Advancing Clinical Research with Pregnant and Lactating Populations Overcoming Real and Perceived Liability Risks (2024) / Chapter Skim
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1 Introduction
1 Introduction
Pages 17-48
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From page 17... ...
To ensure the health and well-being of pregnant and lactating women and their fetuses and newborns, evidence is needed on the safety, effectiveness, and proper dosage of medical products that these individuals may need to take dur ing the perinatal period. Sufficient data on safety and effectiveness allow health care providers and patients to make informed decisions about an intervention's potential benefits and risks.
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This chapter begins with a discussion of the social benefits of research involving pregnant and lactating women and is followed by an explora tion of the human cost of inadequate data, explores the sources of the inadequate data, provides a background to the study, and ends with the committee's approach to their charge. THE HUMAN COSTS OF INADEQUATE DATA Pregnant and lactating women with acute or chronic conditions must make difficult decisions about their health every day.
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However, only 11 percent of drugs approved between 2010 and 2019 included human data to guide prescribing for pregnant women (Byrne et al., 2020) , which makes pre conception prescribing difficult.
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. Without human data on the effects of medical products in early pregnancy, clinicians are unable to provide the best health care and cannot address potential harm in treating women who are intending to or may become pregnant.
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. In addition to infectious diseases, pregnant women are also at higher risk of developing or worsening chronic conditions during pregnancy.
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Gastrointestinal: Multiple factors present in pregnancy -- including delayed gas tric emptying, increased small bowel transit time, reduced muscle tone of the lower esophageal sphincter, and compression attributable to uterine growth -- make gas troesophageal reflux disease common in pregnant women. Implications for Medication Use These changes and many others that occur during pregnancy have implications for the safety and efficacy of medications, owing to changes in the absorption, metabolism, PREPUBLICATION COPY -- Uncorrected Proofs A02260_Advancing_Clinical_Research_CH01.indd 22 4/4/24 1:48 PM
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For example, there are substantial differ ences between pregnant and nonpregnant women in the distribution of buprenor phine, a lipophilic partial opioid agonist used to treat individuals with substance use disorders (Eke et al., 2023)
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. Without human safety data in lactation, many lactating women may choose to cease lactation to take a medical product for their health or continue lactation and delay treatment of their health condition.
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In fact, both PREVENT and PHASES offer guidance on how to achieve ethical inclusion of pregnant women in clinical research. The exclusion of pregnant and lactating women from clinical studies has resulted in a dearth of evidence on the safety, effi cacy, and dosing of medical products that are used or could be used by these populations.
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One reason there is a lack of research involving pregnant popula tions is concern about fetal safety that reinforces decisions not to include pregnant women in clinical research. For example, the lack of human data on the safety of medical products in pregnancy creates anxiety about the unknown risks to the fetus, which causes sponsors and researchers to be hesitant about conducting research involving pregnant women, and ultimately leads to the continued dearth of dosing, safety, and efficacy data of medical products in pregnant women (Santye, 2016)
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Council for International Organizations of Medical Sciences (CIOMS) : In 2002, CIOMS released updated guidelines that stated that pregnant women should be eligible for participation in research (CIOMS, 2002)
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The generalizable evidence gained through biomedical discovery, development, and clinical research leads to new medical products that detect disease, reduce human suffer ing, improve well-being, and save lives. Ultimately, to justify exposing people to potential harms through clinical research, research must have some societal value or benefit (Emanuel et al., 2000)
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. Since sufficient evidence on medical products is also not available to pregnant women in other countries with lower maternal mortality rates, the high rate of U.S.
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. This means that pregnant women of color, who are more likely to enter pregnancy with comorbid conditions and end pregnancy having experienced adverse health events, are disproportionately disadvantaged by the exclusion of pregnant women from clinical studies and the resultant lack of suf ficient data to inform optimal care of their conditions.
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In 2020, as a follow-up to its 2018 report, the PRGLAC Task Force released the PRGLAC Report Implementation Plan, which provided an update on the implementation of the recommendations in the PRGLAC report and provided guidance for making progress on the recommenda tions. The implementation plan called for the following: Convene a panel with specific legal, regulatory, and policy expertise to develop a framework for addressing liability issues when planning or con ducting research with pregnant women and lactating women.
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the govern ment for conducting research specifically on therapeutics and vaccines, including associated medical devices (e.g., diagnostic devices, drug delivery systems) , for medical conditions experienced by pregnant and lactating persons.
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For example, Chapter 5 of the report provides an overview of factors beyond liabil ity that prevent broader inclusion of pregnant and lactating women in clinical research. These factors are not directly tied to liability but may often get conflated with liability and are considered alongside liability in decisions whether to include pregnant and lactating women in clini cal research.
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Clinical studies must be conducted in pregnant and/or lactating women if pregnancy- or lactation-specific medical products are to get to market. However, the basic science research, the pool of obstetrical/lactation clinical investigators, and the infrastructural support that are uniquely focused on the potential problems associated with pregnancy and lactation are in short supply (Longo and Jaffe, 2008)
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During this workshop, the committee heard from a defense attorney, clinical trial insurers, academic medical center counsel, an expert in institutional review boards, research participants, lawyers with expertise in tort law and compensation programs, and researchers who have experience conducting clinical studies involving pregnant and lactating women. The agenda for this workshop and the committee's other public meetings are available in Appendix A
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Lastly, clinical research involves many stakeholders that play differ ent roles in developing medical products that are safe and effective for the people who use them. Box 1-6 provides an overview of the key stakeholders that are involved in conducting research with pregnant and lactating women.
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regulates and approves new medical products. FDA approves applica tions for clinical trials on new medical products (Investigational New Drug Ap plication [IND]
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Recent policy changes have begun to correct the prolonged neglect of women's par ticular health conditions and needs but have not yet overcome the failure to focus on finding the appropriate dosage, safety, and efficacy of drugs during pregnancy or lactation. Using the term women also aligns the report with the language in fed eral guidance and regulations, such as those on conducting clinical trials during pregnancy or lactation.
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For the purposes of this study, the committee has chosen a broad definition of clinical research, which includes: • Preclinical research that uses laboratory and/or animal studies to assess safety and efficacy before testing in humans. • Clinical studies that involve human participants can be divided into four phases: ° Phase I: Small groups, generally of healthy volunteers, are tested to assess pharmacokinetics, pharmacodynamics, dosing, safety and activity.
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Pregnant women may be excluded from clinical studies because of the risk of harm to them and/or their fetuses, the risk of liability for causing harm to them and/or their fetuses, or based on other factors described later in this report (see Chapter 5)
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Chapter 2 provides an intro duction to liability, provides an overview of liability for including preg nant and lactating women in clinical studies, explores perceptions of liabil ity, and discusses the relationship between the risk of harm and the risk of liability. Chapter 3 is about reducing the potential for harms from clinical studies with pregnant and lactating women, both through the current regulatory system and through any improvements that can be made to that system to minimize harm.
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2016. Clinical research involving pregnant women, vol.
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US Pharmacist. https://www.uspharmacist.com/article/breastfeeding-and-medication-safety (accessed December 15, 2023)
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2021. Pregnant women & vaccines against emerging epidemic threats: Ethics guidance for preparedness, research, and response.
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2017. Research with pregnant women: A call to ac tion.
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2018. Task Force on Research Specific to Pregnant Women and Lactating Women.
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2018. Fair inclusion of pregnant women in clinical trials: An integrated scientific and ethical approach.
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