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

5

Dissuasive and Persuasive Factors for the Inclusion of Pregnant and Lactating Women in Clinical Research

In response to its statement of task, the committee focused on exploring how the real and perceived risks of legal liability can be reduced in order to encourage the individuals and organizations that are involved in the development, testing, oversight, approval, and marketing of medications and vaccines to include pregnant and lactating women in clinical research. If a sponsor or other stakeholder considers conducting studies with pregnant and lactating women, it evaluates the reasons for and against doing the research, incorporating considerations related to uncertainties and assessments of legal liability exposure; potential reputational losses; and financial, technical, and practical considerations associated with the complexity of the trial, among others. For pharmaceutical companies in particular, factors that enter into the decision-making process include the state of the science concerning the disease or condition, pathway, and the investigational product; the unmet medical need; the cost and complexity of the laboratory, preclinical, and clinical research; when and whether the company will be able to recoup its costs; the competitive landscape; and regulatory requirements.¹ Companies may also weigh the decision to conduct research with pregnant and lactating women with whether data on safety and efficacy could be collected in animal models or through postmarketing studies, such as pregnancy registries.

If the considerations against doing the research outweigh those in favor of doing the research—for example, because of unpredictable

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¹ As presented to the committee by Kirke Weaver in open session on June 16, 2023.

liability exposure, uncertain financial return, and ambiguity in regulatory requirements—the sponsor and others are likely to decide not to include pregnant and lactating women in research. Thus, decisions to pursue research involving pregnant and lactating women are influenced by perceptions of liability that are inextricably intertwined with other factors that have contributed to the exclusion of pregnant and lactating women from clinical research. For example, a decision about the appropriate selection of participants is only one step in the product’s research and development process, and potential liability is only one factor—and not necessarily the decisive one—in deciding whether to conduct research with pregnant and lactating women. Importantly, changing one or more factors could offset and overcome potential liability concerns, and addressing interrelated factors together could affect how a stakeholder views liability in the decision to do research with pregnant and lactating women.

Because of the interconnected relationship between liability and other such factors, and because factors that enter into decisions to include pregnant and lactating women in research are sometimes termed liabilities even though they involve no legal risk, this chapter presents the committee’s consideration of several factors that can affect liability assessments and contribute to stakeholder decision making concerning the inclusion of pregnant and lactating women in research.

FACTORS THAT DISSUADE SPONSORS AND INVESTIGATORS FROM INCLUDING PREGNANT AND LACTATING WOMEN IN RESEARCH

The factors that dissuade the various stakeholders in the development and use of medical products from including pregnant and lactating women in clinical research affect the entire pathway of medical product development, from preclinical studies to postapproval surveillance. This chapter explores these dissuasive factors, which include the following:

• Culture of exclusion
• Recruiting and enrolling patients
• Lack of expertise in research involving pregnant and lactating women
• Reputational risk
• Cost and complexity
• Lack of financial incentives

As noted above, these factors interact with the potential for legal liability; they also interact with one another and other factors that are perceived as potentially persuasive factors. For example, a lack of financial incentives to conduct a trial with pregnant and lactating women is worsened by the potentially high costs of conducting such a trial, including the

sponsor’s coverage of potential liability. The financial considerations make it less likely that these trials will be conducted, thus contributing to the problem of a dearth of expertise in research involving pregnant and lactating women. Many of these factors overlap and affect one another; any mitigation strategies must take these relationships into account.

Culture of Exclusion

Pregnant and lactating women have historically been excluded from research; this is one of the most entrenched barriers to conducting research on pregnant and lactating women and has become a cultural mindset (Little and Wickremsinhe, 2017; Trahan et al., 2021; White et al., 2021). Gender bias has deep social roots that extend far beyond medicine, but there is no question that its effects are still felt in medicine. Women were systematically excluded from health professions in the nineteenth century, mirroring their exclusion in many other businesses and professions (Starr, 1982). This underrepresentation resulted in an underfunding of research related to women’s health (Mirin, 2021).

By the mid-twentieth century, medical research became centered on the notion of the male norm (Cotton, 1990). This meant that between World War II and 1994, most clinical research focused on men (usually White men). Some of this point of view was sociological, an adoption of male perspective viewing the female physiology as the deviant (IOM, 1994). Some of this point of view was expedient; female sex presents a more complicated medical model. The physiological changes associated with the menstrual cycle add significant variation to testing a drug or other treatment. And females, at least until menopause (which is associated with its own hormonal variability), can become pregnant. Paradoxically, although female variation was a recognized challenge in research, it was generally assumed that women would respond similarly to men once drugs were on the market (IOM, 2001; Liu and Mager, 2016).

The thalidomide and diethylstibestrol (DES) experiences furthered the idea that women of childbearing age and pregnant women should be excluded from trials even though those events were not the result of clinical trials. In fact, it is likely that had clinical trials for thalidomide and DES applied modern study design, these trials would have significantly minimized the damage by revealing that thalidomide was teratogenic and that DES was ineffective for use in pregnancy (see Chapter 2).² Revelations of abuses in human research led to calls for additional protections, especially

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² Although DES was also teratogenic and caused harm in the female offspring of those who took DES while pregnant, those harms likely would not have been uncovered by an appropriately conducted clinical trial because of the long-term follow-up that would be needed to identify the adverse event.

for vulnerable populations. Subsequently, the U.S. Food and Drug Administration (FDA) adopted guidance in 1997 that advised against including women of childbearing potential in Phase I and Phase II clinical studies (FDA, 1997). In excluding women with the potential to become pregnant, the focus was on the protection of not just an existing fetus, but on the protection of a potential fetus.

Only 2 years later, the Belmont Report recommended that the principle of justice guide the fair inclusion of research participants (HEW, 1979), and in 1994, an Institute of Medicine committee directly recommended that pregnant and lactating women not be excluded from clinical studies (IOM, 1994). However, the recommendations focused on pregnant and lactating women from the IOM report were largely not translated into law, policy, or practice. Instead, a culture of fetal protection surrounded the question of women’s participation.

In the late 1980s, the National Institutes of Health (NIH) began to encourage the inclusion of women and minorities in clinical research. The NIH Revitalization Act of 1993 (Public Law 103-43) required the inclusion of women of childbearing age and minorities in federally funded clinical studies. However, as mentioned in Chapter 1, while there has been a growing recognition of the need to include pregnant and lactating women in clinical trials in recent years—such as through the Task Force on Research Specific to Pregnant Women and Lactating Women—the long-standing culture of an exclusion mindset persists, preventing the generation of needed evidence to support medical treatments for pregnant and lactating women.

This lack of evidence generation applies to both understanding the safety and efficacy of approved products in pregnant and lactating women, as well as a lack of development of medical products for conditions specific to pregnancy and lactation. For example, pregnant women were paradoxically excluded from the initial COVID-19 vaccine trials, despite evidence that pregnant women were at risk for more severe complications and at greater risk of death (Rubin, 2021), which also placed their fetuses at risk. The exclusion from trials, and the higher risk of severe outcomes from COVID-19 infection, made it challenging for patients and their providers to make informed decisions about vaccination (Minkoff and Ecker, 2021; Riley, 2021).

In addition to the historical precedent of exclusion, there are several cultural mindsets that contribute to the culture of exclusion: the “fetus-first” mentality, the precautionary principle, and an underappreciation of the benefits of inclusion. In the fetus-first mentality, the life and well-being of the fetus is prioritized over the life and well-being of the pregnant woman (Milne, 2020). With the 2023 Supreme Court decision in Dobbs v. Jackson Women’s Health Organization holding that each state

may determine how to balance the rights of the fetus against the rights of the pregnant woman, some states have moved to adopt “fetal personhood” laws, in which a pregnant woman can be held criminally liable for the injury or death of the fetus (Carpenter, 2023). These laws could target pregnant women who take medications that have the potential to cause fetal harm, whether in the course of regular treatment or in a clinical trial (Carpenter, 2023). These laws—and the associated mentality—further the culture of exclusion, affect the behavior of health care providers, and impede research on women’s health generally (Paltrow, 2022).

A second factor that contributes to the culture of exclusion is the precautionary principle and how it is often applied in the context of pregnant women. The precautionary principle, commonly associated with environmental hazards, reverses the burden of proof by requiring that an intervention or action be proven safe before it is implemented (Kukla, 2016). When applied to research in pregnant women, this principle is often understood to mean that pregnant women should be entirely excluded from clinical research because of the risk of fetal harm (Lyerly et al., 2008). This interpretation has been incorporated into both policy and practice, resulting in the routine and systematic exclusion of pregnant and lactating women from research (Kukla 2016). For example, Subpart B of the HHS regulations requires research involving pregnant women that does not confer either a direct benefit to the pregnant woman or the fetus to involve no more than “minimal risk.”

Although the policy does allow for pregnant women to be enrolled in research that confers more than “minimal risk” if it offers the potential for direct clinical benefit to the pregnant woman or the fetus, in practice, many institutional review boards (IRBs) interpret this policy conservatively, resulting in the exclusion of pregnant women from clinical research, as discussed later in this chapter. However, the exclusion of pregnant and lactating women does not serve to eliminate risks of harm to this population; in fact, exclusion itself presents risks of harm owing to the lack of evidence on safe and effective treatments for pregnant and lactating women.

Much attention has been given to the potential harms of including pregnant and lactating women in research, but there has been less conversation and deliberation about the benefits of inclusion; this lack of appreciation for the benefits of inclusion is another factor that drives the culture of exclusion. Without fully appreciating the benefits of research for the health and well-being of pregnant and lactating women and their offspring, and without recognizing the interconnected nature of the health of pregnant and lactating women and their offspring or the harms to those populations from untreated or inadequately treated medical conditions

resulting from pregnant and lactating women’s exclusion from research, decision-making stakeholders—including IRBs, research institutions, clinicians, and potential research participants—may view research as too risky an endeavor. Yet, pregnant women may choose, and indeed do choose, to enroll in clinical research for a variety of perceived benefits. These include close monitoring from research staff, early access to a new medical product, the potential for better outcomes for themselves and their fetuses, and the ability to help individuals who may be in similar situations as them in the future (Kenyon et al., 2006; Meshaka et al., 2017; Smyth et al., 2012).

Recruiting and Enrolling Participants

The reasons pregnant women participate in clinical trials are the same reasons that people generally participate in trials: aspirational benefits and altruism (van der Zande, 2018). Despite this, recruiting and enrolling participants in clinical research is challenging and many of the factors that may be challenging for enrollment in clinical trials can be heightened during pregnancy or while caring for a newborn or child. Pregnancy and early parenthood can be stressful—particularly if a medical issue arises—and being confronted with a decision about participation in a trial can further complicate an already stressful set of circumstances (Kenyon et al., 2006; Manningham-Buller and Brocklehurst, 2022). Clinicians—who often serve as the gatekeepers to clinical research—may be unaware of potential studies or unwilling to refer their patients to studies (Frew et al., 2014; van der Zande et al., 2016). If patients are aware of investigational studies, they are likely to have concerns about the safety of participation for themselves and their fetus or baby, as well as questions about possible benefits (NASEM, 2023; Rodger et al., 2003). Pregnant and lactating women often have a strong preference for their own provider and may be hesitant to join a study that requires them to visit a different provider (Frew et al., 2014).

Although not specific to pregnant or lactating participants, transportation, access to the study site, and related expenses can all be significant obstacles for participation, especially for lower-income patients (Frew et al., 2014; NASEM, 2023). Some patients, particularly those from historically marginalized groups, may distrust the research enterprise or the health care system, owing to past harms such as the U.S. Public Health Service Syphilis Study at Tuskegee and the unauthorized use of Henrietta Lacks HeLa cells, as well as current harms of not being believed, in addition to racism and bias experienced while receiving health care or trying to access health care (Frew et al., 2014; Le et al., 2022; NASEM, 2023; Russell et al., 2008). Lactating patients may be hesitant to participate in research because of concerns about disruption of breastfeeding, maintaining their

milk supply, cost constraints related to formula feeding and supplementation, and any potential effect on their babies’ health (Zhao et al., 2018).

Furthermore, traditional pharmacokinetic studies to determine the exposure to a drug usually require serial blood draws over a period of 6–24 hours, which can be disruptive to pregnant and lactating women, particularly for those farther along in their pregnancy or who have multiple young children including the child or children they are breastfeeding (NASEM, 2023). These studies may also require pregnant participants to return to a study site multiple times throughout their pregnancy and postpartum to determine how physiological changes throughout pregnancy affect the pharmacokinetics of medications (Avram, 2020). Finally, pregnant and lactating women may have a job outside the home or caregiving responsibilities that they are unable or unwilling to disrupt in order to participate in a trial (Keitt, 2013; NASEM, 2023).

While beyond the scope of this committee, implementing evidence-based strategies for successfully recruiting participants may require enhanced support for investigators and pregnant and lactating women who wish to conduct or participate in clinical research. Evidence points to several factors that may positively influence pregnant women’s decisions to participate in clinical studies, including ease of transportation and access to research sites, supportive attitudes from family and friends, and studies using community-based methods (Frew et al., 2014). At a minimum, clinical investigators must account for cultural considerations, particularly during the informed consent process, and respect the roles of family members, spiritual leaders, and other community leaders during the decision-making process.

Lack of Expertise in Research Including Pregnant and Lactating Women

There is an absence of relevant expertise among researchers, members of IRBs, institutional leaders, and other stakeholders in conducting clinical research with pregnant and lactating women. There are a number of factors that contribute to this absence of expertise. Because clinical trials have historically excluded pregnant and lactating women, researchers, members of IRBs, institutional leaders, and other stakeholders have generally been unable to gain the knowledge and experience necessary to champion and lead research in this area. Research during pregnancy, childbirth, and lactation in general is underfunded; despite high rates of maternal morbidity and mortality in the United States, funding for research in this area has historically been low (Longo and Jaffe, 2008; NIH, 2023d). As a consequence, there is a limited number of grant opportunities, training, and career development opportunities for researchers working in this area (Longo and Jaffe, 2008).

The limited research funding and opportunities for career advancement coupled with competing financial and clinical demands lead clinical investigators to choose other areas of focus, contributing to a shortage of a trained workforce with the expertise and professional knowledge required to conduct research in pregnant and lactating women (Sadovsky et al., 2018). Compounding the lack of advancement opportunities is the shortage of obstetricians and gynecologists and pediatricians who are trained in the various skills of clinical research (NASEM, 2023), including clinical pharmacology for Phase I studies and research design, and execution and evaluation for Phases II and III. In fact, some residents in obstetrics and gynecology report that research is not promoted during their training or is financially disincentivized (Oakley et al., 2013).

The lack of expertise among researchers both contributes to, and is exacerbated by, the lack of expertise among other stakeholders. For example, many IRB members lack training or guidance in assessing the risks and benefits of research with pregnant and lactating women (Lyerly et al., 2008; Saenz et al., 2017; van der Zande et al., 2016), and they may see few, if any, research proposals that include pregnant and lactating women. One study of IRB members across the United States found that over 67 percent of respondents reported infrequently encountering protocols that included pregnant women (White et al., 2021). As a consequence, they may be unable or unwilling even to consider approving such a proposal (Saenz et al., 2017). Denial of these proposals further erodes the opportunities for researchers to pursue work in this area.

Reputational Risks

Conducting research with pregnant and lactating women carries reputational risks for the companies that develop new medical products and the researchers and institutions that carry out the studies required for licensing. Given that injuries to fetuses and babies have particular emotional valence, these stakeholders may fear adverse consequences for their reputation if pregnant and lactating women or babies are harmed in the course of research, particularly if the research is perceived as exploitative or lacking safeguards. For example, researchers and their institutions have a desire to maintain a positive reputation for ethical research in order to attract future funding. Stakeholders may avoid including pregnant and lactating women in research on new medical products owing to fears of injuries and negative media attention such as that which accompanied the harm to pregnant women and their offspring associated with thalidomide, DES, and doxylamine/dicyclomine/pyridoxine (Bendectin) (Manningham-Buller and Brocklehurst, 2022).

Ironically, these high-profile cases involved products that had been licensed for use without being tested in pregnant women. Thalidomide was prescribed to pregnant individuals to treat nausea, but it was not approved in the United States for this indication owing to a lack of safety data. Later, thalidomide was found to cause severe congenital malformations, notably limb deformities.

Among other uses, DES was prescribed to treat pregnancy complications but was discontinued after a link was discovered between the use of DES and a higher prevalence of cancer in the offspring (see Box 2-1). In contrast, many lawsuits were filed against the company that manufactured Bendectin, which was approved to treat nausea and vomiting during pregnancy, claiming it caused congenital malformations. The cost to defend against these lawsuits exceeded the profit made from the drug (Green, 1996) even though research found no association with the drug and malformations (Willhite, 2005). Nonetheless, the company withdrew Bendectin from the market. Another company reintroduced a similar combination product in 2013.

Cost and Complexity

The clinical research community has historically resisted including women in research owing to concerns that factors such as hormonal differences, menstrual cycles, menopause, and pregnancy would make research more complex, time consuming, and costly (Keitt, 2013; Rothenberg, 1996). While there has been significant progress on the inclusion of women in general in clinical research in recent years, pregnant and lactating women are still routinely excluded in part because of the same concerns about complexity and cost (Rothenberg, 1996; van der Zande et al., 2016). Studying the safety and efficacy of a medical product in pregnant or lactating women most likely would require separate trials, rather than simply including pregnant and lactating women in a trial of the general adult population (van der Zande et al., 2016).

Separate trials are needed for pregnant and lactating women because study enrollment must be large enough to detect differences between treatment and nontreatment groups, meaning that the inclusion of a few pregnant and lactating women in a general trial may not produce sufficient information on the safety and efficacy of the product in these subpopulations. And developing medical products for conditions specific to pregnancy and lactation may require even larger trial populations to gain FDA approval. However, conducting these trials incurs costs in addition to the initial costs of research.

Further, if pregnant and lactating women or other small subpopulations are included in clinical studies, the small numbers of patients may

lead to a false finding of a safety signal or a finding of lack of efficacy simply because the more subpopulations that get analyzed, the higher the chances of a spurious result. This finding could raise questions of the safety of the drug overall and delay approval or prevent approval of a medical product, which would delay or deny access to a potentially effective medical product for populations that could benefit from the product and hinder the sponsor’s ability to recuperate its investment in the development of the product, as discussed in the section that follows. Further, a false finding could cause potential liability postmarketing if the product already has FDA approval.

Pregnancy is a complex biological process, and designing and conducting trials that are capable of detecting safety signals in this population of rare or delayed events may be more challenging; for example, a larger sample size may be required (van der Zande et al., 2016). Pharmacokinetics and pharmacodynamics may change during pregnancy, requiring careful dosing and monitoring (Coppola et al., 2022; Zajicek and Giacoia, 2007). Conducting a trial in this population may require additional infrastructure and training for investigators; for example, measuring outcomes related to pregnancy and the health of the newborn may require years of follow-up monitoring, which requires specific expertise to adequately design and run a long-term trial sufficiently powered to detect rare events, along with the associated personnel and financial resources needed (Dangel et al., 2022).

There are also additional costs and potential delays caused by the challenges of recruiting and enrolling these populations in clinical research, as discussed earlier in the chapter. There may be other needs in the research setting that add costs, such as child care, support for nursing participants, and the equipment necessary to monitor the health of both the adult participant and the fetus or baby. Despite the potential increased costs, it should be noted that for research that is funded by NIH, NIH guidelines on inclusion of women and minorities specifically state that cost is not an acceptable reason for excluding a population from a trial, although these guidelines do not apply to industry-sponsored research or other research not funded by NIH (NIH, 2017). Current NIH R01 grant caps may be too low to support the conduct of adequately powered clinical studies with pregnant women or the follow-up of offspring for prolonged periods.

Lack of Financial Incentives

There are few financial incentives for industry researchers to include pregnant and lactating women in clinical research. The market for drugs specifically targeted at pregnancy-related conditions is small, and drugs

for concurrent conditions (e.g., diabetes, hypertension) are already commonly prescribed to pregnant women despite the lack of information about appropriate dosing and evidence about clinical outcomes in this population (Mastroianni et al., 2017). When a drug is approved for use in the adult population, approval extends to pregnant and lactating women unless explicitly stated otherwise on the product label. Unlike the pediatric market, where additional studies can allow a sponsor to add these patients to the label of a drug previously only licensed for use in adult patients, additional testing is not needed to allow these drugs to be marketed to pregnant and lactating women.

One potential financial benefit for conducting studies with pregnant and lactating women is the advertising privileges that would come with conducting safety and efficacy studies in pregnant and lactating women. This may confer some financial benefit for manufacturers, as they could specifically market the product to these populations, whereas other generics without this information would not have these capabilities. However, the market for a particular product may be too small to be much of a financial incentive for sponsors. Thus, a commercial sponsor can expect little to no return from funding clinical research with pregnant and lactating women. Given the competing demands on limited clinical research budgets, it is not surprising that research companies would not prioritize research with pregnant and lactating women over other studies with the prospect of greater financial returns.

Including pregnant and lactating women in clinical trials may add cost, time, and complexity to the trial, while offering few regulatory or marketing advantages (Mastroianni et al., 2017; van der Zande et al., 2016). Indeed, new risks identified through such inclusion could negatively affect the perceived risk–benefit profile and therefore sales of the drug for the broader population. Further, the inclusion of pregnant and lactating women in a trial opens up the possibility of financial risks if the sponsor must provide compensation for harm suffered by the pregnant and lactating women, the fetus, or baby. Of course, liability may arise if an approved product causes harm in clinical use, but the risk of liability generally rests with the health care provider who prescribed the medication, while a manufacturer who has provided the provider with information about the medication that is accurate and adequate for licensing is protected under the “learned intermediary” defense, as discussed in Chapter 2 (Mastroianni et al., 2017). Even when research is conducted by academic institutions, rather than private industry, the financial calculus for including pregnant and lactating women is similar. To attract industry sponsors for public–private partnerships, academic institutions have a strong incentive to conduct research that aligns with the financial interests of private industry (Mastroianni et al., 2017).

FACTORS THAT INCENTIVIZE THE INCLUSION OF PREGNANT AND LACTATING WOMEN

The effectiveness of various policy strategies for mitigating risk and encouraging research in pregnant and lactating women will differ depending on where a drug is on the product development and approval pathway. From the standpoint of financial incentives and study funding, it is most helpful to focus on three stages of the pathway for medical products: preapproval; on-market, on-patent (postapproval before generic entry); and on-market, off-patent (postapproval after generic entry). The sections that follow cover each of these stages in reverse order to first focus attention on the current backlog of medical products on the market for which no or little data from human trials exist to inform their use in pregnancy or lactation. However, it is crucial that policies to promote clinical research target each of these three stages in a product’s life cycle to prevent the perpetuation of the current backlog and so pregnant and lactating women can have access to new therapeutics in a timely manner.

On-Market, Off-Patent Products

The majority of medications that pregnant women take are off-patent (Palmsten et al., 2015). Drug companies generally rely on the time a drug is on-patent to recoup research costs and make a profit (Grabowski et al., 2015). Once a drug’s patent and exclusivity periods have expired and generics have entered the market, companies generally have no financial incentive to conduct additional research, including with respect to use in pregnant and lactating women. Therefore, funding sources beyond pharmaceutical companies are likely needed to conduct research with pregnant and lactating women for products that are off-patent.

Research Investment

As outlined in Chapter 1, conducting research with pregnant and lactating women provides societal value by reducing health inequities in the United States. Given the lack of financial incentives for medical product manufacturers to conduct research after their patent has expired and the societal value this research provides, research for off-patent products in pregnant and lactating women is ripe for government support. As the nation’s largest funder of clinical research, NIH is the most appropriate source of investment in clinical research in pregnant and lactating women for on-market, off-patent products. NIH has already adopted multiple initiatives to improve clinical research in pregnant and lactating women (Box 5-1). Further, there are precedents for the government funding clinical research through NIH to study off-patent medical products. NIH funding

has been deemed necessary for studying off-patent drugs for use in pediatric populations and for repurposing drugs for new indications.

Similar to conducting research on off-patent medical products for pregnant and lactating women, there are few financial incentives to support drug repurposing for an off-patent drug or to conduct clinical research on off-patent drugs for pediatric use (Austin et al., 2021; Haslund-Krog et al., 2021). Owing to the lack of incentives for drug repurposing, there has been a call to increase government investment, specifically from NIH, to fund the necessary studies to expand a drug’s indications (Sachs et al., 2017). In the case of pediatrics, Congress has already responded with the passage of the Best Pharmaceuticals for Children Act (BPCA). The BPCA created an NIH program to fund studies of off-patent drugs within pediatric populations, which has successfully completed over 45 trials and led to 19 product labeling changes (NIH, 2023a). NIH funding to study off-patent medical products in pregnant and lactating women could support much needed research for these populations.

Public-sector investment in research for pregnant and lactating women can lead to indirect benefits for researchers and research institutions that may address other dissuasive factors discussed above. Owing to the influence of government funding in research, increases in public investment can attract researchers who have an interest in aligning their

research pursuits with the priorities of funders (Whitley et al., 2018). Increased NIH funding in research on pregnant and lactating women and related career development opportunities would signal to researchers across the scientific community that research in this area could offer a financially viable career path, as has been demonstrated with funding for Alzheimer’s research (Katiyar et al., 2021).

Further, consistent evidence demonstrates that government funding for biomedical and clinical research paves the way for future research developments from private industry (NRC, 2011). Publicly funded clinical research can produce generalizable knowledge regarding research processes and techniques that industry can use to inform its own clinical research. Public investment in research is also a valuable mechanism that enables funded researchers to develop skills and capacity that can be translated to future studies funded by industry or other sources (Scherer, 2000).

Conducting federally funded studies with pregnant and lactating women may also function to ease some of the expected challenges of beginning to do research with pregnant and lactating women. Federal agencies beyond NIH, including the Agency for Healthcare Research and Quality (AHRQ), Centers for Disease Control and Prevention (CDC), and Department of Defense (DoD) currently fund and/or conduct clinical research with pregnant and lactating women (PRGLAC, 2018). As federally funded researchers innovate and disseminate approaches to include pregnant and lactating women in clinical research more safely, the entire clinical research ecosystem could benefit from the findings obtained from public investments to conduct further research. For example, after the implementation of the BPCA in 2002, NIH began awarding contracts to individual academic centers to study drug safety and efficacy, and to conduct pharmacokinetic studies (Greenberg et al., 2022). However, pediatric trials are ethically complex, (Laventhal et al., 2012) often underpowered, and require special considerations to conduct the research in a timely and efficient manner. Therefore, after several years, NIH created the Pediatric Trials Network (PTN) to develop a more coordinated, succinct approach to conducting pediatric trials (Greenberg et al., 2022). Lessons learned on conducting pediatric trials through the PTN have informed other pediatric drug networks, such as the Global Pediatric Clinical Trials Network, helping to advance drug development in children. A similar approach may help advance research in pregnant and lactating women.

Institutional Review Board Decision Making

IRBs are an essential ethical pillar to ensuring that clinical research protects participants; a study that includes human participants cannot proceed without IRB approval. Therefore, IRBs must be able to define the

safeguards necessary for including and protecting pregnant and lactating women in clinical research and be able to determine when such research is appropriate and when it is not. IRBs must be empowered to independently assess whether the research protocol complies with all laws and regulations relevant to the protection of human research subjects (Grady, 2015). If research concerns off-patent medical products for pregnant and lactating women, or if in fact research during any stage in the product life cycle is to proceed, IRBs will need additional guidance and capacity specific to pregnancy and lactation.

A common critique of the IRB system is that IRBs have been overburdened with fulfilling regulatory requirements that provide little value in terms of protecting research participants (Fost and Levine, 2007). These critics have argued that these requirements for IRBs have led IRBs to overemphasize protecting the research institution from regulatory sanctions rather than protecting research participants from harm, while at the same time stifling the advancement of research. IRBs have also received criticism for overinterpreting a commitment to justice as protecting participants from harm, and not focusing enough on the societal responsibility to include subgroups who have been understudied and underrepresented in clinical research (Bierer et al., 2020). Even the HHS Secretary’s Advisory Committee on Human Research Protections has acknowledged this failure and in 2021, published a document reconsidering the principle of justice under 45 CFR part 46 (HHS, 2021). To rebalance the priorities of IRBs, they will need guidance on interpreting regulations designed to protect pregnant and lactating women in clinical research.

The 2014 National Academies report Proposed Revisions to the Common Rule for the Protection of Human Subjects in the Behavioral and Social Sciences found that there was little information within the Common Rule or related guidance that would help IRBs assess the risks and benefits of clinical research (NRC, 2014). The report found that ambiguity of the minimal risk standard set forth in the Common Rule contributed to inconsistencies in how IRBs interpreted and applied the regulations. The report recommended revisions to the regulations and guidance on minimal risk to provide greater clarity for IRBs and reduce divergent interpretations. The report also addressed the special populations discussed in the Common Rule, including pregnant women, by recommending improved guidance that helps IRBs distinguish between vulnerabilities in participants’ lives and their vulnerability to research risks. This committee endorses these recommendations and asserts that additional guidance specific to pregnancy and lactation would assist IRBs in making impartial decisions regarding the inclusion of these populations.

However, there are strategies that investigators and institutions can take to facilitate success with IRB approval and strengthen protocols

when conducting clinical research with pregnant women. In a study on factors that facilitate research with pregnant women, Mastroianni et al. found that research with pregnant women was more likely to receive IRB approval when investigators took steps during the study design process to minimize risks for potential pregnant participants and their offspring and when they requested safety data from drug companies and FDA. Further, consulting with IRBs throughout the study design process was helpful in identifying potential risks, strengthening the protocol prior to submission, and navigating IRB rules. Finally, having IRB members with proper expertise in pregnancy and pregnancy research was cited as an important factor in conducting research with pregnant women. This might involve formal IRB training on assessing risks on conducting research with pregnant women or including an obstetrician as an IRB member (Mastroianni et al., 2020).

On-Market, On-Patent Products

The manufacturer of a single-source drug (i.e., one without generic competitors) has a financial interest in maintaining its exclusive marketing position for as long as legally feasible. Exclusivity allows the manufacturer to sell its product without competition from generic or biosimilar products, thereby allowing the patented product manufacturer to set prices as a function of what it thinks the market will bear based on product value, the amount needed to recuperate the financial costs of developing the product (as well as the costs of research for other products in the development pipeline that never make it to market), and its safety and effectiveness profile compared to therapeutic alternatives. Because of the importance that manufacturers place on exclusivity, Congress has previously used exclusivity to incentivize medical product companies to conduct certain studies or to develop certain products. Congress has developed several mechanisms to create incentives through extensions of patent and market and data exclusivity periods, including priority review vouchers, the Orphan Drug Act, and the Best Pharmaceuticals for Children Act (BPCA).

In 2007, Congress authorized FDA to award priority review vouchers to drug companies that had developed drugs and received approval for tropical diseases,³ and subsequently authorized priority review vouchers for drugs to treat rare pediatric diseases and medical countermeasures.^4,5

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³ Priority review to encourage treatments for tropical diseases, 21 U.S.C. 360n. (2013).

⁴ Priority review to encourage treatments for rare pediatric diseases, 21 U.S.C. 360ff. (2013).

⁵ Priority review to encourage treatments for agents that present national security threats, 21 U.S.C. 360bbb-4a. (2016).

Priority review vouchers achieve extended patent exclusivity by allowing drug companies to use the voucher to shorten FDA’s review timeline for a product that they submit for approval in the future, enabling that product earlier market entry with more time remaining on the patent (Kesselheim et al., 2015). However, priority review vouchers have had little to no effect on drug development in the areas for which they are available (GAO, 2020).

There has long been a lack of available treatments for rare diseases because the small population for each indication translated to poor return on investment for drug developers. A 7-year extension on market exclusivity was granted through the Orphan Drug Act for products that would not be otherwise developed owing to small patient populations. However, extended market exclusivity and lack of competition in the sector allowed industry to charge prices that were unaffordable for many patients. Less than 10 percent of patients receive treatment with these drugs because of the cost of medications. Experience with the Orphan Drug Act has demonstrated that without properly tailored exclusivity, patients’ access to treatments may be hindered until exclusivity expires and lower priced generics are introduced (Tu, 2023).

The BPCA provides a particularly relevant example of how to use patent and data exclusivity to incentivize the conduct of clinical studies for a specific population once the medical product is already on the market. Unlike priority review vouchers or the Orphan Drug Act, the BPCA targets incentives to drugs that are approved and on-patent but do not have data on the drug’s use in a defined population—children (see Box 5-2).⁶ The BPCA appears to be an enticing incentive for some sponsors. Thirty-five percent of sponsors who received a voluntary request to perform pediatric studies in exchange for extended exclusivity did so (Carmack et al., 2020). The incentive contributed to pediatric labeling changes in over 60 drugs between 1998 and 2018 (Bourgeois and Kesselheim, 2019).

The implementation of the BPCA has not been without its shortcomings, and there are numerous proposed solutions to remedy these challenges. On average, it takes sponsors 7 years from product approval to complete studies in a pediatric population (Carmack et al., 2020). This is partially because, like trials with pregnant and lactating populations, recruitment of children is more difficult than for nonpregnant adults, and pediatric trials often struggle to sufficiently power studies (Joseph, 2015). Furthermore, sponsors have tended to delay their response to FDA’s request for pediatric studies toward the end of patent exclusivity (Olson and Yin, 2018). Extrapolation of efficacy data from adult trials to pediatric

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⁶ Best Pharmaceuticals for Children Act, P.L. 107-109 (2002).

populations is a developing field of regulatory science, which may help to speed pediatric drug development and reduce the number of pediatric participants who need to be enrolled in clinical trials (Sun, 2017). In a sample of the BPCA and PREA labeling changes that used extrapolation, researchers found that the more that FDA accepted extrapolation in a labeling change, the more likely a label change occurred for pediatric populations (IOM, 2012).

Since the BPCA offers a blanket 6-months of exclusivity, drugs that have a large market in adults may benefit more from the incentive than a product that is more frequently used in pediatric populations (Bourgeois and Kesselheim, 2019). An additional critique has been that the exclusivity applies to the active pharmaceutical ingredient rather than the product, which is exemplified in the particularly stark case of Viagra benefiting from the patent extension because it shares the active pharmaceutical ingredient sildenafil with a pulmonary arterial hypertension drug. A policy analysis of the BPCA encouraged Congress to amend the BPCA, including the prioritization of incentives to research products of highest benefit to children and adopting a tiered incentive that favors sponsors that complete studies in a timely manner (Bourgeois and Kesselheim, 2019). An incentive program that rewards manufacturers for conducting additional clinical studies for pregnant and lactating women could effectively compensate for sponsors’ fear of incurring liability for conducting these studies by building on the successes and learning from the challenges of the BPCA.

Payers

Clinical trial results are a critical component in determining coverage decisions by payers, such as private insurers, Medicare, and Medicaid. Theoretically, some payers could use the coverage determination process to encourage product manufacturers to conduct research with pregnant and lactating women and could even restrict coverage unless

further evidence on dosing, safety, and efficacy was available in these populations. However, the committee does not make recommendations targeting this process because it would limit patients’ ability to access medical products they may need, particularly for pregnant and lactating patients.

One promising approach that has been used to generate evidence in certain subpopulations while not limiting access to medical products is the Centers for Medicare and Medicaid Services (CMS) coverage with evidence development (CED) paradigm. CED determination allows for Medicare to provide coverage for “items and services on the condition that they are furnished in the context of approved clinical studies or with the collection of additional clinical data” (CMS, 2023). For example, in 2022, CMS issued a national coverage determination for a medication to treat Alzheimer’s disease under CED, which allows coverage of the medication for patients enrolled in a clinical trial approved by CMS or supported by NIH. CMS highlights the “disappointing lack of inclusion of underserved populations” in their coverage determination memo and requires diversity as a key protocol requirement (CMS, 2022). However, national coverage determinations, which allow for CED determinations, are only made for Medicare and are not made for Medicaid, since Medicaid is a federal-state entitlement program that relies on states to purchase drugs on behalf of Medicaid beneficiaries (CRS, 2014).

According to the federal Medicaid and CHIP Payment and Access Commission, Medicaid directors have asked CMS for the flexibility to apply similar CED determinations in their own states (MACPAC, 2019). However, CMS does not explicitly have the authority to grant that request, and a statutory request is necessary to ensure states can implement coverage criteria similar to Medicare. In 2023, the Medicaid and CHIP Payment and Access Commission voted to approve a recommendation that calls on Congress to allow states to follow CED requirements included in Medicare coverage determinations (MACPAC, 2023). If states are allowed to create CED determinations, this could be a powerful tool for generating evidence on the dosing, safety, and efficacy of medical products in pregnant and lactating women, should states choose to use it. However, until congressional action is taken, CED determinations will remain an option only for Medicare beneficiaries.

Products in Development

Currently, there is little financial incentive for pharmaceutical companies to conduct clinical studies in pregnant and lactating women before drug approval. As described above, priority review vouchers and the Orphan Drug Act are examples of incentives designed to spur research

and the development of new products for disease areas that have not received adequate investment. Both programs are intended to address disease categories, such as rare pediatric diseases or other rare diseases. While there are conditions specific to pregnancy or lactation (e.g., preeclampsia, gestational diabetes, low milk production) for which additional available treatments would be beneficial, most of the conditions common in pregnant and lactating women do not neatly fit into prespecified disease categories. Therefore, it would be difficult to implement a similar incentive that aims to encourage product development within a specific disease category.

Incentives are not the only policy tool that can induce product development. FDA has substantial discretion to determine what studies are necessary to evaluate safety and effectiveness. However, FDA does not have sufficient authority under current law to mandate studies in pregnant and lactating women. In the Pediatric Research Equity Act (PREA), Congress expressly authorized FDA to require studies in pediatric populations, who, like pregnant and lactating women, had long been prescribed medications without adequate evidence (see Box 5-2).⁷ The PREA applies to new drugs and biologics that are in development, and requires that pediatric studies be conducted prior to approval of the product for the adult population, though FDA can grant sponsors a deferral or waiver of the requirement. Studies conducted under the PREA have resulted in 532 labeling changes from its enactment in 2003 through 2018 (Bourgeois and Kesselheim, 2019). While the PREA has led to far more pediatric labeling changes than the BPCA, both programs have been vital in the development of pediatric data, as each targets a separate stage on the product development pathway.

The PREA has been successful in generating dosing, safety, and efficacy information for pediatric use, but there are opportunities to improve upon its existing framework (IOM, 2012). Under the PREA, pediatric studies can only be required for the indication under review for the general population, even if the mechanism of action suggests that it may be effective in treating another condition prevalent in the pediatric population (Bourgeois and Kesselheim, 2019), though an exemption has been made if a drug is a promising candidate for treating pediatric cancers.⁸

Many new drugs in development are for rare diseases and thus receive exemptions from conducting pediatric studies (Bourgeois and Kesselheim, 2019). While there are challenges to conducting pediatric studies for these drugs given the small patient populations, the waivers

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⁷ Pediatric Research Equity Act of 2003, P.L. 108-155. (Dec. 3, 2003).

⁸ FDA Reauthorization Act of 2017, Pub. L. No. 115-52, § 504. (Aug. 18, 2017).

for orphan drugs deprive children of information on these drugs’ safety and effectiveness. Because deferrals can be granted under the PREA if the drug product is ready for approval in the general population, many sponsors receive at least one deferral, and some receive multiple (Bourgeois and Hwang, 2017). This results in most newly approved products being available on the market for many years without any pediatric labeling information (Hwang et al., 2019). In fact, among sponsors required to complete pediatric studies, 34 percent had completed the required studies 7 years after the initial approval.

FDA guidance instructs sponsors to submit their plans for conducting pediatrics studies required under the PREA by the end of Phase II development for the adult population (FDA, 2020), but the deadline for this submission may come too late in the product development process for sponsors to be able to complete pediatric studies before or shortly after product approval (Carmack et al., 2020). Conversely, sponsors in the European context have critiqued the timing of pediatric investigation plans—which are required to be submitted to the European Medicines Agency by the end of Phase I for the adult population—for being premature in the development process and requiring follow-up modifications (Rei Bolislis et al., 2021). Improvements in FDA’s enforcement capacity have been proposed to address these challenges with timely study completion (Bourgeois and Kesselheim, 2019; Hwang et al., 2019). Despite the difficulties with the PREA implementation and enforcement, a similar requirement for studies in pregnant and lactating women for medical products in development could be an effective strategy for developing adequate product labeling for these populations.

CONCLUSIONS

REFERENCES

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