Advancing Clinical Research with Pregnant and Lactating Populations: Overcoming Real and Perceived Liability Risks (2024)

6

Recommendations

Based on the information provided through public testimony and our own research and deliberations, the committee makes nine recommendations to improve the responsible and ethical inclusion of pregnant and lactating women in clinical research while mitigating the risk of legal liability. These recommendations take three interconnected approaches to reducing liability risks associated with including pregnant and lactating women in clinical research—and to aligning perceptions of the liability of including these populations in clinical research with the evidence. The first entails strategies that directly mitigate liability; the second is through minimizing potential harm to research participants and thereby reducing the grounds for liability; and the third aims to allay the concerns that discourage researchers and sponsors from including pregnant and lactating women in clinical research which, as elaborated in Chapter 5, are factors that are weighed alongside the potential for liability. These three strategies are interconnected, as mitigating liability and reducing potential harm will also improve and address perceptions of liability. The committee’s nine recommendations attend to the interests and concerns of the multiple stakeholders and decision makers involved along the medical product development pathway.

In some ways, the goals of the recommendations overlap. This redundancy is intentional. The recommendations addressed to the authority that existing entities have allows them to act in a timely fashion to implement the proposals. These steps can be expanded when, as the committee recommends, Congress passes legislation that can enhance existing

powers and provide greater accountability for the stakeholders involved, but the committee recognizes that enacting such changes can take time. As noted in Chapter 1, it is critical that research involving pregnant and lactating women be started promptly, with the understanding that further changes will need to address all the challenges to conducting such research. Therefore, while achieving the safe and ethical inclusion of pregnant and lactating women in clinical research while mitigating liability risks is the unifying goal of this report, the recommendations are written so each one can stand alone and contribute to overcoming the barriers to the inclusion of pregnant and lactating women in clinical research.

PROVIDE GREATER REGULATORY CLARITY

Clear guidance from the U.S. Food and Drug Administration (FDA) can provide a pathway for critical stakeholders directly engaged in clinical research (e.g., sponsors, clinical investigators, and institutional review boards [IRBs]) to enhance the conduct of research with pregnant and lactating women that minimizes the risk of harm that may be anticipated by that research. By minimizing potential harm, this guidance also mitigates potential liability associated with that harm. While compliance with regulatory requirements does not necessarily preclude a finding of negligence or other failure to behave responsibly, compliance with those requirements may be an important consideration in determining whether a failure of duty did or did not occur (American Law Institute, 2023). Regulatory clarity and consistency are paramount to medical product sponsors and may influence decisions to pursue any particular type of research, including studies involving pregnant and lactating women (Seiguer and Smith, 2005).

In addition to compromising the reassurance regarding liability that sponsors and investigators may achieve by adhering to FDA’s regulatory expectations, uncertainty can also prolong the time and increase the costs of research and development and ultimately delay product approval (Hoerr, 2011; Stern, 2017). Predictable outcomes are important to research investors and funders (Hoerr, 2011; Seiguer and Smith, 2005), who aim for a speedy regulatory approval of their product in order to capitalize on patent exclusivity before the market opens to competitors.

In the absence of clear guidance from regulators, research sponsors may try to mitigate the risk of regulatory delays and rejections by avoiding the conduct of studies with pregnant and lactating women. As exemplified throughout this report, the avoidance of clinical research with pregnant and lactating women has resulted in insufficient evidence on the safety, efficacy, and dosage of the medical products being used by pregnant and lactating women. FDA guidance on how to appropriately

conduct studies with pregnant and lactating women, including the timing of those studies, would help sponsors understand and account for the expected practices that can minimize harm. FDA guidance on the appropriate conduct of real-world evidence studies and other observational research would also help to improve sponsors’ understanding of FDA expectations.

As noted in Box 3-2, as part of the PDUFA VII Commitments, FDA plans to update its framework and guidance on pregnancy postmarketing requirements and commitments. These ongoing efforts by FDA are an important step to clarifying guidance for noninterventional studies involving pregnant women. In regard to the timing of studies that include pregnant and lactating women, FDA may consider whether certain conditions, such as the development of a treatment or vaccine in response to a pandemic, merits inclusion of pregnant and lactating women earlier in the product development pathway. However, the committee emphasizes that the approval of a medical product for the general population is not to be contingent on the completion of clinical studies in pregnant and lactating women.

The federal government has long acknowledged the need to improve the diversity of clinical research (NASEM, 2022). With the passage of the National Institutes of Health (NIH) Revitalization Act in 1993, Congress affirmed that federally sponsored research needed to improve its inclusion of women and racially and ethnically minority populations, who had long been historically excluded and disproportionately underrepresented in clinical research. Congress renewed its commitment to the inclusion of more diverse populations in clinical research through the requirement for medical products sponsors to develop diversity action plans, enacted in the Food and Drug Omnibus Reform Act (FDORA).^1,2 The legislation gives FDA the authority to require diversity action plans from sponsors, which are intended to detail the sponsors diversity goals and

___________________

¹ Food and Drug Omnibus Reform Act (FDORA), (2023).

² Consolidated Appropriations Act, (2023).

strategies for achieving the identified goals. FDORA also requires FDA to develop guidance on the content and format of diversity action plans and includes pregnant and lactating women as groups that may be relevant to include in the plans. As of the start of 2024, FDA is still in the process of developing its guidance and has yet to publicly release draft guidance on the implementation of diversity action plans.

Including pregnant and lactating women as categories in diversity action plans would ensure that sponsors consider these populations at the beginning of the clinical development process. Although this only applies to new medical products in development and not products with FDA approval, this helps start the process of conducting research with these populations. Furthermore, conversations between sponsors and FDA regarding plans to include pregnant and lactating women in clinical studies would promote information exchange about appropriate study designs and safeguards. Requiring the early consideration for the safe inclusion of pregnant and lactating women may reduce the potential for legal liability by promoting intentional and thoughtful planning that aims to reduce harm to study participants.

Likewise, the availability of preclinical data from development and reproductive toxicology (DART) studies can help sponsors, in coordination with FDA, to identify and minimize potential safety risks before pregnant or lactating women are exposed to medical products. It is essential that DART studies be conducted as early as can feasibly be done to generate preclinical data capable of guiding decisions regarding clinical studies with pregnant and lactating women. If DART studies reveal a potential safety signal, it may be appropriate for FDA to request that the sponsor conduct additional toxicology studies to further evaluate the signal.

Furthermore, it is critical that as more research studies involving pregnant and lactating women are conducted, that there is diverse representation within those populations. As the 2022 National Academies report Improving Representation in Clinical Trials and Research found, there has been progress with the representation of White women in clinical research; however, progress has largely stalled in attaining racial and ethnic diversity in clinical research. The lack of racial and ethnic diversity compounds health disparities and inequities, hinders innovation, reduces already low accrual rates, and undermines public trust (NASEM, 2022).

These disparities are particularly pronounced in pregnant populations, with Black and American Indian and Alaskan Native (AIAN) populations having pregnancy-mortality rates that are about three and two times higher, respectively, when compared to White women (Hill et al., 2022). Because of systemic and structural factors, disparities also exist for lactating individuals, with rates of breastfeeding initiation significantly lower for non-Hispanic Black populations and AIAN individuals compared to overall breastfeeding rates (CDC, 2023). Therefore, it is crucial

to consider the inclusion of pregnant and lactating women as part of an intersectional diversity action plan that is reflective of the populations disproportionately burdened by the disease process in question and the entire population in which the medical product may eventually be used.

IRBs serve as the gateway to human subject research, and the ability to conduct research that includes pregnant and lactating women is incumbent on the willingness of IRB members to approve such research.

Unfortunately, many IRB members lack the training or guidance to assess the risks and benefits of research with pregnant and lactating women (Blehar et al., 2013; Lyerly et al., 2008; Saenz et al., 2017; van der Zande et al., 2016). Because of IRBs’ lack of familiarity with research proposals that include pregnant and lactating women, they may be unable or unwilling even to consider approving such a proposal (Saenz et al., 2017). Furthermore, IRBs vary widely in their interpretation of title 45 of the Code of Federal Regulations, part 46, which codifies protections of the rights and welfare of human participants in research, as discussed in Chapter 3. Specifically IRBs may have different interpretations in regard to what “minimal risk” entails in Subpart B of the regulations, which provides additional protections for pregnant women, human fetuses, and neonates (White et al., 2021). IRBs may also vary in whether breastfeeding children of lactating research participants are considered research participants (HHS et al., 2022). If children of lactating research participants are also considered research participants, then Subpart D of the regulations would apply, which provides additional protections for children.

The Office for Human Research Protections (OHRP) has not issued guidance on pregnant and lactating women as research subjects, including guidance for IRBs on interpreting Subpart B nor on the applicability of Subpart D to these populations. In practice, the lack of regulatory clarity often results in conservative interpretations by decision makers that discourage conducting research with pregnant women (Blehar et al., 2013; Mastroianni et al., 2017).

The denial of proposals for research involving pregnant and lactating women further erodes the opportunities for researchers to pursue work in this area and leads to a lack of knowledge, funding, and ultimately, a lack of a trained workforce with expertise in these areas. The current system creates a vicious cycle that undermines the development of knowledge and innovation for the care of pregnant and lactating women.

There are many stakeholders that play a role in educating and promoting research with pregnant and lactating women, including research institutions, professional organizations, educational providers, and community-based nonprofit organizations. The list includes, but is not limited to the following:

• Academy of Breastfeeding Medicine
• American Academy of Pediatrics
• American College of Clinical Pharmacy
• American College of Obstetricians and Gynecologists
• American Society of Health System Pharmacists
• Association of Women’s Health, Obstetric and Neonatal Nurses
• Collaborative Institutional Training Initiative

• Liaison Committee on Medical Education
• Public Responsibility in Medicine and Research
• Society for Maternal–Fetal Medicine
• Society for Women’s Health Research

These groups can provide education and training for IRB staff and committee members, research faculty, and professional and graduate students. For example, the American College of Obstetricians and Gynecologists has released a committee opinion titled “Ethical Considerations for Including Women as Research Participants” that includes a section on risks and benefits, study design, and informed consent within the context of research with pregnant women.

PROVIDE INCENTIVES, FUNDING, AND ACCOUNTABILITY FOR RESEARCH

As described in Chapter 5, legislation passed in the early 2000s has helped to overcome challenges in conducting research in pediatric populations that have similarities to the challenges faced by research with pregnant and lactating women. The committee considered the models for spurring innovation in pediatric populations—the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA)—as well as other policies to incentivize medical product development, and whether similar initiatives might be helpful with pregnant and lactating populations. The BPCA and the PREA serve incentive and requirement functions in increasing pediatric research. The BPCA provides the incentive through a patent extension or provision of public funds for research for products that are off-patent, and the PREA provides the requirement, by establishing a regulatory mandate for sponsors of new products, to collect preclinical and clinical data in pediatric populations. The committee concludes that this coupling of incentives and accountability would likewise spur research in clinical studies on the dosage, efficacy, and safety of drugs, biologics, and vaccines, as well as the efficacy and safety of devices for pregnant and lactating women.

However, the committee acknowledges that while it believes an approach that incorporates an incentive and requirement would be beneficial for driving clinical research in pregnant and lactating women, there are fundamental ethical and regulatory differences between pregnant populations, lactating populations, and pediatric populations that should be acknowledged before applying that approach. First, children are not usually part of the population for the indications that FDA approves as a drug first enters the market. Therefore, to get a pediatric indication, sponsors must submit additional clinical trial data in pediatric populations. However, unlike children, pregnant and lactating women are considered

part of the general adult population for which an adult indication is approved, meaning that for a drug that is approved for general use, it is approved for use in pregnant and lactating women. A prescription for a pregnant or lactating woman of any drug approved for adults, unless it is specifically contraindicated for use in pregnant and lactating women, is considered “on-label” even when there are not data on appropriate dosage and timing, or even on safety and efficacy for such persons.

The committee is not recommending that a separate regulatory category be created for pregnant and lactating women, since that would make the use of most licensed drugs “off-label” for pregnant and lactating women and markedly restrict access for those patients. However, it is important to note that sponsors lack the additional incentive of an expanded indication in conducting clinical studies in pregnant and lactating women that exists with pediatric studies under the PREA and the BCPA. While falling short of a new indication, the Pregnancy and Lactation Labeling Rule (PLLR), finalized by FDA in 2014, requires sponsors to include a descriptive summary of data relevant to pregnancy and lactation on the product label (Appendix D).³ However, nearly a decade after the implementation of the PLLR, there has been little to no increase in the number of products that have collected human data on pregnancy and lactation when compared to products approved prior to PLLR implementation (Byrne et al., 2020). This makes other incentives such as extended exclusivities all the more valuable in the context of the pregnant and lactating population.

Another key difference is that children are defined as persons who have “not attained the legal age for consent to treatments or procedures involved in clinical investigations.” The purpose of using the BPCA and the PREA as a model is not, in any way, to suggest that pregnant and lactating women are a vulnerable population or to suggest that they are not capable of providing consent. Instead, several of the factors that contribute to the lack of clinical research in pregnant and lactating women bear similarities to the challenges faced in spurring clinical research for pediatric populations. Lessons learned from pediatrics show that incentives and accountability measures work and may be similarly effective in spurring medical research for pregnant and lactating women.

The committee acknowledges that experience with the BPCA and the PREA reveals limitations within those frameworks and that there are challenges with the BPCA and the PREA that are likely to also occur in pregnant and lactating women. These include the long wait times for studies conducted under the PREA to be completed, resource challenges for FDA to review all letters of interest from sponsors under the BPCA, and delays

___________________

³ Appendix D can be viewed online at https://nap.nationalacademies.org/catalog/27595.

in translating clinical data collected into labeling changes. Evidence from pediatrics and other areas where postmarketing studies are required also reveals that studies initiated after product approval is received are slower or less likely to be completed (Hwang et al., 2018; Shahzad et al., 2023). Nonetheless, since their enactment in 2002 and 2003, the BPCA and the PREA have led to the labeling of over 1,000 products with pediatric-specific information (FDA, 2022). Labeling changes of that magnitude could make a tremendous difference in reducing uncertainty and potential harm for pregnant and lactating women using medical products.

Despite certain limitations and key differences between pediatric and pregnant and lactating populations, the BPCA and the PREA do serve as useful models for the type of legislation that would provide FDA with the necessary authority to impose requirements for additional study with pregnant and lactating women while also providing incentives needed to stimulate additional research with pregnant and lactating women.

The data generated through clinical studies conducted under the BPCA and the PREA have promoted the health of children who now have access to medical products supported by high-quality evidence. Were Congress to enact programs to increase the development of evidence for the care and treatment of pregnant and lactating women modeled on the BPCA and the PREA, the health of pregnant and lactating women and their fetuses and children would be promoted in a similar way as when Congress prioritized the health of children over 2 decades ago.

Incentives Modeled on the BPCA

The case law data presented in Appendix B and described in Chapter 2 of this report indicate that, based on reported cases, there is limited liability in clinical trials for pregnant women and virtually no liability for lactating women. The case law data indicate that sponsors may actually face considerably more risk of liability for harms related to pregnant women’s use of FDA-regulated products once the product has been approved and is available in the open market. While sponsors are required to submit to FDA postmarketing safety reports and may be subject to postmarketing requirements or commitments—which may be fulfilled through a pregnancy registry,^4,5 there is little indication that sponsors wish to conduct the trials that might indicate future risks once a drug is already on the market.

Chapter 5 explores other factors that might contribute to the reluctance to include pregnant and lactating women in research. One such factor is that

___________________

⁴ Postmarketing reporting of adverse drug experiences, 21 CFR 314.80.

⁵ Postmarketing reporting of adverse experiences, 21 CFR 600.80.

there is little to no financial incentive for sponsors to conduct this research, and there are no requirements to do this research outside of occasional postmarketing requirements imposed by FDA when there is a known serious risk or available data indicate the potential for a serious risk. Providing concrete financial incentives for sponsors is an important mechanism to tip the scales in favor of conducting research in pregnant and lactating women, particularly as sponsors weigh the financial risk of a potential increase in liability for greater use of their product postapproval in pregnant women. As with the pediatric experience, a financial incentive may encourage sponsors to take what would otherwise be costly and potentially unprofitable steps to begin research with pregnant and lactating women.

There is virtually no incentive for product sponsors to conduct additional research once a drug is off-patent, as their limited profits would not offset the costs of such research. Here too, the BPCA provides a useful model for stimulating studies with pregnant and lactating women. Instead of incentivizing sponsors to conduct research in this context, the BPCA provides public funds to aid and incentivize clinical researchers and their institutions to do the needed research. Under the BPCA, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has developed a process for prioritizing medical products to be studied with public funding (FDA, n.d.). In response to the PRGLAC Implementation Plan recommendations 8B and 9A, NICHD has begun the process of identifying priorities for medical products to investigate similar to the approach under the BPCA (NIH, 2023d; PRGLAC Task Force, 2020). Also modeled on the BPCA approach, NICHD has released a request for nominations to identify priority medical products to address knowledge gaps (NIH, 2023d). NICHD plans to appoint a committee of external experts to evaluate the nominations and develop a preliminary priority list, which will be refined in a stakeholder meeting.

In addition, the BPCA requires that the data from those studies be submitted to the U.S. Department of Health and Human Services (HHS) and FDA for review, be made available in the public domain, and if appropriate, FDA will negotiate with the holder of the relevant applications for a label change. An incentive and funding mechanism similar to the BPCA, which was codified through amendments to the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act,⁶ can make decisions to include pregnant and lactating women in clinical research more appealing to sponsors, investigators, and research institutions.

The committee acknowledges that incentives for the pharmaceutical industry, such as extended market exclusivity or tax breaks, are not

___________________

⁶ Best Pharmaceutical for Children Act, P.L. 107-109, (Jan. 4, 2000).

without cost for patients or for the U.S. taxpayer, owing to the high-cost of brand-name prescription drugs (Kesselheim, 2017). Further, longer patent extensions, such as the 7-year extension offered through the Orphan Drug Act, have been criticized for the high prices of orphan drugs and their potential to threaten insurance premiums (ICER, 2022). Additionally, the Orphan Drug Act has led to overuse of the “orphan drug” classification to maximize profits, while preventing more cost-effective therapeutics from entering the market (GAO, 2018; ICER, 2022). Incentives can be designed with appropriate guardrails in place to make them more effective.

While the committee does not have the appropriate expertise to determine the most appropriate incentive for industry, lawmakers could consider a sliding scale for exclusivity depending on the information gathered (e.g., fewer months of exclusivity for pharmacokinetic/pharmacodynamic (PK/PD) studies and longer exclusivity for larger well-controlled studies of safety and efficacy, or a longer period of exclusivity for medical products most likely to be used by pregnant and lactating women, and a shorter period for those with less anticipated use by these populations). Similarly, it may be appropriate for Congress to consider providing more generous incentives for products developed for conditions specific to pregnancy or lactation. In considering the priority of medical products to be studied and eligible for incentives, it will be important for the director of NIH and the FDA commissioner to consider the public health needs for the medical product; availability of information concerning the dosage, safety, and effectiveness of the medical product in pregnant and lactating women; whether additional information is needed; and whether new studies in pregnant and lactating women may have therapeutic value.

Accountability Modeled on the PREA

In 1998, FDA published its Final Rule requiring sponsors of drugs and biologics to conduct studies in pediatric populations, but a federal court found that FDA did not have the authority to require pediatric studies in 2002 (FDA, 2016). Subsequently, Congress passed the PREA to grant FDA this authority by amending the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act. Under the PREA, FDA can require drug sponsors to conduct studies and clinical trials when a drug is deemed “relevant” to pediatric populations. The goal of the PREA is to protect pediatric patients from risks to them that might not have been revealed as part of the premarket review for a drug that was developed for an adult population, as well as to develop pediatric dosing. The PREA does not apply to on-market drugs and biologics and is therefore only required for drugs and biologics under development. FDA authority could be expanded to compel the same requirements to conduct clinical studies for pregnant and lactating women.

Although FDA has authority to encourage study and clinical trials with pregnant and lactating women, it can only require such studies and trials

Because pregnant and lactating women are rarely studied as part of premarket review, many risks to pregnant and lactating women are unknown when the drug enters the market. Like pediatric populations before the PREA was enacted, this leaves pregnant and lactating women unprotected and uninformed until signals are detected through postmarketing surveillance, effectively experimenting on pregnant and lactating women at the population level.

In considering the potential for unintended consequences for requiring sponsors to conduct clinical studies in pregnant and lactating women, the committee recognizes that there are two scenarios in which it may be appropriate to defer or waive such a requirement. First, if a medical product is ready for approval in the general adult population and the sponsor demonstrates that studies in pregnant and lactating women are being conducted or will be conducted with due diligence and at the earliest possible times, it may be appropriate for FDA to grant a deferral to the sponsor. Second, if the sponsor presents evidence that strongly asserts that the medical product would be unsafe or of no therapeutic value in pregnant and lactating women, FDA could grant a waiver, and the evidence presented by the sponsor would need to be included in the product label.

The committee notes that recommendation 5 is related to, but independent of recommendation 1. Whereas FDA has the authority to develop guidance to communicate its expectations and current thinking—as the committee calls for in recommendation 1—a federal district court has previously ruled that FDA does not have the authority to require clinical studies in a specific population⁸—which is the subject of recommendation 5. The implementation of recommendation 1 would enable FDA to provide sponsors with information on how studies with pregnant and lactating women are to be conducted but stops short of requiring those studies to be completed. Recommendation 5 thus tasks Congress with granting

___________________

⁷ Postmarketing studies and clinical trials-implementation of Section 505(o)(3) of Federal Food, Drug, and Cosmetic Act, FDCA 505(o)(3)(B), (Oct. 25, 2019).

⁸ Association of American Physicians and Surgeons, INC v. FDA, 226 F.Supp.2d 204 (D.D.C., 2002).

FDA the authority to require certain clinical studies be conducted with pregnant and lactating women.

Provide NIH Funding for Research

Research that includes pregnant and lactating women has been avoided or deprioritized along the medical product development pathway. As the largest supporter of biomedical research, NIH has a responsibility to encourage and stimulate research in these populations. There is a need to increase basic knowledge of how pregnancy and lactation affect how the body handles and responds to drugs to guide and support future research, and to fund and facilitate research that includes pregnant and lactating women when appropriate. NIH could play a particularly important role in funding research in pregnant and lactating women for

off-patent products, given the lack of incentives for sponsors discussed earlier in this chapter. Research on pregnancy, childbirth, and lactation receives only a small portion of overall NIH funding (NIH, 2023b).

Despite high rates of maternal and infant morbidity and mortality in the United States, funding for research in this area has historically been low in both the United States (Smith, 2023) and the United Kingdom (Manningham-Buller and Brocklehurst, 2022). Implicit in the two recommendations in this section is that NIH will need to reevaluate its funding priorities and potentially increase its budget requests to provide clinical research with pregnant and lactating women the necessary attention. While greater efforts are needed, the committee acknowledges that NIH has begun to take important actions in this area, including several research networks (see Box 5-1).

In addition to these NIH initiatives, other federal agencies, including the Agency for Healthcare Research and Quality, Centers for Disease Control and Prevention (CDC), Health Resources and Services Administration, and FDA (PRGLAC Task Force, 2018), are carrying out activities to develop essential knowledge, expertise, and capacity in research that involves pregnant and lactating women, but they are only beginning to touch the surface of the needed research for these populations. Greater systemic and sustained support and investment are needed. NIH sets the clinical research agenda, and without leadership, emphasis, and prioritization from NIH, research with pregnant and lactating women will not be prioritized and the status quo—a dearth of knowledge about the effects of most drugs on pregnant and lactating women—will remain unchanged.

The NIH Common Fund presents an opportunity to systematically engage the many institutes and centers within NIH to address a high-priority challenge, such as the paucity of clinical research including pregnant and lactating women (NIH, 2023c). Common Fund programs are designed to harness the resources and expertise across NIH’s institutes and centers to respond to NIH priorities that have an opportunity to have a broad impact. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) supports the most NIH grants for research related to pregnancy and lactation of all NIH’s institutes and centers (NICHD, 2018). The creation of an NIH Common Fund program for pregnancy and lactation research would distribute responsibility for supporting this research across NIH’s institutes and centers. However, Common Fund programs are time bound and intended to achieve specific goals within a 10-year period. Therefore, NIH-wide efforts to kick-start clinical research in pregnant and lactating women through the Common Fund would need to be coupled with sustainable research initiatives.

Expanding existing NIH networks can promote sustained infrastructure to conduct research in pregnant and lactating women to answer

key priority research questions by developing institutional capacity at diverse research sites. As described in Boxes 3-3 and 5-1, establishment of the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network has benefited research on human immunodeficiency virus (HIV) treatment during pregnancy and lactation. Other research networks that NICHD supports contribute to research on various conditions experienced by pregnant and lactating women and involve collaborations with other NIH institutes and centers.

Collaboration through research networks comprising diverse populations and geographic sites promotes a greater effect and generalizability of scientific discoveries, innovative thinking, mentorship of early-career researchers, and the development of research capacity and sustained infrastructure (Disis and Slattery, 2010; Jones et al., 2008; Luke et al., 2016; Snowden et al., 2018). Mentorship and research capacity are particularly important factors to the safe inclusion of pregnant and lactating women in clinical research, therefore mitigating the potential for liability. Expansion of existing NIH networks for pregnancy and lactation research is necessary to accommodate the need and demand for highly qualified researchers and research institutions. Consideration of the ability of future network sites to recruit and retain diverse research participants is important to consider.

A primary concern that has stalled the inclusion of pregnant and lactating women in clinical research is the fear that the research may cause harm in the research participant or in their fetus or infant (Frew et al., 2014). Notably, when harms occur among pregnant and lactating women, people of color and those of lower socioeconomic status lacking resources

to pursue a legal remedy are often left with no recourse and no compensation. There is no nationwide requirement or mechanism to compensate research participants who are harmed by their participation in a research study (Henry et al., 2015). The National Vaccine Injury Compensation Program (VICP), discussed in Chapter 4, provides compensation for injured individuals and incentivizes companies to develop and distribute vaccines by providing an alternate route for potential liability claims through a no-fault system (Winter et al., 2021). However, the VICP only covers certain vaccines recommended by CDC.

Although research institutions may have their own policies to compensate individuals with research-related injuries, it is not common practice (Resnik et al., 2014). Researchers and staff at a research university that undertakes research with pregnant women identified the availability of a university mechanism to compensate individuals for research-related injuries as an important contributor to the university’s successful research portfolio in pregnant women (Mastroianni et al., 2020). Moreover, the university’s compensation program may contribute to the low number of research-related lawsuits and tort claims faced by the university.

While the United States does not require the provision of no-fault compensation for research-related injuries, many other countries do (Pike, 2012). Given the shortcomings of the American tort system detailed in Chapter 2, it may be challenging for research participants who are harmed in clinical research to obtain any compensation. A clinical trial insurance plan purchased by an investigator, research institution, or sponsor could be a solution to provide modest compensation for research-related injuries. An insurance policy that covers no-fault compensation enables those harmed by participation in clinical research to receive compensation up to a certain limit for immediate medical expenses without resorting to the tort system (Medmarc, 2022).

Because acquiring clinical trial insurance imposes an additional cost to the study, it would be appropriate for NIH to cover the cost of clinical trial insurance for NIH-funded research involving pregnant and lactating women, which is within its authority (Henry et al., 2015). While the cost of policies for studies including pregnant and lactating women may be expensive at first, owing to scant actuarial data for these populations, the committee finds that the cost of coverage is likely to moderate over time as the uncertainty of insurance underwriters decreases. Moreover, clinical trial insurance would incentivize sponsors and investigators to minimize harm as the price of an insurance policy is likely to decrease if proper safeguards are in place and the investigator and research institution can demonstrate a consistent record of safety (Pike, 2012).

IMPROVE EXISTING DATA AND SAFETY MONITORING

Given the exclusion of pregnant women from clinical trials, most of the in-human safety data related to the use of products by pregnant and lactating women are now generated through postmarketing observational studies (Roque Pereira et al., 2022; Stock and Norman, 2019). Conducting more clinical trials with pregnant and lactating women will not lessen the need to expand the collection and analysis of real-world data to enrich the basic safety and efficacy profile built through clinical trials. Real-world data collected through observational studies are important for detecting rare adverse events and understanding the long-term safety profile of medical products, but the current system of real-world data capture and analysis needs substantial improvement before it can play a major role in increasing knowledge about the effects of medical products in pregnant and lactating women.

FDA has developed draft guidance for industry on postapproval pregnancy safety studies, which provides considerations on the design, use, and analysis of pregnancy exposure registries and complementary databases (FDA, 2019), which is covered in Chapter 3. FDA has also pledged to make improvements to the collection of real-world safety data in pregnancy through the development of a framework and demonstration projects in its Prescription Drug User Fee Act (PDUFA) VII commitments (FDA, 2023). Internationally, Europe’s ConcePTION project, funded through the Innovative Medicines Initiative (IMI), is working to enhance and expand capabilities in collecting and analyzing observational data (IMI, 2023). IMI ConcePTION’s efforts include improving interoperability of data systems, defining core data elements, constructing work-flows for data analysis, and optimizing data linkages between parents and offspring. While there are notable differences between the electronic health data infrastructure of European countries and the United States, many of the lessons from IMI ConcePTION may still be applicable as the United States aims to achieve similar goals.

Existing pregnancy exposure registries are often specific to a product or condition, requiring potential participants or their providers to search for relevant registries. Although FDA maintains a list of pregnancy exposure registries on its website, that list has limited search capabilities and is not complete. Registries are listed only at the request

of the registry sponsor or investigator. A central repository of interoperable pregnancy exposure registries could facilitate enrollment by making registries more accessible for pregnant individuals, clinicians, and researchers. Including the results of complementary database studies in the central repository would also be a useful mechanism to provide pregnant individuals, clinicians, and researchers with information regarding the safety of medical products in pregnancy and during breastfeeding. An important first step in designing such a repository would be to make it an interoperable, searchable resource for clinicians, investigators, or potential participants.

Sponsors conducting pregnancy exposure registries as part of a postmarketing commitment must submit annual status reports to FDA, and registries not conducted under postmarketing commitments are still encouraged to submit such reports (FDA, 2002). Ideally, the repository would be constructed to capture data submitted through these annual status reports. The usefulness of a repository would be greatly increased if it also included summary information from postmarketing adverse event reports that are required to be submitted to FDA.^9,10 While some of these adverse event data are likely to be captured by the FDA Adverse Event Reporting System (FAERS) and Vaccine Adverse Event Report System (VAERS), collecting such information in a single repository focused on pregnancy and lactation would likely improve accessibility for pregnant and lactating women and their health care providers. The repository would benefit from being designed with end users in mind. For example, the repository could have prepopulated submission categories with information requested in FDA’s “Guidance for Industry on Establishing Pregnancy Exposure Registries,” and dropdown menu selections, where relevant. Additionally, nonproprietary information in the status report for each registry that would be useful to be made public in the repository includes:

• Number of pregnant women enrolled to date,
• Number of pregnancies with unknown outcomes,
• Number of pregnancies with outcome pending,
• Number of pregnancies lost to follow-up, and
• Number and type of adverse events reported.

Unlike pregnancy, there are very few lactation registries that exist worldwide. A few product-specific registries exist; however, there is no

___________________

⁹ Postmarketing reporting of adverse drug experiences, 21 CFR 314.80.

¹⁰ Postmarketing reporting of adverse experiences, 21 CFR 600.80.

comprehensive prospective lactation registry. Such a prospective lactation registry, collecting data on maternal medication consumption and adverse events in the child, would be a critical data repository to increase the information on medication safety during lactation. The LactMed database administered by NICHD collects published data on medications and chemicals to which lactating mothers may be exposed, with information on human milk transfer, and concentrations and adverse events in the nursing child (NIH, 2023a).

Most postapproval programs for lactation are focused on developing biobank capacity and preclinical modeling. This is likely because lactation studies generally require the collection of human milk to determine how much of a medication the child is exposed to, which makes the lactation studies interventional and not observational (Covington, 2018). To collect more data on medication use during lactation, NICHD is funding a multicenter study focused on conducting population-based PK studies during lactation for a variety of already approved medications that the lactating parent is already receiving for therapeutic reasons (Pediatric Trials Network, 2023).

The electronic health data that are used to conduct complementary database studies are fragmented across different platforms and health care systems (Reisman, 2017; Turbow et al., 2021). Such fragmentation makes it difficult to share data and to construct large datasets that would enable more robust analyses with greater statistical power. Another challenge is a lack of common data elements that are important to capture relevant to the safety of medical products for pregnant individuals and their fetuses (Richardson et al., 2023). For example, health records often do not collect information about breastfeeding practices, complicating research into the outcomes for breastfeeding children given the inability to determine exposure.¹¹ A lack of data linkage between the pregnant individual and their offspring is another barrier to conducting database studies in pregnant women (Whitmore et al., 2021).

The linkage of parental and offspring electronic health records is vital to understanding fetal and infant outcomes related to exposure to medical products in utero. Yet, creation of these linkages is a challenge for real-world data studies conducted in the United States and may be particularly difficult when using Medicaid data (Johnson et al., 2013). FDA’s Sentinel Initiative added mother–child linkages to its database in 2018, beginning originally with data from private insurers and expanding to include Medicaid data in the last few years. Of the live births in their database, approximately 80 percent have mother–child linkages (Maro, 2023).

___________________

¹¹ As presented to the committee by Christina Chambers in open session on June 15, 2023.

Further attention to addressing these limitations may improve the feasibility of conducting real-world data studies with pregnant and lactating women.

PROTECT RESEARCH PARTICIPANTS’ PRIVACY

The committee’s review of litigation did not reveal any legal liability exposure related to an injured child’s claim based on a parents’ participation in clinical research while the child was in utero. Many states have

some level of parent–child immunity. There are a few atypical cases, however, that have recognized a potential claim by a child against a mother whose negligence caused damages in utero (Clayton, 1994), one of which is a case against a mother who took medication while pregnant that claimed she failed to exercise “reasonable parental discretion.”¹² A number of states also have broad child abuse statutes that might be interpreted to expose a mother to liability because of medications taken while pregnant. Following the U.S. Supreme Court decision in Dobbs v. Jackson Women’s Health Organization, overturning its previous rulings that the U.S. Constitution protected the right to an abortion, research participants may be exposed to new legal liability depending on state laws and local enforcement. Charges of civil or criminal liability could be brought against research participants that experience a spontaneous abortion or seek an elective abortion. Furthermore, an individual’s right to privacy is not necessarily “absolute; rather, it is a conditional right which may be infringed upon a showing of proper governmental interest.”¹³

Certificates of Confidentiality

Certificates of confidentiality (CoCs) provide an opportunity to protect against the potential for legal liability, especially following the Dobbs decision, should the privacy of research participants be breached.

A CoC can help achieve the research objectives and promote participation in studies by safeguarding the confidentiality of subjects’ information by protecting researchers and institutions from being compelled to disclose information that would identify research subjects. CoCs help reassure participants that their data are safe and protected from disclosure or use in legal proceedings. Such protection may be particularly necessary in states with laws that could criminalize or hold liable a pregnant individual should their fetus be harmed in the course of clinical research.

___________________

¹² Grodin v. Grodin, 301 N.W.2d 869, (Mich. App. 1981).

¹³ Planned Parenthood of Southern Arizona v. Lawall, 307 783 (9th Circuit 2002).

REFERENCES