1
Introduction1
Approximately 4 million pregnant people in the United States give birth annually, and 70 percent of these individuals take at least one prescription medication during their pregnancy.2 Yet, due to a number of historical, ethical, legal, scientific, and societal issues, including public reaction to past events, such as the widely publicized case in which thalidomide used during pregnancy was determined to cause severe congenital disabilities in children, pregnant and lactating persons are often excluded from clinical trials (Blehar et al., 2013). As a result, pregnant and lactating persons and their health care providers often have to make treatment decisions without an adequate understanding of the benefits and risks to themselves and their developing or newborn baby (Mastroianni et al., 2017).
To address the lack of safety and effectiveness information on medications used by pregnant and lactating persons, the 21st Century Cures Act established a Task Force on Research Specific to Pregnant Women and
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1 This workshop was organized by an independent planning committee whose role was limited to identification of topics and speakers. This Proceedings of a Workshop was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not endorsed or verified by the National Academies of Sciences, Engineering, and Medicine, and they should not be construed as reflecting any group consensus.
2 See https://www.cdc.gov/pregnancy/meds/treatingfortwo/research.html (accessed September 13, 2022).
Lactating Women (PRGLAC Task Force) to advise the Secretary of Health and Human Services (HHS). The PRGLAC Task Force developed several recommendations, including the need to “reduce liability to facilitate an evidence base for new therapeutic products that may be used by women.” At the time, the PRGLAC Task Force was not in a position to address tort reform and liability issues, so it proposed that the National Academies of Sciences, Engineering, and Medicine (the National Academies) convene a group of experts to “develop a framework for addressing liability issues when planning or conducting research with pregnant and lactating women.”3 Subsequently, the Consolidated Appropriations Act of 2022 provided funding for the National Institute of Child Health and Human Development (NICHD) to sponsor a National Academies consensus study on this topic.4
As a primer for the study, the National Academies’ Forum on Drug Discovery, Development, and Translation convened a public workshop on June 16 and 17, 2022, for stakeholders to examine the current state of evidence generation for drug products used by pregnant and lactating persons and discuss barriers and opportunities for including these populations in clinical trials.5 The agenda for this workshop was developed by an independent planning committee to address the established task (Box 1-1).
Ruth Faden, founding director of the Johns Hopkins Berman Institute of Bioethics, Philip Franklin Wagley Professor of Biomedical Ethics at Johns Hopkins University (JHU), and workshop cochair, acknowledged the limitations of covering this topic in a day and a half-long workshop. In particular, she explained that it is not possible to fully consider implications for both pregnant and lactating persons, which are distinct populations and have different interests and needs with regard to clinical trials. In addition, there are differences in the clinical development and regulation of small molecule drugs versus biological medical interventions including vaccines that could only be touched on in the allotted time.
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3 See the Report Implementation Plan of the Task Force on Research Specific to Pregnant Women and Lactating Women at https://www.nichd.nih.gov/sites/default/files/inline-files/PRGLAC_Implement_Plan_083120.pdf (accessed September 6, 2022).
4 Consolidated Appropriations Act, 2022, Public Law 117-103, 117th Cong. (March 15, 2022).
5 For the purposes of this workshop, the term drug is used as defined by the U.S. Food and Drug Administration (FDA) and is inclusive of biologics.
BACKGROUND
Efforts to Improve Sex and Gender Equity in Health Research
Faden stated that the National Academies has been working to improve sex and gender equity in health research for nearly 3 decades, and she highlighted three key studies as examples. The 1994 consensus report, Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, made recommendations to improve representation of the health interests of women in the national research agenda and in clinical trials, including recommendations specific to pregnant persons (IOM, 1994). She added that, while some of the report recommendations were implemented, there was no action taken on any of the recommendations specific to addressing the insufficient evidence for the medi-
cal treatment of pregnant individuals. In 2010, the National Academies report, Women’s Health Research: Progress, Pitfalls, and Promise, found that progress had been made toward improving sex and gender equity in health research for select diseases (IOM, 2010). However, progress for many conditions remained limited, and research on the health needs of pregnant persons was lacking. In early 2022, the National Academies report, Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups, concluded that pregnant and lactating persons continue to be excluded from clinical trials, which Faden said, “continues to impede the generalizability of clinical trial data and undermines the ability of pregnant and lactating persons to receive evidence-based health care” (NASEM, 2022).
There have been initiatives in the United States and worldwide to narrow the evidence gap caused by the exclusion of pregnant and lactating persons in trials. For example, the Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Project,6 which is led by a multi-institutional research team and funded by the U.S. National Institutes of Health, has developed guidance to enhance access and respect for pregnant persons participating in HIV research. The Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) project, which was funded by the Wellcome Trust, has worked to develop guidance for the “ethically responsible, socially just, and respectful inclusion of the interests of pregnant women in the development and deployment of vaccines against emerging pathogens.”7
The PRGLAC Task Force was established in 2016 under the 21st Century Cures Act and charged with providing advice and guidance to the federal government on “activities related to identifying and addressing gaps in knowledge and research regarding safe and effective therapies for pregnant and lactating persons” (HHS, 2017). The PRGLAC Task Force issued recommendations in 2018 and an implementation plan in 2020.8
Despite these and many other efforts, overall progress to address gaps in evidence on the use of medicines in pregnant and lactating persons has been insufficient, Faden summarized. The negative health consequences of this evidence gap were laid bare during the COVID-19 pandemic. The exclusion of pregnant and lactating persons from COVID-19 vaccine clinical trials resulted in delayed access to the vaccines after emergency use authorization was granted, as clinicians lacked data on the safety and effectiveness of the vaccine for these populations to guide prescrib-
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6 See http://www.hivpregnancyethics.org (accessed October 10, 2022).
7 See https://bioethics.jhu.edu/wp-content/uploads/2022/06/PREVENT-Web.pdf (accessed September 12, 2022).
8 Discussed further in Chapter 7. See https://www.nichd.nih.gov/about/advisory/PRGLAC (accessed September 6, 2022).
ing. Faden pointed out that pregnant people have been shown to be at elevated risk of severe COVID-19 disease, making the exclusion of this population from vaccine development “unjustifiable.” Lack of evidence on the safety and efficacy of drugs for pregnant and lactating persons also impedes public health policy decision-making. The goal of inclusion, Faden emphasized, should be to develop an evidence base for pregnant and lactating persons that is comparable to the evidence base for adults who are not pregnant or lactating. This could be accomplished by the appropriate representation of patient populations in clinical trials and a commitment to implement a national research agenda that meets the health interests of people who are pregnant or lactating, she said.
Ethical Principles That Support Inclusion
Maggie Little, senior research scholar and professor of philosophy at the Georgetown University Kennedy Institute of Ethics, discussed ways in which the exclusion of pregnant and lactating persons from clinical trials violates the specific moral principles that are the foundation of clinical research. The clinical research enterprise is committed to “protecting the safety of those who use drug products by first assessing them under carefully controlled and regulated conditions of a clinical research trial,” she said. The exclusion of pregnant and lactating persons from these studies does not protect them from risk. It only relocates the risk from the controlled research setting to the clinical setting in which products are prescribed without a sufficient evidence base to an even larger population of pregnant and lactating persons (Mastroianni et al., 2017).
Providers are reluctant to prescribe, and national guidelines are reluctant to endorse, the use of next-generation drugs in pregnant and lactating persons without an adequate evidence base. This impedes equitable access to life-saving products as pregnant and lactating persons are often not treated or are treated with older medications. Little noted that “cultural anxiety” about protecting the fetus leads to the default practice of not administering drugs, leaving both the pregnant person and fetus to instead incur the risks of an underlying maternal disease or the risk of acquiring a disease. Further, when pregnant and lactating persons are included in clinical research, studies may only track fetal and/or newborn outcomes and not clinical outcomes specific to the pregnant or lactating person enrolled in the trial (Krubiner et al., 2016). Little pointed out that pregnant and lactating persons are not simply “vessels” for the fetus or the newborn child, so clinical outcomes for both the pregnant person and the fetus should be included in trials. Overall, “the lack of evidence base critically impedes equitable access of pregnant women and lactating women to the medicines that they and their children need,” she summarized.
Evolving Toward Fair Inclusion
Little has observed that in recent years there have been three conceptual shifts in the thinking of whether pregnant and lactating individuals should be included in clinical trials.
One key conceptual shift is the move away from categorizing pregnant and lactating persons as a “vulnerable population” for the purposes of clinical research. At the time of the workshop, the U.S. Food and Drug Administration (FDA) regulations considered pregnant people to be a vulnerable population,9 a classification that also includes children, prisoners, people with disabilities, and economically or educationally disadvantaged persons. Federal regulations on human subject protection describe vulnerable populations as subjects that are “likely to be vulnerable to coercion or undue influence.”10 The perception is often that it is “morally impermissible or anathema” to conduct research in a vulnerable population, Little said. However, while an individual pregnant or lactating person might be vulnerable as a population, there is nothing about being pregnant or lactating that affects the ability of an individual to make valid and informed decisions about consenting to participate in research. Rather, pregnant and lactating persons are a “morally and scientifically complex population” that warrants special protections, she said, and guidances and regulations are beginning to reflect this shift in thinking. For example, as of 2018, the Common Rule (Federal Policy for the Protection of Human Subjects, 45 CFR 46 Subpart A—Basic HHS Policy for Protection of Human Research Subjects) no longer includes pregnant persons as an example of the populations considered to be vulnerable in the context of clinical trial participation.
A second conceptual shift has been the moving away from the concept of protecting pregnant and lactating people from research and toward the concept of protecting these populations through research (i.e., as discussed above, the absence of evidence puts these populations at greater risk in practice). This shift in thinking reflects a similar conceptual shift that took place regarding the ethics of research with pediatric populations nearly 30 years ago (Levine, 1995), and is now being advocated for research with pregnant and lactating persons.
A third emerging shift in thinking is the movement from a position of presumed exclusion of pregnant/lactating persons from trials to a concept of fair inclusion in trials. Little described presumed exclusion as a default position, which was not based on moral principles, rather in reaction to
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9 After the workshop, FDA released a Proposed Rule that would remove pregnant people as a vulnerable population. See 87 FR 58733 (September 28, 2022).
10 45 CFR 46, Protection of Human Subjects.
historical events, such as the thalidomide crisis. Further, because funders of research usually require justification to include pregnant and lactating persons in a study and no justification is needed for exclusion, it is easier to presumptively exclude these populations, she said. In contrast, fair inclusion would mean that all trials should be reviewed to determine if pregnant and/or lactating persons are eligible for inclusion per regulations, which Little noted are generally permissible of including these populations; otherwise, there should be a specific rationale for excluding them.
Applying Lessons from Studies That Have Included Pregnant and Lactating Persons
As mentioned by Faden, there are examples of studies that have successfully included pregnant and lactating persons. The PHASES project focused on improving the evidence base for pregnant persons in the context of HIV and coinfections, and Little discussed ways of applying lessons learned to improve the evidence base for treatment of pregnant and lactating persons in the context of other diseases.11 The HIV research community was an early adopter of including pregnant women in clinical research in an effort to decrease vertical transmission of the virus from pregnant person to child. Little described how a working group conducted consultations across countries and contexts and disciplines, including with people living with HIV, to learn about study designs that would be appropriate and acceptable for pregnant and lactating persons. The PHASES working group made recommendations on a range of topics that could address barriers to inclusion, such as building the capacity of researchers to conduct research with pregnant and lactating persons, finding a company willing to provide trial insurance, working with institutional review boards (IRBs) and funders to promote or incentivize inclusion, and enhancing post-approval safety assessment. Little added that innovative methods for gathering post-approval safety data are needed because the baseline rate of congenital disabilities is 3 percent (CDC, 2019), and a large population is needed for a safety assessment to identify the potential elevated risk to the pregnant person or the fetus, though the sample size needed would depend on the risk of a particular congenital disability occurring.
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11 The PHASES guidance is available at http://www.hivpregnancyethics.org (accessed September 6, 2022).
ORGANIZATION OF THE PROCEEDINGS
This Proceedings of a Workshop summarizes the presentations and discussions that took place during the public workshop held on June 16 and 17, 2022. The workshop included interactive breakout group discussions that were facilitated both in person at the workshop in Washington, DC, and remotely via Zoom for online participants.
Chapter 2 provides an overview of how workshop participants grapple with the evidence gaps in clinical knowledge and their effect on pregnant and lactating persons and the clinicians who care for them. Pregnant and lactating persons shared their perspectives directly, both in person and via recorded video testimony. Chapter 3 reviews how the current legal environment affects the inclusion of pregnant and lactating persons in clinical trials, including stakeholder perspectives on regulatory, liability, and approaches to mitigating liability risks. In Chapter 4, researchers discuss lessons learned from two case examples of attempts to conduct clinical studies with pregnant and lactating persons, and it considers opportunities to apply these lessons to bolster evidence generation across therapeutic areas. Chapter 5 discusses several barriers and practical solutions to including pregnant and lactating persons in clinical trials, as discussed by various workshop participants. Chapter 6 presents innovative approaches to generating robust evidence on the safety and effectiveness of drug products for use by pregnant and lactating persons. The final chapter, Chapter 7, highlights progress thus far in implementing the PRGLAC Task Force recommendations and participant thoughts on the path forward, including closing remarks for the workshop.
