal health and pregnancy.⁹ Another activity is the NICHD Data and Specimen Hub (DASH),¹⁰ which is a centralized resource for sharing deidentified data and requesting biospecimens (including breastmilk) from NICHD-funded clinical studies.

Opportunities for Future Action

Bianchi discussed additional areas covered by the PRGLAC Task Force recommendations and the implementation plan for which action is still needed. With regard to removing regulatory barriers (recommendation 4), pregnant persons were removed as an example of a vulnerable population in the Common Rule in 2019; however, harmonization of FDA regulations with the Common Rule is still needed. Other areas in need of action (which Bianchi noted are generally outside the purview of NICHD) include creating evidence-based communication strategies to raise public, patient, and provider awareness about clinical research with pregnant and lactating persons (recommendations 5 and 6); developing separate programs to study therapeutic products used off-patent in pregnant and lactating people, using the NIH Best Pharmaceuticals for Children Act as a model (recommendation 8); and optimizing registries for pregnancy and lactation” (recommendation 13). She noted that pregnant and lactating persons are taking medications, but data are not being collected and a large-scale registry is needed. The EU ConcePTION project, a private-public partnership, which captures data on medication use by pregnant persons across the EU, navigating multiple languages and data systems, is an example of such a large-scale registry (Thurin et al., 2022)

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⁷ See https://clinicaltrials.gov/ct2/show/NCT03871491 (accessed September 12, 2022).

⁸ See https://grants.nih.gov/grants/guide/pa-files/PAR-20-300.html (accessed September 12, 2022).

⁹ See https://aspe.hhs.gov/collaborations-committees-advisory-groups/os-pcortf/explore-portfolio (accessed September 12, 2022).

¹⁰ See https://dash.nichd.nih.gov (accessed September 12, 2022).

Preparedness for future pandemics is also important, Bianchi said. She referred participants to a commentary in which she and colleagues pointed out that during the height of the COVID-19 pandemic, despite the PRGLAC Task Force recommendations and implementation guidance, “pregnant people were essentially forgotten in terms of including them in the initial vaccine clinical trials” (Bianchi et al., 2021). She also noted that there were few preclinical studies done with pregnant rodents and suggested that all preclinical studies for new vaccines and therapeutics should include pregnant animal models. Epidemics and pandemics will continue to happen, and it is important to plan for the inclusion of pregnant and lactating persons in trials of vaccines and therapeutics for pandemic diseases.

“There are 200 million pregnant women per year in the world, and [of] the medications that they’re taking…about 5 percent of them have been studied specifically for use in pregnancy” (Adam et al., 2011), Bianchi said. She emphasized that “pregnant people need to be treated exactly the same as nonpregnant people. They don’t need to be excluded; they need to be thoughtfully included.” She encouraged stakeholders to be proactive and to work together to change the research culture and advocate for the inclusion of pregnant and lactating persons in clinical trials.

PATHWAYS FORWARD

The inclusion of pregnant people in research is both a public health issue and reproductive justice issue, Leslie Meltzer Henry, University of Maryland Carey School of Law, said. Legal concerns can be addressed, and lawyers knowledgeable in this area can advise stakeholders on developing creative risk management strategies that can help enable these studies, and she mentioned several opportunities to address obstacles. Regulatory revisions are needed to address ambiguities, including some inconsistencies between FDA and HHS regulations. There has been some progress and she mentioned the removal of pregnant persons as a vulnerable population in the Common Rule. Regulatory guidance is needed to help researchers make more inclusive decisions across the clinical trial continuum, and Henry noted that FDA is moving new guidances forward. However, she said

She also highlighted the need for more research and education on liability issues, and studies of the practicality of different injury compensation strategies. There is also the opportunity to implement legal

and/or financial incentives to promote the conduct of studies that include pregnant and lactating persons. As examples, Henry mentioned existing incentives designed to increase research on products for rare diseases and tropical diseases.

Changes on the horizon also have the potential to affect the inclusion of pregnant and lactating persons in clinical trials, including the forthcoming Supreme Court decision on Dobbs v. Jackson Women’s Health Organization and changes to state laws. Henry said that, if Roe v. Wade and Casey v. Planned Parenthood are overturned by Dobbs, there will be “significant implications for the status of the fetus” which will affect civil and criminal laws.¹¹

Lynne Yao, FDA, emphasized the importance of recognizing that “the health of a child begins with the health of the mother.” She discussed that statutory requirements and incentives associated with the Pediatric Research Equity Act and BPCA, respectively, have been successful in advancing the development and labeling of drugs for use in pediatric populations (see Chapter 3). However, the data needed for pregnancy and lactation are different, and she noted that drugs approved for use by adults of reproductive potential are generally also approved for use in pregnancy unless specifically contraindicated. It is important to keep the differences between studying drugs for use in children and studying drugs for use by pregnant or lactating persons in mind when considering legislative solutions. What worked for pediatric studies might not be the best solution for studies with pregnant or lactating persons. Yao emphasized the need for “careful consideration and collaboration with stakeholders in moving forward with any legislative efforts.”

Kathryn Schubert, Society of Women’s Health Research, agreed with others about the need to shift the research culture toward inclusion as the expectation, and about the need to evaluate what solutions are possible, particularly within the current political climate. She emphasized the importance of engaging all stakeholders across the clinical trial continuum, including researchers, clinicians, sponsors, regulators, and especially patients. The infrastructure for studies that include pregnant and lactating persons exists, and she said that there is a role for patient advocacy groups in raising awareness among researchers, clinicians, and pregnant and lactating persons about the need for these studies.

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¹¹ One week after this workshop, on June 24, 2022, the U.S. Supreme Court issued a decision in Dobbs overturning the Roe v. Wade and Casey v. Planned Parenthood decisions. The workshop discussions took place in the context of the anticipated decision based on the leaked draft opinion by Justice Samuel Alito.

CLOSING REMARKS

Ruth Faden, workshop cochair, observed that, over the course of the workshop, there was both disappointment that there has been attention to these issues for so long and yet the progress made seems minimal, as well as optimism that the presentations showed how much work is ongoing, and that change is on the horizon. This is “both a glass half full and as glass half empty story,” she said. Although there have been intensive efforts in recent years to increase the inclusion of pregnant and lactating persons in clinical trials, pregnant and lactating persons were still excluded from the initial COVID-19 vaccine clinical trials. Nevertheless, many groups have come together in recent years around the crucial need to improve representation of pregnant and lactating persons in clinical trials, including NIH, FDA, industry, clinicians, academic researchers, the National Academies, and pregnant and lactating persons themselves. It is time for this collective body “to make that next big push,” she concluded.

Shirley Sylvester, workshop cochair, reminded workshop participants that the issues discussed at the workshop will be the subject of a forthcoming National Academies consensus study which will make practical recommendations for addressing the barriers that are impeding the inclusion of pregnant and lactating persons in clinical studies. She emphasized the importance of ensuring that the voices of all stakeholders are represented in the National Academies committee’s work.

In closing, Sylvester reiterated the recurring theme across the workshop discussions of “protect[ing] pregnant and lactating people through research and not from research.”

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