Advancing Clinical Research with Pregnant and Lactating Populations Overcoming Real and Perceived Liability Risks (2024) / Chapter Skim
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5 Dissuasive and Persuasive Factors for the Inclusion of Pregnant and Lactating Women in Clinical Research
5 Dissuasive and Persuasive Factors for the Inclusion of Pregnant and Lactating Women in Clinical Research
Pages 149-178
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From page 149... ...
For pharmaceutical com panies in particular, factors that enter into the decision-making process include the state of the science concerning the disease or condition, path way, and the investigational product; the unmet medical need; the cost and complexity of the laboratory, preclinical, and clinical research; when and whether the company will be able to recoup its costs; the competitive landscape; and regulatory requirements.1 Companies may also weigh the decision to conduct research with pregnant and lactating women with whether data on safety and efficacy could be collected in animal models or through postmarketing studies, such as pregnancy registries. If the considerations against doing the research outweigh those in favor of doing the research -- for example, because of unpredictable 1 As presented to the committee by Kirke Weaver in open session on June 16, 2023.
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Because of the interconnected relationship between liability and other such factors, and because factors that enter into decisions to include preg nant and lactating women in research are sometimes termed liabilities even though they involve no legal risk, this chapter presents the commit tee's consideration of several factors that can affect liability assessments and contribute to stakeholder decision making concerning the inclusion of pregnant and lactating women in research. FACTORS THAT DISSUADE SPONSORS AND INVESTIGATORS FROM INCLUDING PREGNANT AND LACTATING WOMEN IN RESEARCH The factors that dissuade the various stakeholders in the develop ment and use of medical products from including pregnant and lactating women in clinical research affect the entire pathway of medical product development, from preclinical studies to postapproval surveillance.
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experiences furthered the idea that women of childbearing age and pregnant women should be excluded from trials even though those events were not the result of clini cal trials. In fact, it is likely that had clinical trials for thalidomide and DES applied modern study design, these trials would have significantly mini mized the damage by revealing that thalidomide was teratogenic and that DES was ineffective for use in pregnancy (see Chapter 2)
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required the inclu sion of women of childbearing age and minorities in federally funded clinical studies. However, as mentioned in Chapter 1, while there has been a growing recognition of the need to include pregnant and lactating women in clinical trials in recent years -- such as through the Task Force on Research Specific to Pregnant Women and Lactating Women -- the long-standing culture of an exclusion mindset persists, preventing the generation of needed evidence to support medical treatments for preg nant and lactating women.
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. For example, Subpart B of the HHS regulations requires research involving pregnant women that does not confer either a direct benefit to the pregnant woman or the fetus to involve no more than "minimal risk." Although the policy does allow for pregnant women to be enrolled in research that confers more than "minimal risk" if it offers the poten tial for direct clinical benefit to the pregnant woman or the fetus, in practice, many institutional review boards (IRBs)
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. Recruiting and Enrolling Participants The reasons pregnant women participate in clinical trials are the same reasons that people generally participate in trials: aspirational benefits and altruism (van der Zande, 2018)
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Evidence points to several factors that may positively influence pregnant women's deci sions to participate in clinical studies, including ease of transportation and access to research sites, supportive attitudes from family and friends, and studies using community-based methods (Frew et al., 2014)
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For example, researchers and their institutions have a desire to maintain a positive reputation for ethical research in order to attract future funding. Stakeholders may avoid including pregnant and lactating women in research on new medical products owing to fears of injuries and negative media attention such as that which accompanied the harm to pregnant women and their off spring associated with thalidomide, DES, and doxylamine/dicyclomine/ pyridoxine (Bendectin)
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. Study ing the safety and efficacy of a medical product in pregnant or lactating women most likely would require separate trials, rather than simply including pregnant and lactating women in a trial of the general adult population (van der Zande et al., 2016)
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. Current NIH R01 grant caps may be too low to support the conduct of adequately pow ered clinical studies with pregnant women or the follow-up of offspring for prolonged periods.
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Including pregnant and lactating women in clinical trials may add cost, time, and complexity to the trial, while offering few regulatory or marketing advantages (Mastroianni et al., 2017; van der Zande et al., 2016)
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However, it is crucial that policies to promote clinical research target each of these three stages in a product's life cycle to prevent the perpetuation of the current backlog and so pregnant and lactating women can have access to new therapeutics in a timely manner. On-Market, Off-Patent Products The majority of medications that pregnant women take are off-patent (Palmsten et al., 2015)
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. • The Global Network for Women's and Children's Health Research supports and conducts clinical trials in resource-limited countries, with the aim of improving maternal and child health while building local research capacity (NIH, 2023d)
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Similar to conducting research on off-patent medical products for pregnant and lactating women, there are few financial incentives to sup port drug repurposing for an off-patent drug or to conduct clinical research on off-patent drugs for pediatric use (Austin et al., 2021; Haslund-Krog et al., 2021)
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. Lessons learned on conducting pediatric trials through the PTN have informed other pediat ric drug networks, such as the Global Pediatric Clinical Trials Network, helping to advance drug development in children.
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The report recommended revisions to the regulations and guidance on minimal risk to provide greater clarity for IRBs and reduce divergent interpretations. The report also addressed the special populations discussed in the Com mon Rule, including pregnant women, by recommending improved guid ance that helps IRBs distinguish between vulnerabilities in participants' lives and their vulnerability to research risks.
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found that research with pregnant women was more likely to receive IRB approval when investigators took steps during the study design process to minimize risks for potential pregnant participants and their offspring and when they requested safety data from drug companies and FDA. Further, consulting with IRBs throughout the study design process was helpful in identifying potential risks, strengthening the protocol prior to submission, and navigating IRB rules.
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Unlike priority review vouchers or the Orphan Drug Act, the BPCA targets incentives to drugs that are approved and on-patent but do not have data on the drug's use in a defined population -- children (see Box 5-2) .6 The BPCA appears to be an enticing incentive for some spon sors.
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Although a number of efforts attempted to include more research on pediatric populations over the years, change really began in the late 1990s with the passage of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA)
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. populations is a developing field of regulatory science, which may help to speed pediatric drug development and reduce the number of pediatric participants that need to be enrolled in clinical trials (Sun, 2017)
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As described above, priority review vouchers and the Orphan Drug Act are examples of incentives designed to spur research PREPUBLICATION COPY -- Uncorrected Proofs A02260_Advancing_Clinical_Research_CH05.indd 169 3/20/24 2:00 PM
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. While there are challenges to conducting pediatric studies for these drugs given the small patient populations, the waivers 7 Pediatric Research Equity Act of 2003, P.L.
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Conclusion 5-2: Financial incentives can be a powerful counterbalance to the dissuasive factors that sponsors, researchers, research institutions, and other stakeholders weigh in their decisions concerning inclusion of pregnant and lactating women in clinical research. Conclusion 5-3: A legal requirement that sponsors conduct clinical studies in pregnant and lactating women would advance product labeling information on the safety, efficacy, and dosing of medical products for these populations.
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2020. Best Pharmaceuticals for Children Act and Pediatric Research Equity Act - Status report to Congress.
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In Clinical research involving pregnant women, vol. 3, edited by F
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2020. The pathway for ward: Insights on factors that facilitate research with pregnant women.
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. PRGLAC Task Force (Task Force on Research Specific to Pregnant Women and Lactating Wom en)
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2021. Physician perspectives on including pregnant women in Covid-19 clinical trials: Time for a paradigm change.
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2018. Factors influencing the recruitment of lactating women in a clinical trial involving direct oral anticoagulants: A qualitative study.
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PREPUBLICATION COPY -- Uncorrected Proofs A02260_Advancing_Clinical_Research_CH05.indd 178 3/20/24 2:00 PM
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