Proceedings of a Workshop—in Brief

Research with Pregnant and Lactating Persons: Mitigating Risk and Liability

Proceedings of a Workshop—in Brief

INTRODUCTION

The Committee on Developing a Framework to Address Legal, Ethical, Regulatory, and Policy Issues for Research Specific to Pregnant and Lactating Persons at the National Academies of Sciences, Engineering, and Medicine held a hybrid workshop on March 23, 2023. The workshop focused on the real and perceived liability considerations surrounding research on pregnant and lactating persons (PLP) and explored approaches to balance risks and benefits. The purpose of the workshop was to help inform the committee’s deliberations and to supplement the committee’s evidence gathering for its consensus report. Invited speakers at the workshop included representatives from academia, non-profit research and professional organizations, private law firms, biomedical corporations, an insurance company, and individual research participants. This Proceedings of a Workshop—in Brief highlights the presentations and discussions that occurred at the workshop; it should not be seen as reflecting findings, conclusions, or recommendations of the workshop participants or of the committee. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the National Academies of Sciences, Engineering, and Medicine or the committee and they should not be construed as reflecting any group consensus. The committee’s consensus report will be available in Spring of 2024.

Mimi Foster Riley (Professor of Law, University of Virginia) opened the workshop with an overview of the agenda. The first session examined the role of product liability considerations in the generation of evidence on safety and efficacy in the PLP population and considered what incentives and accountability measures might promote evidence generation. The second session looked at the role of risk management and trial insurance, examined the factors that influence decisions to include or exclude PLP from clinical research, explored the risk/benefit analysis for research in this population, and identified opportunities to apply risk mitigation and management strategies to clinical research. The third session focused on equity considerations and looked at research participants’ decision-making process, perspectives on compensation for injury, the benefits and drawbacks of different compensation schemes, and opportunities to improve existing compensation schemes to make them more equitable. Finally, the last session explored case studies in risk mitigation, considering different approaches for mitigating risk and

liability in clinical research, challenges and successes of these strategies, and opportunities to scale mitigation strategies to research studies including PLP. Each session included time for committee members and other workshop participants to make comments and ask questions of the panelists.

PRODUCT LIABILITY CONSIDERATIONS

Bruce Kuhlik (Director, Power to Decide; Pathfinder International; Martha’s Table) introduced the first session, which was a discussion with John Beisner (Partner, Skadden, Arps, Slate, Meagher & Flom LLP and Affiliates). The session explored product liability considerations that may influence decisions to include PLP in clinical research.

There is an assumption in the medical literature that the risk of liability is a strong motivator to exclude PLP from clinical studies, though Beisner stated he is “somewhat dubious of that proposition.” While clinical trial participants have at times brought lawsuits, the risk of litigation does not appear to be the strongest motivating factor in decisions on whom to include and exclude in trials. Other considerations—such as concerns about heightened risks to certain participants or complicating the integrity of the trial process due to inclusion of certain populations—are likely more influential, he said.

Kuhlik asked Beisner to comment on whether a company would increase or decrease its risk of litigation by including PLP in a clinical trial for a general condition (i.e., not for a condition specific to pregnancy or lactation). Beisner said that including PLP would likely increase the risk to the company. He added that there are several theories of liability in medical product lawsuits, but it would be uncommon to see a lawsuit alleging that there were insufficient studies on the product. FDA is a “core character” in litigation over a product; if FDA has approved a product, a defense attorney would argue that the approval implies that there was sufficient information to determine that the product was safe and efficacious. If a company conducts additional studies post-approval, Beisner said this could create a higher risk of liability because it provides an additional target for the plaintiff’s attorney (e.g., to argue that the designs of the additional studies were improper).

The potential injuries to a fetus, baby, or PLP related to the use of a medical product are serious and of “great concern in the industry,” said Beisner. Injuries to a fetus or baby could result in lifetime afflictions, severe limitations, and significant disabilities; plaintiffs with these types of injuries are very sympathetic and a very serious matter for the defendant. Causation is the “primary battleground” in product liability cases, and defense attorneys will look for other potential causes of the injury not related to the product. For example, if a plaintiff suffers an injury after taking a drug, the defense attorney might point to the plaintiff’s history of smoking or obesity for an alternative explanation of the injury. In product liability cases involving fetuses or young children, it would be much harder to identify alternative factors, and, posited Beisner, the jury is more likely to believe that the drug played a role in the injury.

Kavita Shah Arora (Associate Professor and Division Director of General Obstetrics and Gynecology, University of North Carolina, Chapel Hill) noted that much of the discussion surrounding the use of a drug in PLP focuses on the risks to the fetus or baby and not on the maternal benefit. She asked Beisner whether there is a legal mechanism in tort law that allows for a balancing of the risks and benefits, as there is for, say, family law. He replied that tort law involves an analysis of the benefits and risks and looks at whether warnings and information provided were adequate. However, even in a tort case, the court will likely focus more on the consequences of using the product rather than the policy question of whether FDA should have required certain types of clinical testing before approval (e.g., testing in PLP).

THE ROLE OF RISK MANAGEMENT & CLINICAL TRIAL INSURANCE

Patricia Danzon (Celia Moh Professor Emeritus at the Wharton School of the University of Pennsylvania) introduced the next session of the workshop, which focused on the challenges of research on PLP, balancing risks and benefits, and approaches for mitigating and managing risks to involved parties. This session, along with the session on equity considerations, included a

discussion about additional considerations for conducting clinical research in pregnant populations in light of the Dobbs v. Jackson Women’s Health Organization decision, described in Box 1.

Clinical Trial Insurance Perspective

Sara Dyson (Vice President of Underwriting Operations & Risk Management, Medmarc) gave workshop participants an overview of insurance and how insurers think about risk. The insurance model, she said, is a bit like gambling. An insurance company wants to align itself with clients who are low-risk and aims to keep those clients long-term so that the desired clientele pays for their own losses over time. Thus, Dyson explained, the insurer must make wise choices about the companies

it insures. In the field of life sciences, there are several products that are now or have historically been difficult to insure, including latex, silicone, contraceptives, inferior vena cava (IVC) filters, vaccines, and opioids. These products are difficult to insure, said Dyson, because it is “economically impossible” for them to pay their own way. For example, there was a time when companies stopped making vaccines because of liability, which caused a public health crisis. The solution, she said, was the creation of a federal administrative compensation system in which patients could make a claim. Vaccine manufacturers still buy insurance, but the risks to the insurer are different because of the administrative compensation system. Dyson suggested that this model could be useful in the context of PLP. Compared to products like vaccines, the liability risks for pregnant and lactating persons are not on the extreme end of the scale, but they are “on that end of the scale.” From an insurer’s perspective, risk can be related to frequency or likelihood of a claim or the severity of a claim. Dyson said that while there’s no evidence to suggest that there would be a disproportionate number of claims filed by PLP related to injuries from a clinical trial, such a claim would likely prevail if it went to court. Juries are “very punishing” to companies that injure PLP or children, she said.

Both manufacturer-sponsors and non-manufacturer sponsors of clinical trials may be insured, said Dyson. For example, Medmarc insures several universities that conduct clinical trials; these policies cover medical care that is needed as the direct result of the trial (up to a certain limit with no requirement of a showing of fault) and cover injuries that occur after the trial. Dyson explained that coverage for the long-term follow-up of a trial can be challenging because the latent risk of a drug could last for many decades.

While a clinical trial that includes PLP involves a certain amount of risk, said Dyson, there are multiple ways a sponsor could make a trial more attractive to an insurer, including:

• Demonstrate a recognition and knowledge of important safety risks;
• Develop warnings and mitigation plans for important safety risks;
• Conduct significant bench testing before clinical trials;
• Capture informed consent on video in order to prove acknowledgment of risks and consent to move forward;
• Provide reasonable compensation for participants that does not cross the line into coercion;
• Consult with multiple institutional review boards (IRBs); and
• Select a trial site with a specialty in high-risk pregnancy.

While there are many ways to design a clinical trial that is more friendly to PLP, most sponsors do not even reach the point of considering these measures because they have already opted to exclude this population, said Dyson.

Academic Medical Center Perspective

The Office of General Counsel and Risk Management at the University of California (UC) evaluates risk system-wide for programs and activities of its campuses and medical centers, said Hillary Noll Kalay (Principal Counsel, University of California Office of the President). The office generally does not evaluate individual study protocols, unless there is a particular legal risk or question, but instead identifies and explains risks to researchers and IRBs in a more general sense. UC has explicit policies for research, said Kalay. For industry sponsor-initiated studies, commercial sponsors must cover all costs of a study, including any cost related to subject injuries. The sponsor must indemnify, defend, and hold harmless UC from costs or claims for injuries that arise from the study, with limited carve-outs for UC’s negligence or failure to comply with the protocol. For investigator-initiated studies and those that are federally funded or funded by a foundation or consortium, UC is responsible for the treatment of injuries where the study was not intended to provide a therapeutic benefit, however this is limited to what insurance will cover. Like many large universities, UC self-insures and then buys excess coverage to cover

certain risks. Establishing coverage agreements, said Kalay, plays a role in “significantly slowing down” initiation of research studies due to the challenges of negotiation. While there is a mechanism for exemption, it requires the chancellor of the medical center and research institution to determine that the university is prepared to assume the risk of a particular study.

Institutional Review Board Perspective

Institutional review boards (IRBs) are “very conservative” when it comes to weighing the risks and benefits of including PLP in research, said Elisa Hurley (Executive Director, Public Responsibility in Medicine and Research). The risk mitigation strategy of IRBs is primarily exclusion. IRBs are beholden to the Common Rule¹ and FDA regulations. Pregnant people were removed from the list of vulnerable subjects in the 2018 revisions to the Common Rule but are still classified as such in FDA regulations.² The Common Rule regulations in Subpart B govern federally funded research with pregnant women, fetuses, and neonates; these regulations and FDA guidance are “notoriously ambiguous, complex, and unclear,” said Hurley. Subpart B lays out the conditions under which research can be conducted; among these are the requirement that risk to the fetus must be “not greater than minimal.” However, said Hurley, there is wide disagreement among IRBs on what constitutes minimal risk. Another condition in Subpart B requires that data from preclinical studies and studies on nonpregnant women are available and used to assess potential risks to pregnant people and fetuses. There is disagreement among IRBs on what kinds of research should be considered adequate for approval. IRBs even have different interpretations of what constitutes a research risk, Hurley said, although FDA has fairly clear guidance on this point.

Habit and tradition influence how IRBs make decisions; IRBs are not used to seeing PLP included in research, and they are not in the habit of asking investigators to justify exclusion. Hurley also noted that the framework in which IRBs evaluate risks does not generally consider the risks of not doing the research on a certain population.

IRBs serve as important gatekeepers to research and are well-positioned to require justification for exclusion of PLP from research or to institute extra protections to facilitate inclusion. IRBs could benefit from more guidance, particularly on the minimal risk standard; this guidance could be provided by regulators or through clearer policies and decision charts from the institution itself, Hurley said. Using IRBs to promote or facilitate research in the PLP population will require the commitment of the institution behind the IRB.

EQUITY CONSIDERATIONS FOR INJURY COMPENSATION

Anne CC Lee (Director of Global Newborn Health, Brigham and Women’s Hospital; Harvard Medical School) introduced the next workshop session, which focused on equity considerations for injury compensation schemes. According to Lee, PLP and certain racial and ethnic groups have traditionally been excluded or underrepresented in clinical research. She continued, a major barrier to participation in clinical research is the concern for injury or harm; to increase the participation of marginalized populations in clinical research, it is critical to address these concerns and ensure equitable access to injury compensation for participants in clinical trials.

Research Injury Compensation Models

Efthimios Parasidis (Chief Justice Thomas J. Moyer Professorship for the Administration of Justice and Rule of Law, Ohio State University) spoke about what a compensation fund for research injuries could look like and potential developmental considerations. There are several models that could be learned from for such a fund, he said, including the National Vaccine Injury Compensation Program (NVICP), the Countermeasures Injury Compensation Program (CICP), the 9/11 Compensation Fund, and mass tort settlements for adverse reactions to Agent Orange and asbestos exposures. One major challenge in compensation programs is the issue of causation; a high bar for causation can create “almost insurmountable hurdles” for those who are injured.³ Parasidis suggested that if a research participant provided some evidence of a

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research-related injury, a research injury fund could shift the burden of proof to the research institution to show that an injury was not related to a particular drug, instead of the burden resting on research participants to demonstrate that it was. He continued, while this structure would err on the side of overcompensating, this might be an ethically appropriate choice, given the benefits that volunteer participants bring to research and society in general.

Parasidis noted three important considerations for a research injury compensation fund:

• Protecting participants: provide participants with a “very thorough and honest” assessment of risks prior to enrollment and an understanding of what compensation will look like, including a minimum amount for economic damages. One consideration is a tiered approach to a compensation fund, which would examine the severity of injury and provide a range of amounts available to a research participant so that each case is not litigated individually.
• The concerns of research participant priorities: provide participants with a thorough assessment of risk prior to enrollment along with an accurate safety assessment as the research is ongoing and after it has ended.
• Fair compensation: include the costs of long-term health surveillance, costs of health care for research-related injuries, reimbursement for time off work and costs of travel, and take into account the pain, suffering, and other harms related to injuries.

A Self-Indemnity Approach: Human Subjects Division at the University of Washington

The University of Washington has a unique injury compensation program called the Human Subjects Assistance Program (HSAP), said Jason Malone (Director of the Human Subjects Division, University of Washington). HSAP is a no-fault discretionary program⁴ that offers compensation for injury or illness that has occurred as the result of participation in University of Washington (UW) research. If a participant receives care at UW, HSAP waives charges up to $250,000; treatment provided elsewhere is reimbursed up to $10,000. Prior to HSAP, the university had commercial insurance for trial-related injuries, but an analysis found that the cost of the premiums far outweighed the cost of the claims paid. HSAP was created in 1979 as a self-insured general liability program funded by UW central administration.

Malone said that HSAP does not cover medical issues that are the natural progression of the underlying condition; does not pay for lost wages, lost time, or pain and suffering; and does not cover expenses covered by other programs such as NVICP. Industry-funded or initiated research is also not covered under HSAP.

The program is administered by the Human Subjects Division (HSD) and the Office of Clinical Risk Management (CRM). HSD assesses studies for eligibility, ensures HSAP language is part of the informed consent process, and evaluates whether a reported event qualifies. Malone said that the determination of eligibility generally relies on the judgment of the investigator; if the investigator feels that the issue was “more likely than not” caused by participation in the study, the person is eligible for compensation. CRM makes a final determination of eligibility and administers the benefits.

The biggest challenge of the program, said Malone, is access; the burden is on the participant or researcher to report an event. Within the last five years, only around 10 claims have been made to their office; Malone said this seems small considering the amount of research conducted at UW. Due to the low number of claims, funding the program is not currently a problem, but it could become an issue if the number of claims increases.

No Fault Compensation: National Vaccine Injury Compensation Program

Renée Gentry (Principal Partner, The Law Office of Renée J. Gentry) gave participants an overview of the National Vaccine Injury Compensation Program (NVICP). NVICP was established in the 1980s to compensate the small number of people who experience a severe reaction to a vaccine. There are two types of cases

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that can be filed, said Gentry. The vaccine injury table lists injuries that are covered if they occur within the stated time listed after adminstration of the specific vaccine.⁵ If a person qualifies for a “table case,” there is a presumption of causation, and the case typically goes straight to damages. If the injury does not fall within the requirements of the table, it is a cause-in-fact case, which proceeds similar to regular litigation. The overwhelming majority of cases are table cases, said Gentry. One significant issue in non-table cases is showing causation. Gentry continued, while technically the system does not require supporting literature, a claim is likely to be dismissed if there is not a body of literature that supports a scientific explanation for causation. Once enough claims have been dismissed, other people with the same type of injury stop filing claims because there is no “reasonable basis” for bringing it forward; without a reasonable basis, attorneys’ and experts’ fees are not covered. This has a “dramatic chilling effect,” said Gentry, and leads to claimants opting out of the system. Gentry said that if a compensation scheme similar to NVICP were to be created for research participants, it should include coverage for attorney’s fees.

The infrastructure of the NVICP has not been updated since its inception, and, according to Gentry, the lack of modernization is a major challenge. The program was created to compensate children who were injured by vaccines, but the overwhelming majority of petitioners today are adults. The number of cases has increased dramatically in recent years, but the number of factfinders working on cases has not increased. This has created an overwhelming backlog, she said, with nearly 4,000 cases on the docket for the eight Special Masters.⁶ People with claims can wait over a year to get a response from the government and two to three years to schedule a hearing; the original statute expected the cases to be resolved within 240 days. “The system is at a breaking point,” Gentry said, and updating is desperately needed. In addition, the calculation of the amount available to injured individuals has not been updated, despite a large amount of available funding. The program is funded through a 75-cent excise tax on each vaccine dose, and there is around $4 billion currently in the fund.

Gentry emphasized that injury compensation programs need to be designed with the ability to grow. Without statutory flexibility to grow and adapt, any changes must be approved by Congress, which is very difficult In addition, said Gentry, a compensation program needs to provide a meaningful alternative to tort litigation. If a compensation program is not adequately reimbursing people for injuries, they will opt-out of the program and pursue their case in the courts. Programs like NVICP can be a very effective mechanism for compensating people for injury, but they need to be able to do so in an efficient and adequate manner, Gentry concluded.

Tort Law for Compensation

Given some of the challenges of compensation systems, said Michelle Mello (Professor of Law and Health Policy, Stanford University), is tort law a better alternative for injured research subjects? There is a precedent for human research participants seeking compensation through the tort system, and there are many types of claims that can be brought. However, Mello said that she does not believe tort law is a better system for these claims than an administrative compensation system. In the context of medical malpractice, tort has not performed its core functions very well, and there is no reason to think that research participants will fare any better than malpractice plaintiffs. Instead of considering tort as a viable alternative, Mello said it would be preferable to focus on fixing the things that are wrong with existing models of administrative compensation.

Mello shared her vision of what a well-functioning tort system would look like. Such a system would have the following features:

• Direct compensation to all the people, and only those people, who qualify for it; that is, all people injured by negligence would be compensated, and those who were not injured by negligence would not be compensated.

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• Easily accessible to anyone with a meritorious claim and would be able to rapidly identify people who do not.
• Predictable so that litigants could make good decisions about bringing a claim, and insurance companies could accurately price products.
• Equitable both vertically and horizontally; people with more severe injuries would get more money than those with less severe injuries, and people with similar injuries would get similar awards.

Unfortunately, said Mello, the current tort system for medical malpractice does not meet these standards. There is imprecision in who gets money—it is “outrageously inaccessible” to plaintiffs, it is slow, it is unpredictable, and people get “wildly varying awards” for similar injuries.

The issues in medical malpractice tort are likely to also be issues in the research participant context, said Mello. Further, tort law only compensates people who are injured due to negligence in the study; it would not be useful in a situation where, for example, the study was conducted well but the intervention turned out to be harmful. Causation would be difficult to prove, particularly if the investigational treatment is new and little is known about it. It is very difficult to prove causation for injuries to fetuses, and calculating economic damages for infants using actuarial tables can systematically undercompensate minoritized populations and girls, stated Mello. It could be difficult for would-be plaintiffs to find an attorney to take on their case, given the unpredictability and variability in awards.

Mello suggested that the government could require private institutions to set up a system of no-fault compensation rather than providing it through the government. Ifeyinwa Asiodu (Associate Professor of Family Health Care Nursing, University of California, San Francisco) noted that “not all research institutions are created equally;” there are significant inequities in funding and endowments, and universities that historically serve Hispanic and Black students often have fewer resources. However, these institutions may have greater access to a more diverse pool of research participants. If institutions were required to provide privately funded compensation, Asiodu posed, could this perpetuate inequities in research? Mello agreed that it could and suggested there might be ways to shift the costs. For example, the costs of a compensation scheme could eventually be negotiated as part of the indirect costs of a grant.

Research Participant Perspective

Jillian Brown shared her experiences as a clinical trial participant during pregnancy and nursing. During both of her pregnancies, Brown consented to participate in a screening for Cytomegalovirus (CMV) during an ultrasound. She tested positive for CMV during the second pregnancy, which put her at a high risk for complications. Brown said she was given information about the risks and told that there was no treatment or cure. She was offered the opportunity to participate in a study that included monthly infusions, additional ultrasounds, and testing of her child for two years after birth. A stipend was provided. Brown said that her participation in the trial was “a wonderful experience.” From her perspective, she and her child were already at risk because of CMV, so any risks of the trial seemed minimal in comparison. She did note that attending all the appointments was sometimes a lot to manage, especially when pregnant, but she believed in the research and wanted to contribute. However, Brown said that if she had not had a flexible job and reliable childcare, “there would’ve been no way” she could have participated.

Brown’s daughter was born healthy and has no health issues. Brown said that until getting invited to this workshop, she hadn’t deeply thought about the potential harms of the study and how she would have felt if something had gone wrong. If her daughter had been born with health issues because of her participation in the study, Brown said she would have felt guilty about voluntarily choosing to do something that put her child in harm’s way.

Marcela Smid also shared her experiences participating in a Respiratory Syncytial Virus (RSV) study while pregnant.

Smid said that the decision to participate was made easier by the fact that the clinical trial was conducted at her workplace, and she hoped to gain some protections against RSV—an infectious respiratory disease—while COVID-19 was also circulating. There was a heavy overrepresentation of healthcare workers participating due to the location of the trial; Smid noted that this trial did not do a good job of recruiting participants from all walks of life.

CASE STUDIES IN RISK MITIGATION

In the final session of the workshop, three panelists shared their practical experiences in mitigating risk when conducting research with PLP, moderated by Anna Mastroianni (Research Professor, Johns Hopkins University).

Nonprofit Perspective: Accelerating Innovation for Mothers

The development of Accelerating Innovation for Mothers was motivated by the fact that there have been relatively few innovations in the prevention and treatment of pregnancy-specific conditions for the last 30 years, said Metin Gülmezoglu (Executive Director, Concept Foundation). The tragedies related to the use of thalidomide and diethylstilbestrol (DES) in pregnant persons “created a culture of risk aversion in the field” that lasted for decades. The result of this culture, he said, is a lack of data for medicines used during pregnancy, both for general conditions and pregnancy conditions. Risk aversion, said Gülmezoglu, does not get rid of the risk but instead shifts the risk to another party. In the context of PLP, avoiding research on this population shifts the risk to care providers or pregnant people themselves.

In the absence of major public sector funding in this area, pharmaceutical companies represent the only viable option to develop evidence for PLP, said Gülmezoglu, but from his perspective they are reluctant to do so for several reasons:

• there is a low profit margin;
• the severe morbidity and mortality rates are relatively low in high-income countries;
• there is a perceived risk around liability;
• there are reputational and financial risks; and
• most products in development will fail and few will succeed.

Due to these challenges, there is a need for public-private partnerships to work together for drug development and evidence generation. The risks of this work could be mitigated through several mechanisms, including pooled insurance schemes, which involves grouping multiple insurance plans together into one collective to distribute risk amongst all the participants in the pool, thereby reducing the costs of premiums. There are successful examples of these schemes from low- and middle-income countries (LMIC). Alternatively, insurance could be funded by donors or the national government; this type of help to pharmaceutical companies could be accompanied by an obligation to research drugs in PLP. Gülmezoglu said that these mechanisms are unlikely to “create a flurry of innovations and new evidence,” but they would still be helpful in moving the field forward.

Nonprofit Perspective: PATH

PATH is a nonprofit that aims to advance health equity through innovation and partnerships across the public and private sectors, said Niranjan Bhat (Senior Medical Officer, PATH). PATH serves as a connector of funders, researchers, manufacturers, laboratories, governments, NGOs, and others, said Bhat, and partners with industry in exchange for public health commitments. Bhat works in maternal immunization and has worked on encouraging maternal influenza immunization in LMIC, evaluating a new pertussis vaccine for pregnant women and developing new vaccines for RSV and Group B streptococcus.

There are several reasons why PATH is well-suited to work in the area of maternal immunization, said Bhat. First, PATH has always been focused on underserved populations, which could be defined by socioeconomic status, racial or ethnic group, or pregnancy status. There are systems and infrastructure in place that allow PATH to propose and conduct research in these populations “without hesitation.” Part of this system is no-fault liability insurance, which reduces barriers and eases the

threat of litigation, said Bhat. Clinical trial insurance for investigators serves as the primary coverage, and a global umbrella policy serves as secondary coverage.

Beyond insurance, Bhat said that PATH is careful to ensure that trials meet scientific and regulatory standards and follow special precautions for trials involving PLP. All clinical development plans involve a discussion about the need for maternal immunization and the need to include reproductive toxicology studies before studying a product in humans. PATH works with funders and manufacturers to explain the considerations for maternal immunization trials, the staged progression that needs to happen before studying a vaccine in PLP, and the financial implications. One critical part of any research study is determining whether the research is likely to benefit the community; the local IRB looks at this when balancing risks and benefits. For example, if the burden of disease is high in a population, it may be worth a higher degree of risk to find an effective vaccine. Bhat noted that the risk-benefit calculation is different for vaccines than for drugs because a real, known risk is being given in return for a hypothetical benefit. In addition, in PLP, there is the question of who is expected to benefit from the vaccine or drug; some diseases can be minimal in the mother but very serious for the fetus or infant. This presents ethical implications to consider.

Each maternal immunization study is subjected to review within different countries and across different cultures that may have different perceptions of risk or tolerances for risk, said Bhat. He noted that the U.S. tends to be quite risk averse due to concerns of liability, whereas partners in other countries are “surprised or unaware” of any need for special consideration for research in PLP. As different regulatory agencies gain more experience working in PLP, they can set the standard for others.

Industry Perspective: Ferring Pharmaceuticals

Ferring Pharmaceuticals has a core mission of developing therapies for reproductive medicine and maternal health, said Lorien Urban (Senior Medical Director, Clinical Development, Ferring Pharmaceuticals). For example, Urban described work by Ferring to develop a product to help women who experience preterm birth and struggle with low milk supply. Because Ferring is committed to serving this population, they have been able to embrace the barriers and find ways to overcome them, she said. One of the barriers to conducting clinical trials with PLP is dealing with regulatory expectations. For example, safety follow-up is a “big question mark” in this area; it is unclear how long maternal participants and infants should be monitored for safety outcomes, and there is no defined pathway to help make decisions. If an investigator is required to follow participants for two years, this is a “tremendous barrier” to getting a product to market. Urban said that one approach for reducing this barrier is to allow the study to end at a certain point (e.g., one year) and require safety followups for a certain period (e.g., an additional year). At Ferring, studies in PLP populations often include a safety monitoring committee; this structure “goes a long way to mitigating risk” because of the frequent review of safety events. Another challenge is separating adverse events related to the investigational product from health issues that arise during pregnancy and lactation. One way to manage this barrier, Urban said, is to clearly define safety signals ahead of time compared to what is expected in the population.

There are not a lot of clear precedents to follow in approval of medical products for PLP. Laying out a clearer and more concise regulatory pathway to approval would lower the barrier to entry for companies, particularly those who do not have a history of working with the PLP population. Defining the pathway would require the engagement of the FDA, she said. One specific area in which clarity is needed is in what is required for studies on pregnant people versus lactating people. It is possible to measure whether and to what extent a drug is transferred to the baby through milk, but it is not clear how this evidence fits into the approval process (e.g., appropriate follow-up time for a drug that does not pass into milk). Urban concluded, there is a pervasive lack of understanding about the differences in risk between pregnant and lactating populations.

DISCLAIMER This Proceedings of a Workshop—in Brief has been prepared by Erin Hammers Forstag as a factual summary of what occurred at the meeting. The statements made are those of the rapporteur or individual workshop participants and do not necessarily represent the views of all workshop participants; the consensus study committee; or the National Academies of Sciences, Engineering, and Medicine.

*The National Academies of Sciences, Engineering, and Medicine’s consensus study committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop—in Brief rests with the institution.

REVIEWERS To ensure that it meets institutional standards for quality and objectivity, this Proceedings of a Workshop—in Brief was reviewed by Michelle Mello, Stanford University, and Anup Challa, AstraZeneca. Leslie Sim, National Academies of Sciences, Engineering, and Medicine, served as the review coordinator.

STAFF Alex Helman, Andrew March, Carolyn Shore, Emily McDowell, Melvin Joppy, and Clare Stroud, Board on Health Sciences Policy, Health and Medicine Division, National Academies of Sciences, Engineering, and Medicine.

SPONSORS This workshop was supported by the National Institutes of Health (Contract No: HHSN263201800029I, Task Order: 75N98022F00010).

For additional information regarding the workshop, visit https://www.nationalacademies.org/event/03-23-2023/research-with-pregnant-and-lactating-persons-mitigating-risk-and-liability-and-committee-meeting-2.

SUGGESTED CITATION National Academies of Sciences, Engineering, and Medicine. 2023. Research with pregnant and lactating persons: Mitigating risk and liability: Proceedings of a workshop—in brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/27142.

Health and Medicine Division Copyright 2023 by the National Academy of Sciences. All rights reserved.