A qualitative study on acceptable levels of risk for pregnant women in clinical research

U.S. researchers and scholars often point to two legal factors as significant obstacles to the inclusion of pregnant women in clinical research: the Department of Health and Human Services' regulatory limitations specific to pregnant women's research participation and the fear of liability for potential harm to children born following a pregnant woman's research participation. This article offers a more nuanced view of the potential legal complexities that can impede research with pregnant women than has previously been reflected in the literature. It reveals new insights into the role of legal professionals throughout the research pathway, from product conception to market, and it highlights a variety of legal factors influencing decision-making that may slow or halt research involving pregnant women. Our conclusion is that closing the evidence gap created by the underrepresentation and exclusion of pregnant women in research will require targeted attention to the role of legal professionals and the legal factors that influence their decisions.

BackgroundBioethicists argue that inclusion of pregnant women in clinical research should be more routine to increase the evidence-base for pregnant women and foetuses. Yet, it is unknown whether pregnant women and others directly involved are willing to be routinely included. Therefore, we first need to establish what these stakeholders think about research participation in regular pregnancy-related research. However, studies on their views are scarce. In our study, we piggy-backed on a relatively conventional RCT, the APOSTEL VI study, to identify the views of stakeholders on inclusion of pregnant women in this study.MethodsWe conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed pregnant women (n = 14) recruited for the APOSTEL VI study, in addition to healthcare professionals (n = 14), Research Ethics Committee members (RECs) (n = 5) and regulators (n = 7) involved in clinical research in pregnant women.ResultsThree themes characterise stakeholders’ views on inclusion of pregnant women in the APOSTEL VI study. Additionally, one theme characterises stakeholders’ interest in inclusion of pregnant women in clinical research in general. First, pregnant women participate in the APOSTEL VI study for potential individual benefit and secondarily for altruistic motives, contrary to hypothetical studies. Second, a gatekeeping tendency hampers recruitment of pregnant women who might be eligible and willing, and questions about pregnant women’s decisional capacities surface. Third, healthcare professionals sometimes use the counselling conversation to steer pregnant women in a direction. Fourth, all stakeholders are hesitant about inclusion of pregnant women in clinical research in general due to a protective sentiment.ConclusionsPregnant women are willing to participate in the APOSTEL VI study for potential individual benefit and altruistic motives. However, an underlying protective sentiment, resulting in gatekeeping and directive counselling, sometimes hampers recruitment in the APOSTEL VI study as well as in clinical research in general. While bioethicists claim that inclusion of pregnant women should be customary, our study indicates that healthcare professionals, regulators, RECs and pregnant women themselves are not necessarily interested in inclusion. Advancing the situation and increasing the evidence-base for pregnant women and foetuses may require additional measures such as investing in the recruitment and feasibility of RCTs and stimulating pregnant women’s decisional capacities.

The lack of human data available to inform evidence-based treatment for illness during pregnancy has led to calls for greater inclusion of pregnant women in research, but the extent of their current representation is poorly characterized. Our objective was to measure the current exclusion of pregnant women from industry-sponsored clinical trials as a baseline for future comparison. We compiled data from studies enrolling women of childbearing potential posted on www.ClinicalTrials.gov between 1 October 2011 and 31 January 2012. The review was limited to open United States-based phase IV interventional studies sponsored by the pharmaceutical industry evaluating treatment of conditions that may be experienced by but are not limited to pregnant women and did not involve a medication classified as potentially teratogenic. If there was no mention of pregnancy in the inclusion or exclusion criteria, we contacted a study representative to confirm that pregnant women could be enrolled. Of 558 qualifying industry-sponsored studies, five (1%) were designed specifically for pregnant women. Of 367 phase IV clinical trials with verified inclusion and exclusion criteria, 348 (95%) excluded pregnant women and 19 (5%) did not. We found the exclusion of pregnant women from industry-sponsored clinical trials to be common practice. Moving beyond reflexive exclusion and developing thoughtful criteria for inclusion of pregnant women in clinical research would likely advance the evidence base to inform treatment decisions during pregnancy and lead to better health outcomes for women and children.

Accelerating the paradigm shift toward inclusion of pregnant women in drug research: Ethical and regulatory considerations

Scanty evidence exists about the safety and effectiveness of drugs-and of their efficacious dosing-that women may need to treat acute and chronic health issues during their pregnancies. This lack of evidence puts pregnant women and their fetuses at risk of harm from the use or avoidance of drugs during pregnancy. In light of the protectionist approach in regulations governing research with pregnant women and fetuses, trial sponsors, researchers, clinicians, and institutional review boards (IRBs) have been reluctant to include pregnant women in clinical drug trials, applying ethical reasoning for exclusions that reflects a default exclusionary approach. Yet in recent years, many clinicians, researchers, bioethicists, and professional societies have called for a reexamination of the routine practice of excluding pregnant women from clinical research. This paper proposes a practical approach to an ethical framework for IRBs that supports fair inclusion, rather than routine exclusion, of pregnant women in clinical research. This guidance will aid IRBs in ethically including and appropriately protecting pregnant women in research.

Topics

Though much progress has been made on inclusion of non-pregnant women in research, thoughtful discussion about including pregnant women has lagged behind. We outline resulting knowledge gaps and their costs and then highlight four reasons why ethically we are obliged to confront the challenges of including pregnant women in clinical research. These are: the need for effective treatment for women during pregnancy, fetal safety, harm from the reticence to prescribe potentially beneficial medication, and the broader issues of justice and access to benefits of research participation. Going forward requires shifting the burden of justification from inclusion to exclusion and developing an adequate ethical framework that specifies suitable justifications for excluding pregnant women from research.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Facilitating inclusion of pregnant women in clinical research could help answer important questions about the effects of medication use during pregnancy and the ways in which pregnancy alters pharmacokinetics and drug effects.

Enrolling Pregnant Women: Issues in Clinical Research

Therapeutic tragedies of the past, ethical concerns, and legal risks, among other factors have led to a conservative approach to clinical research during pregnancy, resulting in a de facto exclusion of pregnant women from most clinical therapeutics trials. As a result, there is a deficit of knowledge regarding the safety and proper dosing of medications during pregnancy, leaving prescribers with limited information available to support clinical decision-making. Additionally, there is little development of treatments for pregnancy-specific conditions. This review describes the current need for therapeutic development in pregnant women, summarizes the history of regulations impacting this research area, and describes current efforts to increase the information used to help make decisions regarding the use of drugs during pregnancy and lactation. This is a brief review of the literature, federal regulations, and policies on research in pregnant women. While therapeutic development in pregnant women has been limited in the past, recent efforts by academic researchers, bioethicists, industry, advocacy groups, and federal agencies have sought to enhance strategies to increase the participation of pregnant women in clinical research that may benefit them and/or their fetus. Collaborative efforts from all stakeholders, including industry, academia, advocacy groups, regulators, and other governmental agencies, if successful will increase the information needed to help make decisions regarding the use of drugs during pregnancy and lactation.

BackgroundNotwithstanding the need to produce evidence-based knowledge on medications for pregnant women, they remain underrepresented in clinical research. Sometimes they are excluded because of their supposed vulnerability, but there are...

Though much progress has been made on inclusion of non-pregnant women in research, thoughtful discussion about including pregnant women has lagged behind. We outline resulting knowledge gaps and their costs and then highlight four reasons why ethically we are obliged to confront the challenges of including pregnant women in clinical research. These are: the need for effective treatment for women during pregnancy, fetal safety, harm from the reticence to prescribe potentially beneficial medication, and the broader issues of justice and access to benefits of research participation. Going forward requires shifting the burden of justification from inclusion to exclusion and developing an adequate ethical framework that specifies suitable justifications for excluding pregnant women from research.

The article deals with the need of compulsory participation of pregnant women in clinical research of drugs. By the beginning of the 90‑s of the last century, the majority of drugs prescribed to women was characterized by unsubstantial evidence of effectiveness and safety for women. Moreover, pregnant women almost did not participate in clinical research. Though pregnancy is a dynamic condition that can be compared with itself only. Then supervisory bodies created some documents regulating compulsory participation of the population in the research of drugs. However, until now, women are not sufficiently involved in the research of new original drugs, and pregnant women do the same very rarely. Possible scenarios of participation of pregnant women in clinical research have been reviewed. In particular, research of drugs used in therapy of abnormal conditions associated with pregnancy; drugs to treat chronic and acute pathological processes not related to pregnancy, and when a woman gets pregnant during the research have been distinguished. The importance of inclusion of pregnant women into the trials of effectiveness and safety of drugs in the presence of socially significant diseases, including the ones found during COVID‑19 pandemics, is postulated.

Various national and international research guidelines and regulations limit the inclusion of pregnant women in clinical research by classifying them as vulnerable. This exclusion has widely acknowledged negative consequences for the health of women, foetuses, and future children. Another negative consequence is the threat to a pregnant woman’s autonomy and agency when she is treated as a ‘vulnerable’ person without cause. Research guidelines and regulations around the world continue to be overly protectionist. The limitations on autonomy they imply (and create) infantilise pregnant women, treating them ‘as if’ they are vulnerable – as if they, in fact, lack autonomy and the capacity to make informed choices about their own research participation. The hypothetical ‘as if’ becomes actual as research guidelines and regulations effectively reduce the autonomy and agency of pregnant women, making them unable to protect their own interests, including their interests in protecting their future children.