Inclusion of Pregnant and Lactating Persons in Clinical Trials Proceedings of a Workshop (2023) / Chapter Skim
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3 The Legal Landscape
3 The Legal Landscape
Pages 19-42
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From page 19... ...
• Conducting clinical trials that include pregnant and lactating persons is legally and ethically permissible, but regulatory ambiguities, perception of liability, risk management chal lenges, and state laws undermine the inclusion of these popu lations in clinical research. (Henry)
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From page 20... ...
The regulations for the protection of human subjects in research address research involving pregnant persons, fetuses, and neonates -- as addressed
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From page 21... ...
Henry explained that there is immunity from liability associated with medical countermeasures used in response to a public health emergency. Based on a series of consultations with legal experts, Henry and colleagues found that "lawyers and regulators have the potential to be involved in decision-making that influences the conduct of research at every point throughout the research pathway," including decisions around the inclusion of pregnant persons in studies.
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From page 22... ...
Henry said fear that including pregnant persons in clinical trials will lead to "another thalidomide" is misplaced. She pointed out that the thalidomide crisis occurred because pregnant people were not included in clinical studies of the drug before it was widely used in pregnant persons.
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From page 23... ...
Regulatory Barriers to Inclusion The Common Rule no longer includes pregnant persons as a potentially vulnerable population with regard to consenting to clinical trial participation. However, Maggie Little, Georgetown University, said there are concerns that 45 CFR 46 Subpart B, Additional Protections for Pregnant Women, Human Fetuses, and Neonates Involved in Research, still presents regulatory barriers to conducting clinical trials in pregnant and lactating individuals.6 One of these, as mentioned by Henry, is the ambiguity around the term minimal risk to the fetus.
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From page 24... ...
Negative and positive and inconclusive results of pediatric studies must be placed in labeling • 2012 FDASIA legislation makes permanent BPCA and PREA • 2017 RACE for Children Act: PREA changed to address challenges in pediat ric cancer development by requiring studies in molecular targets substantially relevant to the growth or progression of a pediatric cancer • 2022 Anticipate 1,000th pediatric-specific labeling change under BPCA and PREA expected to be approved NOTE: AAP, American Academy of Pediatrics; BPCA, Best Pharmaceuticals for Children Act; FD&C, Food, Drug, and Cosmetic; FDAA, Food and Drug Administration Reauthorization Act; FDAMA, Food and Drug Administration Modernization Act; FDASIA, Food and Drug Admin istration Safety and Innovation Act; PREA, Pediatric Research Equity Act; RACE, Research to Accelerate Cures and Equity. SOURCES: Yao presentation, September 17, 2022; FDA, 2018; IOM, 2008; NICHD, n.d.
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From page 25... ...
She highlighted three common sources of drug-related risk during pregnancy and the patient perceptions behind them. In her experience, she said that newly pregnant persons often discontinue a drug they are taking for an existing condition because they perceive it to be harmful during pregnancy.
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From page 26... ...
Roberts suggested that involving OBGYNs in clinical trials, even when not specifically designed to evaluate pregnant individuals, could begin to remove barriers to inclusion of this population. Research Perspective Jessica Cohen, director of the Office of Research Affairs at PATH, discussed a range of questions and concerns associated with liability risk for researchers across the clinical research continuum.
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From page 27... ...
• Managing injury and adverse events. Managing liability claims will vary based on where the research with pregnant persons is being conducted.
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From page 28... ...
The primary concern for a company conducting a clinical trial is protecting trial participants while taking "informed and necessary risks" to gather sufficient evidence to bring a product to market and enable providers to make informed decisions for their patients, she said. Wein emphasized the importance of getting products to those who need them without delay and pointed out that "adding complex populations to those trials is a consideration." While the risk of liability is a consideration pre- and postapproval, she said that any hesitancy to include pregnant and lactating people in trials is not attributable solely to liability risk.
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From page 29... ...
Different stakeholders in clinical research have different levels of risk tolerance and ability to manage liability, and she said that expanding inclusion of pregnant and lactating persons in clinical trials "will require all parties to confront their fears of liability for injuries." INSTITUTIONAL POLICIES AND PRACTICES THAT PROMOTE INCLUSION IN RESEARCH Anna Mastroianni, Charles I Stone professor of law at the University of Washington (UW)
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From page 30... ...
Mastroianni noted that the UW IRB review of research involving pregnant participants routinely includes an obstetrician, and that the transparency and consistency of the IRB process has helped build a trust ing relationship between the investigators and the IRB. Another enabling factor identified by the study is the UW Human Subjects Assistance Program, a self-funded compensation program that provides medical and other assistance to participants who incur injuries that are "more likely than not caused by UW-conducted research." Mastroianni said study respondents felt the compensation program also protected researchers, and information provided indicates that "UW has fewer research-related lawsuits and tort claims than comparable institutions." Mastroianni added that a multipronged approach is required to overcome the legal hurdles impeding the inclusion of pregnant and lactating persons across the clinical trial continuum, she said.
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From page 31... ...
The guidance, Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials, discusses issues such as balancing the risks and benefits of continued trial participation for a person who becomes pregnant during a trial.11 The Postapproval Pregnancy Safety Studies guidance addresses the design of required postmarketing studies such as prospective cohorts (i.e., registries) and complementary studies to close gaps in data.12 Other relevant guidances mentioned by Sewell address the design of clinical lactation studies and increasing diversity in clinical trials.13 Additionally, FDA has worked to better harmonize FDA regulations with the Common Rule by removing references to pregnant persons as a vulnerable population in this context.14 10 Sewell noted that the opinions expressed are her own and do not necessarily represent an official position of FDA.
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From page 32... ...
This expansion will help identify areas where clinical studies are needed to address treatment needs during pregnancy, Sewell said. Roberts described FDA's efforts to increase data collection from pregnant persons during the development of COVID-19 vaccines.16 The first FDA guidances addressing the development of COVID-19 vaccines encouraged sponsors to remove the requirement for contraception (after conducting reproductive toxicology studies to provide adequate support for the safe initiation of studies in pregnant persons)
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From page 33... ...
Mastroianni emphasized that lawyers manage risk on a daily basis. A first step could be to engage lawyers as partners in the study development process and prioritize focusing on ways to address the liability risks of including pregnant and lactating persons in clinical trials, Mastroianni said.
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From page 34... ...
Sewell encouraged sponsors to engage with FDA early on in trial development through a preinvestigational new drug application meeting with the agency. Ruth Karron, professor of international health at the JHU Bloomberg School of Public Health, said there is a perception that a product sponsor's vested interest in bringing a product to market quickly dissuades them from including pregnant persons in trials.
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From page 35... ...
it was emphasized that financial factors play a role in study design and "to not mistake something as legal when what is actually going on is financial." Brittany Bettendorf, University of Iowa, asked if the learned intermediary doctrine creates a disincentive for pharmaceutical companies to include pregnant persons in clinical studies, as shifting liability risk downstream to the clinician would seem to be in the best interest of the company. Henry said that including pregnant persons in studies would provide clinicians with information to support shared decision-making with the patient.
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From page 36... ...
She speculated that, under 45 CFR 46 Subpart B as written, research with a direct benefit to the fetus might be more acceptable than including pregnant persons in studies of products with no pregnancy-specific benefit. Potential Effect of Fetal Personhood on Clinical Trials with Pregnant Persons Panelists discussed how potential federal and state laws governing the personhood status of a fetus might affect the liability associated with clinical trials involving pregnant persons.17 Henry noted that some states have existing statutes regarding the personhood of a fetus and said, "There is no evidence to date that any of these statutes have been used to prevent research with pregnant or lactating people." However, misuses of these statutes remain a concern.
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From page 37... ...
Awarding the fetus legal personhood creates two separate entities and could lead to two competing sets of interests. Sabra Anckner of the Association of Maternal and Child Health Programs suggested that pregnant persons have been considered a vul nerable population with regard to clinical trial participation because of concerns about the fetus, not the pregnant person.
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From page 38... ...
The following is a list of potential solutions to address liability risk that were discussed: • Establishing requirements for the inclusion of pregnant and lac tating persons in clinical trials. Participants discussed that the lack of any requirement to include pregnant or lactating persons in studies is a barrier for clinical investigators.
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From page 39... ...
Solutions suggested by participants (drawn in part from lessons learned from COVID-19 clinical trials expe riences) included allowing more flexibility in how samples for laboratory testing can be collected (e.g., by a local laboratory, by home health care workers, self-collection)
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From page 40... ...
Several participants discussed the need for more clarity around issues such as what constitutes minimal risk and what data are sufficient to justify inclusion of pregnant or lactating persons in a trial. It was noted that what constitutes minimal risk might vary over the course of pregnancy, and that this is not addressed by 45 CFR 46 Subpart B
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From page 41... ...
• Establishing requirements for inclusion. Incentives and require ments for including pregnant and lactating persons in clinical trials were also discussed by participants considering the liability issues for sponsors.
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