How Should the Precautionary Principle Apply to Pregnant Women in Clinical Research?

The precautionary principle is often invoked in relation to pregnant women and may be one of the underlying reasons for their continuous underrepresentation in clinical research. The principle is appealing, because potential fetal harm as a result of research participation is considered to be serious and irreversible. In our paper, we explore through conceptual analysis whether and if so how the precautionary principle should apply to pregnant women. We argue that the principle is a decision-making strategy underlying risk-benefit decisions in clinical research, which can be applied to pregnant women. However, the current application is a strong one, leading to the promotion of absolute exclusion or, less often, absolute inclusion of pregnant women. In order to change this paralyzing situation, a shift toward weak precautionary thinking is necessary. Instead of automatic extreme precaution, a balance will be found between harms and potential benefits of including pregnant women in clinical research.

A qualitative study on stakeholders' views on the participation of pregnant women in the APOSTEL VI study: a low-risk obstetrical RCT.

BACKGROUND: Bioethicists 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. METHODS: We 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. RESULTS: Three 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. CONCLUSIONS: Pregnant 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.

How the CIOMS guidelines contribute to fair inclusion of pregnant women in research.

As early as 2002, CIOMS stated that pregnant women should be presumed eligible for participation in research. Despite this position and calls of other well-recognized organizations, the health needs of pregnant women in research remain grossly under-researched. Although the presumption of eligibility remains unchanged, the revision of the 2002 CIOMS International ethical guidelines for biomedical research involving human subjects involved a substantive rewrite of the guidance on research with pregnant women and related guidelines, such as those on fair inclusion and vulnerability. However, close reading of the guidelines reveals morally relevant different approaches to fair inclusion of pregnant women and other under-represented groups, such as children and incompetents. Where CIOMS sets out that children and adolescents must be included unless a good scientific reason justifies their exclusion, no such claim of having to justify exclusion appears in the guideline on pregnant women. Instead, CIOMS claims that research relevant to pregnant women's health needs must be promoted. This paper analyses how and to what extent the guideline on pregnant women differs from other guidance on fair inclusion in the document. Accordingly, the paper evaluates to what extent the current phrasing may contribute to fair inclusion of pregnant women in research. We will conclude that a system change towards a learning health system is essential to break down the status quo of knowledge generation in the field of medication use during pregnancy and argue that the CIOMS guidelines allow for this system change.

Vulnerability of pregnant women in clinical research.

BACKGROUND: Notwithstanding 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 no universally accepted criteria for considering pregnant women as vulnerable. Our aim was to explore whether and if so to what extent pregnant women are vulnerable as research subjects. METHOD: We performed a conceptual and empirical analysis of vulnerability applied to pregnant women. ANALYSIS: A conceptual analysis supports Hurst's definition of vulnerability. Consequently, we argue that pregnant women are vulnerable if they encounter an identifiably increased likelihood of incurring additional or greater wrong. According to the literature, this increased likelihood could exist of four alleged features for pregnant women's vulnerability: (i) informed consent, (ii) susceptibility to coercion, (iii) higher exposure to risk due to lack of knowledge, (iv) vulnerability of the fetus. DISCUSSION: Testing the features against Hurst's definition demonstrates that they all concern the same issue: pregnant women are only vulnerable because a higher exposure to risk due to lack of scientific knowledge comprises an increased wrong. Research Ethics Committees have a responsibility to protect the vulnerable, but a higher exposure to risk due to lack of scientific knowledge is a much broader issue and also needs to be addressed by other stakeholders. CONCLUSIONS: The only reason why pregnant women are potentially vulnerable is to the extent that they are increasingly exposed to higher risks due to a lack of scientific knowledge. Accordingly, the discussion can advance to the development of practical strategies to promote fair inclusion of pregnant women in clinical research.

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

BACKGROUND: There is ambiguity with regard to what counts as an acceptable level of risk in clinical research in pregnant women and there is no input from stakeholders relative to such research risks. The aim of our paper was to explore what stakeholders who are actively involved in the conduct of clinical research in pregnant women deem an acceptable level of risk for pregnant women in clinical research. Accordingly, we used the APOSTEL VI study, a low-risk obstetrical randomised controlled trial, as a case-study. METHODS: We conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed healthcare professionals, Research Ethics Committee members (RECs) and regulators who are actively involved in the conduct of clinical research in pregnant women, in addition to pregnant women recruited for the APOSTEL VI case-study in the Netherlands. RESULTS: Three themes characterise the way stakeholders view risks in clinical research in pregnant women in general. Additionally, one theme characterises the way healthcare professionals and pregnant women view risks with respect to the case-study specifically. First, ideas on what constitutes an acceptable level of risk in general ranged from a preference for zero risk for the foetus up to minimal risk. Second, the desirability of clinical research in pregnant women in general was questioned altogether. Third, stakeholders proposed to establish an upper limit of risk in potentially beneficial clinical research in pregnant women in order to protect the foetus and the pregnant woman from harm. Fourth and finally, the case-study illustrates that healthcare professionals' individual perception of risk may influence recruitment. CONCLUSIONS: Healthcare professionals, RECs, regulators and pregnant women are all risk adverse in practice, possibly explaining the continuing underrepresentation of pregnant women in clinical research. Determining the acceptable levels of risk on a universal level alone is insufficient, because the individual perception of risk also influences behaviour towards pregnant women in clinical research. Therefore, bioethicists and researchers might be interested in changing the perception of risk, which could be achieved by education and awareness about the actual benefits and harms of inclusion and exclusion of pregnant women.

Towards an appropriate framework to facilitate responsible inclusion of pregnant women in drug development programs.

Evidence-based treatment for pregnant women will ultimately require research conducted in the population of pregnant women. Currently, few scholars have addressed the issue of responsible inclusion of pregnant women in drug research. Because of additional risks associated with including pregnant women in drug research and the altered ways in which drugs are processed by the pregnant body, pregnant women cannot be treated as an ordinary subgroup in the various phases of drug development. Instead, responsible inclusion of pregnant women requires careful design and planning of research for pregnant women specifically. Knowledge about these aspects is virtually nonexistent. In this article, we present a practical framework for the responsible inclusion of pregnant women in drug development. We suggest that the framework consists of using a question-based approach with five key questions in combination with three prerequisites which should be addressed when considering inclusion of pregnant women in drug research. The five questions are: A. Can we consider the drug safe (enough) for first exposure in pregnant women and fetuses? B. In which dose range (potentially depending on gestational age) can the drug be considered to remain safe in pregnant women? C. At what dose (regimen, within the range considered safe) can we expect efficacy in pregnant women? D. Can efficacy be confirmed at the target dose, either similar to the initial population or different? E. Can clinical safety be confirmed at a sufficiently acceptable level at the target dose for pregnant women and fetuses, so as to conclude a positive benefit-risk ratio? Combining questions and prerequisites leads to a scheme for appropriate timing of responsible inclusion of pregnant women in drug research. Accordingly, we explore several research design options for including pregnant women in drug trials that are feasible within the framework. Ultimately, the framework may lead to (i) earlier inclusion of pregnant women in drug development, (ii) ensuring that key prerequisites, such as proper dosing, are addressed before more substantial numbers of pregnant women are included in trials, and (iii) optimal use of safety and efficacy data from the initial (nonpregnant) population throughout the drug development process.

Facilitators and barriers to pregnant women's participation in research: A systematic review.

BACKGROUND: Although there is consensus among many that exclusion of pregnant women from clinical research should be justified, there is uncertainty as to whether and why pregnant women themselves would be willing to participate even if they were found to be eligible. The objective was to identify the reasons why pregnant women participate in clinical research and thereby to distinguish between facilitators and barriers. METHODS: We conducted a systematic review of articles regarding pregnant women's reasons for participation in clinical research. We used the PubMed/MEDLINE, EMBASE, PsycINFO and CINAHL databases and retrieved additional articles through manually searching the reference lists. We included all articles that reported on pregnant women's reasons for participation in clinical research. We accumulated all reasons that were mentioned in the total of articles and collated them to themes, classifying these themes as a facilitator or a barrier. RESULTS: The search identified thirty articles that met the inclusion criteria. Themes classified as facilitators: aspirational benefits, collateral benefits, direct benefits, third party influence and lack of inconvenience. Themes classified as barriers: inconveniences, risks, randomisation, lack of trust in research enterprise, medical reasons and third party influence. CONCLUSIONS: Pregnant women report mostly altruistic and personal reasons for their willingness to participate in clinical research, while barriers primarily relate to inconveniences. It appears that pregnant women's described reasoning is similar to the described reasoning of non-pregnant research subjects. Enhancing the facilitators and overcoming the barriers is the next step to increase the evidence-base underlying maternal and foetal health.

Fair inclusion of pregnant women in clinical trials: an integrated scientific and ethical approach.

BACKGROUND: Since 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. METHODS: Conceptual ethical and methodological analysis and evaluation of fair inclusion. RESULTS: Fair 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. CONCLUSIONS: Fair 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.