Summary
Pregnant and lactating patients and their clinicians must currently make decisions regarding what drugs and vaccines they should use during pregnancy and lactation without the benefit of high-quality evidence regarding the products’ safety and efficacy. The inadequacy of that evidence prompts some pregnant and lactating women to forgo necessary treatment, which results in harm to them or their fetus or child, while others decide to use the medical product, which entails an unknown likelihood of harm and provides uncertain benefits.
Before medical products are licensed, they must undergo clinical studies to evaluate the efficacy, safety, and appropriate dosage in the populations in which they would be prescribed. Policies on clinical research require that the participants in clinical studies be as diverse as the expected patient population. Nonetheless, pregnant and lactating women continue to be excluded from most clinical studies to the detriment of their health and that of their fetuses and children. Past studies have attributed their exclusion to concerns about legal liability for the investigators and institutions that conduct and sponsor clinical research should research participants, or their fetuses or children, experience negative effects from the study intervention. Yet the committee has found limited evidence of such liability. Rather, excluding pregnant and lactating women from clinical research appears to increase the potential for harm, and by extension liability, when medical products are marketed without relevant information from research with pregnant and lactating women. Generating and reporting data about the safety, efficacy, and dosage of
medications in pregnant and lactating women would reduce the latter sort of liability. To generate such data, policies need to counteract existing disincentives to the responsible and ethical inclusion of pregnant and lactating women in clinical studies.
The committee offers nine recommendations for action by Congress, Department of Health and Human Services, National Institutes of Health, Food and Drug Administration, Office for Human Research Protections, and clinical investigators, which if implemented would result in the appropriate inclusion of pregnant and lactating women in clinical research and thus provide more of the evidence that they and their health care providers need to make informed health care decisions.
A DANGEROUS LACK OF INFORMATION AND THE BENEFITS OF RESEARCH
Each year in the United States, more than 3.5 million individuals give birth, and some experience serious diseases or conditions that are unique to pregnancy, including gestational diabetes, preeclampsia, and severe nausea and vomiting. Being pregnant also makes them more likely to acquire, or experience worse outcomes from, infectious diseases such as influenza and COVID-19. Pregnant women—and the nearly 3 million women who initiate breastfeeding each year—also experience the same diseases and conditions as other adults, such as depression, diabetes, hypertension, cancer, lupus, and human immunodeficiency virus (HIV). If left untreated, those conditions threaten the health and lives of pregnant and lactating women and their fetuses and children.
Seventy percent of pregnant women take one or more prescription medications during pregnancy, as is also true for at least half of lactating women. Pregnant and lactating women are generally excluded from clinical studies; they and their health care providers lack the sort of data about the dosage, efficacy, and safety of medical products that are available for other members of the adult population. Although pregnancy and lactation are physiologically unique, pregnant and lactating women and their clinicians must usually rely on data derived from clinical studies in nonpregnant and nonlactating adults, as well as from any preclinical studies in pregnant and lactating animals.
While pregnant and lactating women are permitted to use licensed products, the absence of relevant evidence not only presents individuals with a conundrum about how to proceed but also, at the population level, erects barriers to delivering safe, effective, and timely therapeutic and preventive measures, thus exacerbating existing health inequities for pregnant and lactating women.
The absence of a sufficient evidence base means that almost all pregnant and lactating women with a condition for which a medical product might be appropriate are, in effect, participants in large, uncontrolled experiments that typically will not produce useful data. Not surprisingly, a consensus has arisen in recent years that the more ethical and responsible course would be to include pregnant and lactating women in clinical research. In sum, the benefits to pregnant and lactating women of being included in well-designed, ethical clinical research on medical products is now generally accepted. Yet such studies are still not routinely conducted.
THE COMMITTEE’S TASK
In 2016, Congress authorized the creation of the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC Task Force) to evaluate gaps in knowledge about safe and effective therapies for pregnant and lactating women. In its 2018 report, the PRGLAC Task Force noted that the possibility of legal liability is frequently cited as a reason for not enrolling pregnant and lactating women in clinical research or for dismissing trial participants who become pregnant. Legal liability refers to a party’s breach of duty that results in harm to another. To address this concern for liability, Congress called on the National Academies of Sciences, Engineering, and Medicine to convene a committee to examine the real or perceived risk of liability arising from research conducted with pregnant and lactating women.
The statement of task asked the committee to study the evidence and report “findings, conclusions, and recommendations for safely and ethically including pregnant and lactating persons in clinical research that substantially mitigates or avoids incurring liability.” The statement of task also asked the committee to develop a matrix of relative liability to various stakeholders for medical product development. After reviewing the evidence, the committee concluded that a matrix would be subjective rather than based on empirical analysis because the bounds of liability are imprecise and quantifying relative liability is not possible. Therefore, a matrix would give a mistaken illusion of scientific precision. The committee instead thoroughly examined liability for harms alleged to have occurred during clinical research and in the clinical use of licensed medical products. The committee complemented this examination with a discussion of the laws and regulations applicable to clinical research involving pregnant and lactating women in order to explore when and how liability arises. This approach illuminated the relationship between legal liability—and perceptions thereof—and other regulatory, economic, and social influences on pregnant and lactating women’s exclusion from clinical studies.
THE LIABILITY LANDSCAPE
The collection of safety and efficacy data in clinical research raises potential liability concerns stemming from evidence of potential harm that may arise from use of an investigational product. The possibility of injury to a child who was exposed to an investigational product in utero or while breastfeeding is of primary concern to research participants. These concerns also affect other stakeholders involved in clinical research. An injury could tarnish the sponsoring company’s reputation and diminish public trust in its other products. The potential for injury to a child also creates fear of a court trial in which their every decision and action is scrutinized publicly, leading possibly to a large damage award. Scrutiny may be magnified for an injured child who did not choose to take the risk and may live with the injury for a lifetime.
If an approved medical product injures the fetus or child of pregnant or lactating women, the total amount of harm done could be much greater than what would occur in a clinical trial. Thus, failing to have conducted rigorous and regulated trials with pregnant and lactating women potentially shifts the risks of harm from the small number of well-monitored pregnant and lactating women and their offspring in the trials to the larger number in clinical settings. This failure also seems to increase the potential liability of the individuals and organizations who manufacture, distribute, and prescribe the medical product without providing dosing, safety, and efficacy information that is relevant to a distinct group of patients who are expected to use the product. That said, manufacturers have generally mitigated this risk through labeling, promotion, and postmarket surveillance in accordance with FDA regulations and guidance, rather than by including pregnant and lactating women in clinical research. If injury does occur, manufacturers may argue that they had neither knowledge of possible risks relating to use of the product in pregnant and lactating women nor a duty to acquire such knowledge in the absence of any FDA requirement to test in these populations.
A case law analysis revealed no reported claims of liability for research-related injuries relating to lactating women’s participation in clinical research. One marketed drug was the subject of several reported cases involving injury to the lactating woman, without injury to the child. The committee found no reported cases relating to participation of pregnant women in clinical trials since 1962 when the U.S. Food and Drug Administration (FDA) was granted the authority to require proof of safety and efficacy of products before they go on the market. There were, however, many cases involving liability claims related to pregnant women’s use of on-market drugs approved for treatment of conditions in the adult population.
Although there are limitations to the review of the case law—including that the likelihood that encountering liability is diminished by the reality that many clinical trials exclude pregnant and lactating participants, and that the analysis partially relies on extrapolation from general knowledge about the regulatory context and litigation regarding pharmaceutical products—the analysis revealed three important points.
- Little evidence exists of liability resulting from including either lactating or pregnant women in clinical trials.
- Little evidence has been found that lactating women’s use of approved and marketed products gives rise to liability.
- There is substantial evidence of liability related to pregnant women’s use of approved and marketed products, and some evidence that aspects of that liability might have been avoided had pregnant women been included in the clinical trials for those products.
In light of these findings, the committee considered drivers of the perception that including pregnant and lactating women in clinical studies creates a high liability risk. Perceptions of liability appear to be based in fear of uncertainty, given that those involved in clinical research with pregnant and lactating women have a poor understanding of the risks of harm, legal liability, and how other factors may contribute to liability. The perception of liability is also shaped by the cultural significance of preventing fetal harm linked to actions taken by pregnant women. Consequently, the public, policy makers, and others perceive research involving pregnant and lactating women as legally risky. The reality is that not conducting research involving pregnant and lactating women has the potential to generate far greater harm arising from treatments and preventives that have not been tested in pregnant and lactating women, and thus a greater risk of liability for all those associated with the clinical encounter to the extent that they are found to have violated a duty under applicable state tort law.
ABATING LIABILITY BY REDUCING POTENTIAL HARM
Harm and liability are interconnected: harm refers to the injury suffered; liability refers to the legal responsibility for that harm. Notably, harm can result from inclusion in clinical research as well as exclusion from clinical research. Employing strategies to reduce potential harm can play a role in mitigating both liability and the effect of perceived liability arising from a pregnant woman’s research participation. The current drug development pathway and the protections offered through clinical
research regulations have been instrumental in reducing harm to research participants and patients. However, there are opportunities to improve current regulatory systems to further minimize harm for research involving pregnant and lactating women.
Clinical research is essential for advancing scientific knowledge and improving health outcomes. However, the exclusion of pregnant and lactating women from clinical studies can produce harm resulting from inadequate or inappropriate treatment or nontreatment in the absence of adequate evidence. Producing data by conducting research with pregnant and lactating women reduces this harm. Doing so responsibly requires strategies to mitigate the potential harm from including them in research.
Clinical studies conducted with pregnant and lactating women raise distinct considerations related to risk–benefit assessments because of the physiological differences in pregnancy and lactation and, significantly, the intimate relationship of the research participant and the fetus or nursing child who may be directly or indirectly exposed to unknown or uncertain risk from the investigational product.
Clearer guidance from the U.S. Food and Drug Administration (FDA), detailing the expected study designs, safeguards, and product-specific monitoring for conducting clinical studies with pregnant and lactating women would equip sponsors and investigators with crucial information for safely executing these trials, and compliance with such guidance, though not a formal defense, manifests due care and hence may reduce the likelihood of being found liable. Moreover, the Office for Human Research Protections (OHRP) under HHS offers guidance to institutional review boards (IRBs) on interpreting HHS regulations. However, ambiguity in HHS regulations for including pregnant women in clinical research, particularly related to the concept of minimal risk, leads IRBs to reject studies that propose including pregnant women. Research sponsors can also design clinical research using innovative methodologies and can increase equity through pragmatic trials and opportunistic studies.
MITIGATING POTENTIAL LIABILITY IN CLINICAL INVESTIGATIONS
The legal liability that is relevant to the participation of pregnant and lactating women in clinical research is tort liability. This branch of law aims to compensate parties who have been injured by the negligent or wrongful acts or omissions of others or by products or conditions that create undue risk. Tort liability also encourages reasonable and responsible behavior to reduce future harm. In the context of clinical care and research, part of health care professionals’ responsible behavior is providing patients and research subjects with a clear, complete, and
comprehensible description of the potential benefits and risks of a medical intervention and of alternatives as part of the process of obtaining their informed, voluntary consent. Along with clear regulatory guidance on protecting participants from harm, strengthened informed consent processes could help mitigate potential liability.
In some situations—especially when actors have departed from the applicable standard of care—reaching an individualized judgment about liability is important for fulfilling tort law’s remedial and deterrence objectives. However, the process is time consuming, expensive, and arduous for all concerned. No-fault compensation provides an attractive alternative because it eliminates the burden on the harmed individual to prove their injury is the result of another’s breach of duty, and it mitigates liability for those who may be the subject of a lawsuit through the tort system. Permitting U.S. investigators to use federal grant funds to purchase clinical trial insurance, which offers no-fault compensation plans, could help mitigate the liability concerns of institutions and investigators.
Following the 2022 Supreme Court decision in Dobbs v. Jackson Women’s Health Organization, the breadth of privacy issues for pregnant research participants may increase as states propose and enact new laws aimed at preventing abortion, protecting fetal life, and regulating the choices of pregnant women. Overall, the Dobbs decision is likely to increase liability for including pregnant women in clinical research. It is yet unclear how the Dobbs decision and newly passed or enforced state laws will affect pregnant women’s willingness to participate in research and sponsors’ and research institutions’ willingness to support research in states that may penalize fetal harm. Certificates of confidentiality (CoCs) can be a valuable tool to protect research participants against privacy issues and could address pregnant participants’ concerns that their health information will be shared. CoCs likely provide privacy protections in many of the contexts involving pregnant and lactating women in clinical research.
FACTORS INFLUENCING PERCEPTIONS OF LIABILITY
The committee determined that decisions regarding research with pregnant and lactating women are influenced by perceptions of liability that are intertwined with other factors that have contributed to the exclusion of pregnant and lactating women from clinical studies. When a sponsor or other stakeholder is deciding whether to conduct research 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. This includes the regulatory reality that FDA does not require that research be conducted with pregnant and lactating women in order to market a product to the adult population. If the considerations against doing the research outweigh those in favor of doing the research, the sponsor and others are likely to decide not to conduct the research. Each stakeholder’s decision weighs the potential for liability along with other factors, including
- the culture of exclusion;
- challenges in recruiting participants;
- lack of expertise in research involving pregnant and lactating women;
- reputational risk;
- cost and complexity of trials; and
- lack of financial incentives.
Changing one factor, such as offering regulatory predictability or financial incentives, could offset and overcome potential liability concerns; addressing these interrelated factors together could affect how stakeholders view liability regarding research with pregnant and lactating women.
Recommendations
The committee drew on public testimony, research, and deliberations to arrive at nine recommendations to improve the safe and ethical inclusion of pregnant and lactating women in clinical research while mitigating the risk of liability. The recommendations address liability with attention to the multiple stakeholders involved along the medical product development pathway and the ways in which they perceive liability. The recommendations address the liability risk—and perceptions of liability risk—of various stakeholders through three interconnecting approaches. The first is through strategies that directly mitigate liability. The second is through strategies that minimize harm, and therefore diminish the potential for liability. The third approach involves addressing the factors that discourage the inclusion of pregnant and lactating women in clinical research that sponsors and researchers weigh alongside the potential for liability.
Recommendation 1. The U.S. Food and Drug Administration (FDA) should revise guidance to make clear its expectation that pregnant and lactating women should be included as early as possible in the studies conducted for product approval
of medical products that pregnant and lactating women are expected to use, and that studies to provide explicit support for the safety, efficacy, and dosage in these populations be initiated no later than the end of Phase III studies in the general population. The studies with pregnant and lactating women should continue into the postapproval period and be completed as quickly as possible postapproval. FDA should bring all related guidance documents into conformity with the revised guidance.
- The revised guidance should set forth the study designs, safeguards, and product-specific monitoring expected for conducting clinical studies with pregnant and lactating women, and include considerations for how sponsors should determine appropriate study designs, safeguards, and product-specific monitoring.
- The revised guidance should make clear that research plans and all necessary study protocols are prepared, research sites are identified, and monitoring and oversight committees are appointed for pharmacokinetic, pharmacodynamic, and dosage determination studies with pregnant and lactating women while Phase III studies for the product are being carried out in the general adult population.
- The revised guidance should specify contents of a streamlined Investigational New Drug Application for use by academic and other noncommercial sponsors to study a drug in pregnant and lactating women in the event that studies are not initiated and completed in a timely manner by the New Drug Application, Biologics License Application, or Premarket Approval holder as contemplated by the guidance.
- The revised guidance should make clear the requirement to conduct studies with pregnant and lactating women is dependent upon (i) the product having the potential for use by pregnant and lactating women and (ii) that use being consistent with available clinical and preclinical safety and efficacy data in these populations. If the product sponsor believes that data from preclinical studies of the product, or evidence concerning the safety of other products in the same class, raises concerns about the potential harm to pregnant and lactating women or their offspring, the sponsor may submit to FDA a justification for not including pregnant or lactating women in the clinical studies outlining the basis
- for such for concerns and why the potential harms cannot be adequately prevented or mitigated in light of the potential benefits to these populations. If FDA reviewers agree with the justification, trials in pregnant or lactating women are not to be carried out and the safety information must be included in the drug labeling.
Recommendation 2. The U.S. Food and Drug Administration (FDA) should use the authority outlined in Public Law 117-328 to require that diversity action plans include pregnant and lactating women as part of an intersectional plan to increase the inclusion of diverse populations in clinical research. FDA should revise its guidance relating to such diversity action plans to include the following:
- Formal discussion, such as during meetings before an Investigational New Drug Application is granted, on FDA’s expectation for the inclusion of pregnant and lactating women in clinical trials of the product and on the sponsor’s plans to include these populations in clinical trials.
- Submission of, or if already completed, reference to relevant preclinical data that support the determination of dosage, safety, and efficacy in pregnancy and lactation, including developmental and reproductive toxicology studies and, as available, any safety data on pregnancy and lactation for other drugs in the same class. If the preclinical data presented in the diversity action plans raises safety concerns for conducting human trials in pregnant and lactating women, a justification for not conducting clinical studies must be submitted along with the diversity action plan outlining the evidence for concerns. When FDA reviewers agree there are safety concerns regarding clinical testing in pregnant and lactating women, trials are not to be completed and the safety information must be included in the drug labeling.
- Plans for conducting pharmacokinetic and pharmacodynamic studies in pregnant and lactating women, including dosing studies through each stage of pregnancy. The plans for these studies should be submitted to the agency no later than the submission of a New Drug Application or Biologics License Application for the general population.
Recommendation 3. The Office for Human Research Protections (OHRP) within the U.S. Department of Health and Human Services should provide clarity on the inclusion of pregnant and lactating women as research subjects. OHRP should provide guidance documents that help clinical researchers, institutional review boards (IRBs), and data and safety monitoring boards ensure that pregnant and lactating women who participate in clinical research are adequately protected without creating undue burdens for their participation. OHRP should work with the Food and Drug Administration (FDA) to harmonize applicable guidance pertinent to research with pregnant and lactating women.
- OHRP should issue guidance that provides definitions and interpretation for 45 CFR 46, Subpart B, particularly “minimal risk” and “additional safeguards” that are conducive to the responsible and ethical inclusion of pregnant and lactating women in clinical research.
- OHRP should issue guidance to clarify the applicability of 45 CFR 46, Subpart D, for clinical research that enrolls lactating women who breastfeed their children during the study.
- OHRP should issue a list of frequently asked questions that could assist clinical researchers and IRBs to assess risk in clinical research that involves pregnant and lactating women and to provide justifications for the inclusion or exclusion of pregnant or lactating women in clinical research.
- OHRP guidance should, like FDA guidance, recommend that IRBs have experts in pregnancy, lactation, and neonates participate in the review of study protocols involving such participants.
- The OHRP Division of Education and Development should offer training and outreach for researchers and IRBs to develop expertise in research in pregnancy and lactation.
- OHRP should create a subcommittee for research with pregnant and lactating women within the Secretary’s Advisory Committee on Human Research Protections that will provide detailed recommendations on how to conduct more research with pregnant and lactating women safely and ethically.
Recommendation 4. The U.S. Congress should pass legislation modeled on the Best Pharmaceuticals for Children Act to encourage and incentivize additional studies to provide more
information in labeling on the safety and efficacy of approved medical products for pregnant and lactating women. This legislation should:
- Direct the director of the National Institutes of Health, in consultation with the commissioner of the Food and Drug Administration (FDA) and experts in pregnancy and lactation, to develop and publish annual prioritization lists of both on-patent and off-patent approved medical products for which additional studies are needed to assess the dosage, safety, and effectiveness of the use of the medical products in pregnant and lactating women.
- Direct the secretary of the Department of Health and Human Services (HHS) to award contracts to entities that have the expertise to conduct clinical studies in pregnant and lactating women to study medical products that are no longer subject to relevant patent or exclusivity protections, thus enabling the entities to conduct studies in pregnant and lactating women of one or more of the off-patent medical products identified in part (a) of this recommendation.
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Grant the secretary of HHS the authority to make a written request to the patent holder of medical products subject to patent or exclusivity protections to conduct clinical studies involving pregnant and lactating women concerning one or more of the on-patent medical products identified in part (a) of this recommendation.
- To incentivize manufacturers to complete these studies, Congress should create incentive programs, such as extended market or data exclusivity or tax breaks, to the holder of the approved application if studies are completed within the requested time frame and data are submitted to FDA for inclusion in product labeling.
- This incentive program should be authorized for an initial 5-year period, with reauthorization based on experience with the program and a determination of whether continuation is necessary.
Recommendation 5. The U.S. Congress should pass legislation modeled on the Pediatric Research Equity Act to authorize the Food and Drug Administration (FDA) to require research
related to the use of drugs, biologics, vaccines, and medical devices in pregnant and lactating women.
- Congress should direct the secretary of the Department of Health and Human Services to require any entity that submits an application for a new drug, biologic, vaccine, or medical device, or a supplement for a new indication, new dosage form, new dosing regimen, or new route of administration, to submit data on the dosage, administration, safety, and effectiveness of its use in pregnant and lactating women.
- Congress should amend Section 505(o)(3)(B) of the Federal Food, Drug, and Cosmetic Act to include “(iv) to identify and characterize risks to pregnant and lactating women and their offspring” as a justification for requiring postmarketing studies and postmarketing clinical trials.
- To ease the initial challenges that may be faced in implementing this requirement, Congress should create programs, such as extended market exclusivity or tax breaks, for the holder of an approved New Drug Application, Biologics License Application, or Premarket Approval when studies are completed within the required time frame and data are submitted to FDA for inclusion in product labels. These programs should expire after several years, once sponsors have experience conducting these studies.
Recommendation 6. The National Institutes of Health (NIH) should develop an action plan to prioritize research that includes pregnant and lactating women across its institutes and centers. At a minimum, the action plan should include the following:
- NIH should create a new program with the NIH Common Fund to study the pharmacokinetics, pharmacodynamics, and dosage determination of on-market drugs in pregnant and lactating women.
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development should expand and sustain its network of institutions with expertise in conducting clinical research with pregnant and lactating women, with considerations for the equitable access of potential research participants.
Recommendation 7. The National Institutes of Health (NIH) and other federal agencies that fund clinical research should cover the cost of clinical trial insurance on clinical trial grants that include pregnant and lactating women for research that is conducted domestically. The additional expense of this insurance should be deemed as outside of the NIH cap for direct costs for grant awards.
Recommendation 8. The U.S. Department of Health and Human Services should form an interagency task force, including the Food and Drug Administration, National Institutes of Health, Centers for Disease Control and Prevention, Health Resources and Services Administration, Office of the National Coordinator for Health Information Technology, and the National Library of Medicine to create and maintain infrastructure and guidelines for the conduct of postmarketing pregnancy and lactation safety studies that would use safety information, annual status reports from existing pregnancy and lactation exposure registries, and data generated through database studies. From within its membership, the task force should identify agency leads to carry out the following activities:
- Develop a central repository to collect postmarketing safety data from pregnancy and lactation exposure registries and database studies.
- Release guidelines on the content and format of data to be submitted to the central repository from existing pregnancy and lactation exposure registries, which should include, at a minimum, the following: number of pregnant and lactating women enrolled to date, number of pregnant and lactating women with unknown outcomes, number of pregnant and lactating women with pending outcomes, number of pregnant and lactating women lost to follow-up, and number and types of adverse events reported in pregnant and lactating women.
- Adopt standards requiring that the electronic health records of pregnant and lactating women be capable of being linked with records for their offspring in research databases.
- Evaluate the infrastructure, data elements, and resources that would be required to develop and maintain a centralized national registry for collecting and evaluating postmarketing data from pregnant and lactating women.
Recommendation 9. If research being conducted with pregnant individuals, or individuals who may become pregnant over the course of the study, is not already covered by a certificate of confidentiality issued by the National Institutes of Health or other federal agency, the principal investigator of the study should apply to the National Institutes of Health for a certificate of confidentiality.
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