Canadian physician perspectives on the inclusion of pregnant women in trials of intervention for COVID-19

Pregnant women's appetite for risk

There is paucity of evidence to support clinical decision making and counselling related to medication use in pregnancy. Despite multiple efforts from legislative bodies and advocacy groups, the inclusion of pregnant women in clinical drug trials assessing efficacy and safety remains scarce. Pregnancy can be complicated by multiple comorbidities that require pharmacological intervention; these interventions primarily target the pregnant woman but also sometimes have secondary effects for the foetus. The US Food and Drug Administration has issued multiple guidance documents on incorporating pregnant women in clinical trials to aid pharmaceutical companies in designing a protocol to ensure safety and adherence to ethical standards. Advances in paediatric pharmacology studies provide lessons for researchers on the best practice of designing clinical trials with inclusion of patients from special populations. In this review, we present the status of pregnant women in clinical trials, highlighting the ethical stigma and possible future directives.

IntroductionLassa fever runs a uniquely severe course in pregnancy. There are plans for Lassa fever vaccine clinical trials in endemic West African countries. We assessed the perception of West African investigators to include pregnant women in these studies.Methodsinterviews were conducted with eight sub-Saharan African investigators. These investigators, listed as speakers at the 9th European and developing countries clinical trials partnership (EDCTP) congress and had clinical research experience in sub-Saharan Africa, were purposefully included as study participants. Six are from West Africa. The information was analyzed thematically.Resultswe interviewed eight (six in-person and two on the phone) out of fifteen earmarked investigators. Respondents had limited experience with pregnant women in clinical trials, but desired a paradigm shift. They identified pregnant women's willingness, a robust community engagement strategy, and adequate safety data as enablers, while lack of safety data, persistent fears about potential harm to pregnant women and offspring, and inappropriate community engagement activities as potential barriers.Conclusionthe inclusion of pregnant women in Lassa fever vaccine clinical trials should be a priority of vaccine developers. Investigators are willing to conduct these studies provided adequate measures to ensure safety is in place.

How often have you seen or heard ‘do not take this medication if you are pregnant (or nursing)’? Whether in media advertisements, pharmacies or provider offices, pregnant women are often warned to avoid many things. However, often the evidence behind these recommendations is not clearcut. The reason is that for a long time, pregnant women were excluded from participating in clinical trials. The ethical framework that led to telling women ‘no’ to participating in clinical trials continues to make it difficult to recruit women into research studies. However, the importance of including pregnant women and instead saying ‘yes’ is critical for the future of pregnancy therapeutics. The last few decades have seen major changes in the landscape of research ethics. Very few areas have seen changes the scope of those seen regarding the inclusion of pregnant women in clinical trials, particularly medication trials. In the wake of many revelations of unethical research, including problems arising from research involving drugs in pregnant women, children and the fetus, a protectionist research ethics model was adopted. Codified by the National Research Act in 1974, reproductive-aged women were excluded from many trials to avoid accidental early fetal exposure. Vulnerable populations such as pregnant women were given additional protections, such that unless there was a compelling reason for inclusion, pregnant women would not be included in research. The general proscription model, however, was unsustainable as both clinicians and researchers realized that clinical trial data was not always generalizable from studied populations (usually men) to pregnant women. Pregnancy introduces an array of physiological changes that render dosing models from many clinical trials irrelevant. Owing to these changes, drug concentrations in pregnant women may be too low to be effective [1–3]. However, there was great concern about including pregnant women in clinical trials due to the often unknown effects drugs may have on the developing fetus. The lack of long-term developmental safety information for almost any drug further compounded this concern. In addition, animal model data had given false reassurance in the high-profile case of thalidomide. During the late 1980s, however, a growing debate occurred about including pregnant women in clinical trials. Two landmark clinical trials helped push the ethical discussion forward and away from the strict protectionist model. The international studies demonstrating that prenatal vitamin supplementation (with folic acid) could reduce the incidence of recurrent and primary neural tube defects represented a departure from prior clinical trials that were centered on treating a condition [4,5]. These studies were about giving drugs (even if only prenatal “As the inclusion of pregnant women in clinical trials has moved from ‘no’ to ‘yes’, ethical models and the informed consent process are guiding forces leading to medical answers and breakthroughs that improve the lives of pregnant women and their babies.”

Historically, women have been underrepresented in clinical research, requiring physicians to extrapolate medical recommendations for women from clinical research done in cohorts consisting predominantly of male participants. While government-funded clinical research has achieved gender parity in phase-3 clinical trials across many biomedical disciplines, improvements are still needed in several facets of women's health research, such as the inclusion of women in early-phase clinical trials, the inclusion of pregnant women and women with physical and intellectual disabilities, the consideration of sex as a biological variable in preclinical research, and the analysis and reporting of sex and gender differences across the full biomedical research continuum. The National Institutes of Health (NIH) Office of Research on Women's Health and the Office of Women's Health of the U.S. Food and Drug Administration (FDA) cosponsored a preconference symposium at the 25th Annual Women's Health Congress, held in Arlington, VA in April, 2017, to highlight gains made and remaining needs regarding the representation of women in clinical research, to introduce innovative procedures and technologies, and to outline revised policy for future studies. Six speakers presented information on a range of subjects related to the representation of women in clinical research and federal initiatives to advance precision medicine. Topics included the following: the return on investment from the NIH-funded Women's Health Initiative; progress in including women in clinical trials for FDA-approved drugs and products; the importance of clinical trials in pregnant women; FDA initiatives to report drug safety during pregnancy; the NIH-funded All of Us Research Program; and efforts to enhance FDA transparency and communications, including the introduction of Drug Trials Snapshots. This article summarizes the major points of the presentations and the discussions that followed.

BackgroundSince pregnant women are severely underrepresented in clinical research, many take the position that the exclusion of pregnant women from research must be justified unless there are compelling “scientific reasons” for their exclusion. However, it is questionable whether this approach renders research with pregnant women fair. This paper analyzes and evaluates when research with pregnant women can be considered as fair and what constitutes scientific reasons for exclusion.MethodsConceptual ethical and methodological analysis and evaluation of fair inclusion.ResultsFair inclusion of pregnant women means (1) that pregnant women who are eligible are not excluded solely for being pregnant and (2) that the research interests of pregnant women are prioritized, meaning that they ought to receive substantially more attention. Fairness does not imply that pregnant women should be included in virtually every research project, as including only a few pregnant women in a population consisting only of women will not help to determine the effectiveness and safety of a treatment in pregnant women. Separate trials in pregnant women may be preferable once we assume, or know, that effects of interventions in pregnant women differ from the effects in other subpopulations, or when we assume, or know, that there are no differences. In the latter case, it may be preferable to conduct post-marketing studies or establish registries. If there is no conclusive evidence indicating either differences or equivalence of effects between pregnant and non-pregnant women, yet it seems unlikely that major differences or exact equivalence exist, the inclusion of pregnant women should be sufficient. Depending on the research question, this boils down to representativeness in terms of the proportion of pregnant and non-pregnant women, or to oversampling pregnant women.ConclusionsFair inclusion of pregnant women in research implies that separate trials in pregnant women should be promoted. Inclusion of pregnant women has to be realized at the earliest phases of the research process. In addition to researchers and research ethics committees, scientific advisory councils, funders, drug regulatory agencies, pharmaceutical companies, journal editors and others have a joint responsibility to further develop the evidence base for drug use in pregnant women.

Poor representation of pregnant and lactating women and people in clinical trials has marginalised their health concerns and denied the maternal-fetal/infant dyad benefits of innovation in therapeutic research and development. This mixed-methods systematic review synthesised factors affecting the participation of pregnant and lactating women in clinical trials, across all levels of the research ecosystem. We searched 8 databases from inception to 14 February 2024 to identify qualitative, quantitative, and mixed-methods studies that described factors affecting participation of pregnant and lactating women in vaccine and therapeutic clinical trials in any setting. We used thematic synthesis to analyse the qualitative literature and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. We compared quantitative data against the thematic synthesis findings to assess areas of convergence or divergence. We mapped review findings to the Theoretical Domains Framework (TDF) and Capability, Opportunity, and Motivation Model of Behaviour (COM-B) to inform future development of behaviour change strategies. We included 60 papers from 27 countries. We grouped 24 review findings under 5 overarching themes: (a) interplay between perceived risks and benefits of participation in women's decision-making; (b) engagement between women and the medical and research ecosystems; (c) gender norms and decision-making autonomy; (d) factors affecting clinical trial recruitment; and (e) upstream factors in the research ecosystem. Women's willingness to participate in trials was affected by: perceived risk of the health condition weighed against an intervention's risks and benefits, therapeutic optimism, intervention acceptability, expectations of receiving higher quality care in a trial, altruistic motivations, intimate relationship dynamics, and power and trust in medicine and research. Health workers supported women's participation in trials when they perceived clinical equipoise, had hope for novel therapeutic applications, and were convinced an intervention was safe. For research staff, developing reciprocal relationships with health workers, having access to resources for trial implementation, ensuring the trial was visible to potential participants and health workers, implementing a woman-centred approach when communicating with potential participants, and emotional orientations towards the trial were factors perceived to affect recruitment. For study investigators and ethics committees, the complexities and subjectivities in risk assessments and trial design, and limited funding of such trials contributed to their reluctance in leading and approving such trials. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people. This systematic review highlights diverse factors across multiple levels and stakeholders affecting the participation of pregnant and lactating women in clinical trials. By linking identified factors to frameworks of behaviour change, we have developed theoretically informed strategies that can help optimise pregnant and lactating women's engagement, participation, and trust in such trials.

Cardiovascular disease (CVD) is the most common cause of death in American women and accounts for a full one-third of all deaths.1 Although the common perception may be that CVD affects mainly men, there is equal prevalence of this disease between the genders by the age of 40, and by the age of 60 more women than men are affected. More women than men have died from CVD causes on a yearly basis since the mid 1980s, and whereas the CVD mortality has steadily declined in men over the past 30 years, it has remained steady in women until very recently when CVD mortality was noted to decrease for both genders.2 See accompanying article on page 277 The impact of cardiovascular disease (CVD) on the health status of American women is gaining more recognition and has become the focus of public education efforts such as the “Go Red for Women” campaign sponsored by the American Heart Association and the “Red Dress” project sponsored by the Department of Health and Human Services, the National Institutes of Health (NIH), and the National Heart Lung and Blood Institute (NHLBI). These programs are, in part, a response to the increasing awareness of cardiovascular disease as a major source of morbidity and mortality in U.S. women. The importance of CVD as a major source of mortality in women was recognized early on by federally funded institutes including the Public Health Service Task Force, which brought attention to concerns about the health information available to women and the historical lack of research focus on women’s health in its 1985 Report of the Public Health Service Task Force on Women’s Health Issues .3 In response to this report, the National Institutes of Health adopted a policy for the inclusion of women in clinical research …

IntroductionTo adequately ascertain drug safety and efficacy, drug trials need to include participants from all groups likely to receive the medication following approval. Pregnant women, however, are mostly excluded from trials, and women participating are often required to use highly effective contraception and taken off study product (even off study) if they conceive. There is little commercial incentive for including pregnant women in clinical trials, even when preclinical animal and human pharmacokinetic and safety data appear reassuring. With this conservative approach, large numbers of pregnant women are exposed to drug postlicensing with little known about drug safety and efficacy, and little done to systematically monitor outcomes of pregnancy exposure.DiscussionThe article focuses on antiretrovirals for treating and preventing HIV, and presents potential approaches which could extend to other therapeutic areas, to obtaining adequate and timely data to inform use of these drugs in this population. Most importantly the pregnancy risk profile of investigational agents can be systematically stratified from low to high risk, based on guidelines from regulatory bodies. This stratification can determine the progress through preclinical work with animals and non‐pregnant women to opportunistic studies among women who become pregnant on a clinical trial or within routine clinical treatment. Stratification can include pregnant women in clinical trials, concurrent with Phase II/III trials in non‐pregnant adults, and ultimately to postmarketing surveillance for outcomes in pregnant women and their infants. Each step can be enabled by clear criteria from international and local regulatory bodies on progression through study phases, standardized protocols for collecting relevant data, collaborative data sharing, pregnancy outcomes surveillance systems supported by committed funding for these endeavours.ConclusionsA formalized step‐wise approach to including pregnant women in antiretroviral drug research should become the new norm. Systematic implementation of this approach would yield more timely and higher quality pregnancy dosing, safety and efficacy data. Through more vigorous action, regulatory bodies could responsibly overcome reluctance to include pregnant women in drug trials. Funders, researchers and programme implementers need to be galvanized to progressively include pregnant women in research – the use of newer, more effective drugs in women is at stake (349).

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.

* Abbreviations: FDA — : Food and Drug Administration NAAEDR — : North American Antiepileptic Drug Registry Information on the safety of medications that pregnant women may need is key to protecting the health of the woman and her fetus. When new drugs are first marketed, this information is scarce, because pregnant women are generally excluded from randomized clinical trials. Broader inclusion of pregnant women in clinical research is being discussed by regulatory authorities and funders.1 But even with greater inclusion of pregnant women in clinical trials, safety data from those trials would be limited by the combination of study size, low frequency of many key outcomes, and strict conditions for enrollment. Postapproval observational studies still would be needed to assess drug safety in routine health care. These assessments can be conducted as pregnancy exposure registries or by using existing health databases. Currently, because of our overreliance on pregnancy exposure registries and underuse of database studies, we are missing an opportunity to provide information that would help women and their physicians make better informed decisions about treatment in pregnancy. Pregnancy exposure registries, usually sponsored by a single pharmaceutical company, are a primary method requested by the US Food and Drug Administration (FDA) for postapproval safety studies in pregnant women.2 However, these registries often fail to enroll a sufficient number of exposed pregnancies, and when they do, it is often difficult to interpret results because they generally do not include an internal comparison cohort and rely on comparisons to external data sources, such as the Metropolitan Atlanta Congenital Defects Program.2 The pregnancy registries that have been most successful in enrolling … Address correspondence to Andrea V. Margulis, MD, ScD, RTI Health Solutions, Diagonal 605, 9-1, 08028 Barcelona, Spain. E-mail: amargulis{at}rti.org

The need for a global COVID-19 maternal immunisation research plan

The call for the inclusion of pregnant women in clinical trials has received renewed attention recently. This interest springs from articles in various medical journals highlighting the gaps in medical knowledge and the need to improve health care for pregnant women.It is not a simple decision whether to include pregnant women in studies or not. The general thought is that it's too dangerous for the baby if a pregnant woman is participating in a trial, and the absence of research on how medications work in pregnant women leave doctors guessing about how to safely and effectively treat patients through pregnancy.Excluding pregnant women from clinical trials are not automatic, not unethical nor is it arbitrarily determined. The regulatory framework is based on sound ethical and legal reasoning that demonstrates when inclusion in a clinical trial is appropriate or when clear and compelling reasons for exclusion are presented. LEARNING OBJECTIVE: Readers will learn about limitations of research, history of the inclusion and exclusion of pregnant women in clinical trials, reticence for inclusions, as well as regulations designed using reasoned legal and ethical principles, such as: Principle of Autonomy, Informed Consent, and Beneficence and Nonmaleficence.

This empirical chapter provides a systematic review of literature relevant to the inclusion of pregnant women in clinical trials. In particular, it addresses barriers to fair inclusion identified within the literature. The 31 articles reviewed discuss the exclusion of pregnant women from clinical trials. Reasons given for such exclusion were grouped under several themes, including: foetal safety, collective memory or social controversies, liability, regulations, research ethics committee interpretations, research design, willingness to participate and consent. The discussion reviews arguments in the literature for how many of these barriers to fair inclusion can be surmounted. The authors find that barriers to fair inclusion of pregnant women in clinical research interact. While there are practical solutions for surmounting some barriers, others require further discussion.

Characteristics and treatment of hospitalized pregnant women with COVID-19