Institutional review boards, tasked with facilitating ethical research, are often pulled in competing directions. In what we call the protection-inclusion dilemma, we acknowledge the tensions IRBs face in aiming to both protect potential research participants from harm and include under-represented populations in research. In this manuscript, we examine the history of protectionism that has dominated research ethics oversight in the United States, as well as two responses to such protectionism: inclusion initiatives and critiques of the term vulnerability. We look at (...) what we know about IRB decision-making in relation to protecting and including “vulnerable” groups in research and examine the lack of regulatory guidance related to this dilemma, which encourages protection over inclusion within IRB practice. Finally, we offer recommendations related to how IRBs might strike a better balance between inclusion and protection in research ethics oversight. (shrink)

This paper attempts to philosophically articulate empirical evidence on the positive effects of illness within the wider context of a discussion of the positive aspects of vulnerability. The conventional understanding holds that to be vulnerable is to be open to harms and wrongs; it is to be fragile, defenseless, and of compromised autonomy. In this paper, we challenge the assumption that vulnerability consists of nothing but powerlessness and dependence on others. This paper attempts to: (1) outline the theoretical conceptualisation of (...) the positive aspects of coping with illness, while simultaneously showing how these findings provide empirical support for some classical philosophical ideas; (2) influence a change in the manners in which the ill are usually perceived (as weak, dependent, robbed of a good life) and (3) point to the importance of modernising the prevalent biomedical conception of illness with the subjective dimension of health. Biomedical understanding of illness focuses on the vulnerable experience of the sufferer, suggesting the importance of philosophical additions. (shrink)

Although the principle of fair subject selection is a widely recognized requirement of ethical clinical research, it often yields conflicting imperatives, thus raising major ethical dilemmas regarding participant selection. In this paper, we diagnose the source of this problem, arguing that the principle of fair subject selection is best understood as a bundle of four distinct sub-principles, each with normative force and each yielding distinct imperatives: (1) fair inclusion; (2) fair burden sharing; (3) fair opportunity; and (4) fair distribution of (...) third-party risks. We first map out these distinct sub-principles, and then identify the ways in which they yield conflicting imperatives for the design of inclusion and exclusion criteria, and the recruitment of participants. We then offer guidance for how decision makers should navigate these conflicting imperatives to ensure that participants are selected fairly. (shrink)

BackgroundThere 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.MethodsWe conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed healthcare professionals, Research Ethics Committee members 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.ResultsThree 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.ConclusionsHealthcare 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. (shrink)

Background There is longstanding consensus on the need to include pregnant women in research. The goal of clinical research is to find highly regulated, carefully controlled, morally responsible ways to generate evidence about how to effectively and safely prevent illness or treat sick people. This manuscripts present a conceptual analysis of the ethicality of clinical trials in 3 scenarios: where the pregnant is involved in clinical trials as a participant during pregnancy for data that addresses pregnancy complications, where the pregnant (...) woman consents to clinical trial participation for an unborn baby that has complications, to generate data on complications at this stage of life, and where the mother may consent for participation of their newborn child in clinical trials. Methods Conceptual analysis. Findings Investigators often choose to exclude pregnant women and newborns from research, even where there is possibility for them to benefit from the study intervention. Objections include vulnerability of pregnant women, altered pharmacokinetics and risk of adverse effects, with a need to balance potential maternal and fetal risks and benefits of research participation. While the objections may be valid, not performing research magnifies what should be a carefully controlled risk during research, pushing this risk into the clinical setting, and subsequently posing a challenge to clinicians who are faced with making treatment decisions for pregnant patients with limited evidence of efficacy and safety. The potential benefits of fair inclusion in clinical trials outweigh the potential risks. Conclusion Research involving pregnant women is necessary to provide women with effective treatment during pregnancy, to promote fetal safety, and to reduce avoidable harm from suboptimal care and to provide pregnant women, their fetuses and newborns. (shrink)

Background There is longstanding consensus on the need to include pregnant women in research. The goal of clinical research is to find highly regulated, carefully controlled, morally responsible ways to generate evidence about how to effectively and safely prevent illness or treat sick people. This manuscripts present a conceptual analysis of the ethicality of clinical trials in 3 scenarios: where the pregnant is involved in clinical trials as a participant during pregnancy for data that addresses pregnancy complications, where the pregnant (...) woman consents to clinical trial participation for an unborn baby that has complications, to generate data on complications at this stage of life, and where the mother may consent for participation of their newborn child in clinical trials. Methods Conceptual analysis. Findings Investigators often choose to exclude pregnant women and newborns from research, even where there is possibility for them to benefit from the study intervention. Objections include vulnerability of pregnant women, altered pharmacokinetics and risk of adverse effects, with a need to balance potential maternal and fetal risks and benefits of research participation. While the objections may be valid, not performing research magnifies what should be a carefully controlled risk during research, pushing this risk into the clinical setting, and subsequently posing a challenge to clinicians who are faced with making treatment decisions for pregnant patients with limited evidence of efficacy and safety. The potential benefits of fair inclusion in clinical trials outweigh the potential risks. Conclusion Research involving pregnant women is necessary to provide women with effective treatment during pregnancy, to promote fetal safety, and to reduce avoidable harm from suboptimal care and to provide pregnant women, their fetuses and newborns. (shrink)

This commentary explores the notion of vulnerability applied to pregnant women in clinical research. The use of this notion, related to a semantic problem, raises an ethical issue and participates in the quasi-systematic exclusion of this sub-population from the research process.

As a feminist bioethicist, I have frequently wondered why the exclusion of pregnant women has been the default position for most clinical research and how social values have influenced this decision. Relatedly, I wonder what responsible research involving pregnant women would look like. As a theorist who conducts research on the concept of vulnerability, I have often wanted to know why there has been so little research into the harmful effects of the routine exclusion of pregnant women, including questions such (...) as: What do pregnant women actually think about participating in research? How should we treat pregnant women and their fetuses for the purposes of consent (are they two separable persons or one complex... (shrink)

The recent Common Rule revision process took almost a decade and the resulting changes are fairly modest, particularly when compared to the ambitious ideas proposed in the advance notice of proposed rulemaking and notice of proposed rulemaking. Furthermore, the revision process did not even attempt to tackle any of the Common Rule subparts pertaining to vulnerable populations where commentators think the rules unduly restrict important research. We believe that this was a missed opportunity to make desirable changes, and that given (...) the usual process the next opportunity to revisit the Common Rule is unacceptably remote. In this article, we argue that the Common Rule should be regularly reassessed, with a mechanism for making substantive changes. Drawing on lessons learned from the recent revision process, we make recommendations about ways to structure future attempts to maximize the ability to make timely and necessary changes. (shrink)

El Foro Global de Bioética en Investigación (GFBR por sus siglas en inglés) se reunió el 3 y 4 de noviembre en Buenos Aires, Argentina, con el objetivo de discutir la ética de la investigación con mujeres embarazadas. El GFBR es una plataforma mundial que congrega a actores clave con el objetivo de promover la investigación realizada de manera ética, fortalecer la ética de la investigación en salud, particularmente en países de ingresos bajos y medios, y promover colaboración entre países (...) del norte y del sur.a Los participantes en el GFBR provenientes de Latinoamérica incluyeron a eticistas, investigadores, miembros de comités de ética y representantes de autoridades sanitarias provenientes de Argentina, Brasil, Chile, Colombia, Ecuador, El Salvador, Guatemala, Honduras, Panamá, Perú, Nicaragua y la República Dominicana. Una legítima preocupación por la protección de las mujeres embarazadas y sus embriones o fetos ha llevado a la mayoría de los países de la Región de las Américas a limitar la realización de estudios con mujeres embarazadas exclusivamente a aquellos estudios específicos sobre el embarazo, y a requerir la exclusión sistemática de las mujeres embarazadas o de las mujeres que quedan embarazadas en el curso del estudio. Ciertamente, a lo largo de la historia de la ética de la investigación, se ha creído erróneamente que proteger a una población es sinónimo de excluirla de los estudios. Se sabe ahora que proceder así implica exponer a riesgos mucho mayores a la población que se busca proteger. El embarazo implica cambios fisiológicos sustantivos e impacta profundamente la manera como el cuerpo metaboliza los medicamentos. Sin embargo, por evitar hacer investigación con mujeres embarazadas, no se ha producido la evidencia científica necesaria para tomar decisiones sobre tratamientos e intervenciones preventivas con dosis eficaces y seguras para ellas y sus embriones o fetos. A manera de ilustración, en el 2001 había en los Estados Unidos apenas más de una docena de medicamentos aprobados para uso en el embarazo (1) y en el 2011 la Food and Drug Administration (FDA) aprobó por primera vez en 15 años un medicamento para su uso en el embarazo (2). Como consecuencia de no haber producido la evidencia necesaria, se pone en riesgo la salud de las mujeres embarazadas cada vez que se les da atención médica. Las mujeres embarazadas se enferman y las mujeres enfermas se embarazan, y no se sabe si los medicamentos que se les da son eficaces o siquiera seguros para ellas y sus embriones o fetos. (shrink)

Subpart B of 45 Code of Federal Regulations Part 46 (CFR) identifies the criteria according to which research involving pregnant women, human fetuses, and neonates can be conducted ethically in the United States. As such, pregnant women and fetuses fall into a category requiring “additional protections,” often referred to as “vulnerable populations.” The CFR does not define vulnerability, but merely gives examples of vulnerable groups by pointing to different categories of potential research subjects needing additional protections. In this paper, I (...) assess critically the role of this categorization of pregnant women involved in research as “vulnerable,” both as separate entities and in combination with the fetuses they carry. In particular, I do three things: (1) demonstrate that pregnant women qua pregnancy are either not “vulnerable” according to any meaningful definition of that term or that such vulnerability is irrelevant to her status as a research participant; (2) argue that while a fetus may be vulnerable in terms of dependency, this categorization does not equate to the vulnerability of the pregnant woman; and (3) suggest that any vulnerability that appends to women is precisely the result of federal regulations and dubious public perceptions about pregnant women. I conclude by demonstrating how this erroneous characterization of pregnant women as “vulnerable” and its associated protections have not only impeded vital research for pregnant women and their fetuses, but have also negatively affected the inclusion of all women in clinical research. (shrink)

Non-human animal models of human diseases advance our knowledge of the genetic underpinnings of disease and lead to the development of novel therapies for humans. While mice are the most common model organisms, their usefulness is limited. Larger animals may provide more accurate and valuable disease models, but it has, until recently, been challenging to create large animal disease models. Genome editors, such as Clustered Randomised Interspersed Palindromic Repeat, meet some of these challenges and bring routine genome engineering of larger (...) animals and non-human primates well within reach. There is growing interest in creating NHP models of brain disorders such as autism, depression and Alzheimer’s, which are very difficult to model or study in other organisms, including humans. New treatments are desperately needed for this set of disorders. This paper is novel in asking: Insofar as NHPs are being considered for use as model organisms for brain disorders, can this be done ethically? The paper concludes that it cannot. Notwithstanding ongoing debate about NHPs’ moral status, animal welfare concerns, the availability of alternative methods of studying brain disorders and unmet expectations of benefit justify a stop on the creation of NHP model organisms to study brain disorders. The lure of using new genetic technologies combined with the promise of novel therapeutics presents a formidable challenge to those who call for slow, careful, and only necessary research involving NHPs. But researchers should not create macaques with social deficits or capuchin monkeys with memory deficits just because they can. (shrink)

Concern for human vulnerability seems to be at the heart of bioethical inquiry, but the concept of vulnerability is under-theorized in the bioethical literature. The aim of this article is to show why bioethics needs an adequately theorized and nuanced conception of vulnerability. We first review approaches to vulnerability in research ethics and public health ethics, and show that the bioethical literature associates vulnerability with risk of harm and exploitation, and limited capacity for autonomy. We identify some of the challenges (...) emerging from this literature: in particular, how to reconcile universal human vulnerability with a context-sensitive analysis of specific kinds and sources of vulnerability; and how to reconcile obligations to protect vulnerable persons with obligations to respect autonomy. We then briefly survey some of the theoretical resources available within the philosophical literature to address these challenges, and to assist in understanding the conceptual connections between vulnerability and related concepts such as harm, exploitation, needs, and autonomy. We also sketch out a taxonomy of sources and kinds of vulnerability. Finally, we consider the implications for policy evaluation of making vulnerability an explicit and central focus of bioethics. Our investigation is in the form of a broad survey motivating a research agenda rather than a detailed analysis. (shrink)

The Médecins Sans Frontières ethics review board has been solicited in an unprecedented way to provide advice and review research protocols in an ‘emergency’ mode during the recent Ebola epidemic. Twenty-seven Ebola-related study protocols were reviewed between March 2014 and August 2015, ranging from epidemiological research, to behavioural research, infectivity studies and clinical trials with investigational products at early development stages. This article examines the MSF ERB’s experience addressing issues related to both the process of review and substantive ethical issues (...) in this context. These topics include lack of policies regarding blood sample collection and use, and engaging communities regarding their storage and future use; exclusion of pregnant women from clinical and vaccine trials; and the difficulty of implementing timely and high-quality qualitative/anthropological research to consider potential upfront harms. Having noticed different standards across ethics committees, we propose that when multiple ethics reviews of clinical and vaccine trials are carried out during a public health emergency they should be accompanied by transparent communication between the ECs involved. The MSF ERB experience should trigger a broader discussion on the ‘optimal’ ethics review in an emergency outbreak and what enduring structural changes are needed to improve the ethics review process. (shrink)

Calls are increasing for American health care to be organized as a learning health care system, defined by the Institute of Medicine as a health care system “in which knowledge generation is so embedded into the core of the practice of medicine that it is a natural outgrowth and product of the healthcare delivery process and leads to continual improvement in care.” We applaud this conception, and in this paper, we put forward a new ethics framework for it. No such (...) framework has previously been articulated. The goals of our framework are twofold: to support the transformation to a learning health care system and to help ensure that learning activities carried out within such a system are conducted in an ethically acceptable fashion. (shrink)

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: informed consent, susceptibility to coercion, higher exposure to risk due to lack of knowledge, 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. (shrink)

A new study published in Journal of Medical Ethics by van der Zande et al 1 further highlights why classifying pregnant women as a ‘vulnerable population’ in the context of research is deeply problematic. Because the designation of ‘vulnerable’ is otherwise applied to populations whose decision-making capacity about research participation is somehow compromised—such as children and adults of limited cognitive ability—many of us have been arguing for some time that using this designation for pregnant women is inappropriate and disrespectful.2–4 There (...) is nothing about the state of pregnancy that renders pregnant women incapable of offering valid research consents or refusals. Moreover, rather than protecting the health interests of pregnant women and their offspring, this designation has had the opposite effect. It has contributed to the widespread exclusion of pregnant women from research activities, which is itself pernicious to the health of pregnant women.5 We know that pregnant women encounter a range of health needs across their pregnancies. In the USA, for example, approximately 9 out of every 10 women use some kind of medication during pregnancy to manage health conditions.6 Yet because pregnant women have largely been …. (shrink)

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. (shrink)

Despite the attempts to promote the inclusion of pregnant women into clinical research, this group is still widely excluded. An analysis of the “vulnerability of pregnant women” that questions deeply internalized stereotypes is necessary for finding the right balance in the protection of pregnant women as research participants. Criticism of the traditional account of vulnerability will lead to an alternative that focuses on situations rather than groups and on the obligations of responsible parties. The paper adds to the current general (...) discussion of vulnerability and at the same time addresses the specific problem of drug treatment during pregnancy. (shrink)

Background Maternal mental health during the peripartum period is critically important to the wellbeing of mothers and their infants. Numerous studies and clinical trials have focused on various aspects of interventions and treatments for perinatal mental health from the perspective of researchers and medical health professionals. However, less is known about women’s experiences of participating in perinatal mental health research, and the ethical issues that arise. Aim To systematically review the literature on the ethical issues that emerge from pregnant and/or (...) postpartum women’s experiences of taking part in perinatal mental health-related research. Methods Systematic review of nine bibliographic databases, from inception to July 2021. Qualitative, quantitative and mixed method studies were included if they reported on ethical issues experienced by perinatal women. Research ethical issues encompassed any issue relating to women’s experiences of being offered study information, recruitment, consent, retention and respect for autonomy. Titles, abstracts and full text screening, appraisal of the methodological quality of included studies, and data extraction, were conducted independently by two reviewers. Ethical considerations Ethical approval was not required for this systematic review. Findings A total of 9830 unique citations was retrieved. Six studies met the inclusion criteria. Studies were clinically and methodologically heterogenous, and only one was purposively designed to explore women’s experiences. The key finding was the establishment of trust between the researcher and participant in all stages of the research process. Findings are presented according to recruitment and consent processes, participation and retention, and study follow-up and completion. Conclusion The establishment of trust between the researcher and perinatal women leads to a dynamic with research ethical implications relevant to all stages of perinatal mental health-related research. Further research on the research ethical issues experienced by perinatal women is required because of the limited literature. (shrink)

Calls are increasing for American health care to be organized as a learning health care system, defined by the Institute of Medicine as a health care system “in which knowledge generation is so embedded into the core of the practice of medicine that it is a natural outgrowth and product of the healthcare delivery process and leads to continual improvement in care.” We applaud this conception, and in this paper, we put forward a new ethics framework for it. No such (...) framework has previously been articulated. The goals of our framework are twofold: to support the transformation to a learning health care system and to help ensure that learning activities carried out within such a system are conducted in an ethically acceptable fashion. (shrink)

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. (shrink)

It has long been taken for granted that clinical research involving human subjects is ethical only if it holds out the prospect of producing socially valuable knowledge. Recently, this social value requirement has come under scrutiny, with prominent ethicists arguing that the social value requirement cannot be substantiated as an ethical limit on clinical research, and others attempting to offer new support. In this paper, I argue that both criticisms and existing defenses of the social value requirement are predicated on (...) what I call the “transactional model of stakeholder obligations”. I go on to problematize this framework, and to introduce an alternative framework for conceptualizing ethical obligations within clinical research. In defending this framework, which I call the “basic structure model of stakeholder obligations”, I also demonstrate how it provides a stronger grounding for the social value requirement that is not vulnerable to critiques grounded in the transactional model. (shrink)

Pregnancy is a frequently applied exclusion criteria for many forms of research. Common justifications for this exclusion include the potential for teratogenicity, as well as the potential for physiologic changes in pregnancy to impact the research itself. The systematic exclusion of pregnant persons from clinical studies has created a significant gap in knowledge regarding medication safety and efficacy in pregnancy, which continues to cause significant harm to pregnant persons in need of medical therapy. To produce meaningful data and facilitate effective (...) knowledge translation to the clinical setting, special consideration to the pharmacology of pregnancy, as well as to outcomes of concern for this population is essential. The exclusion of pregnant participants from research is not ethically justifiable, as it violates the principles of autonomy, justice and nonmaleficence. While the inclusion of pregnant patients in research presents it’s own challenges, with appropriate methodological, ethical, and clinical considerations, we may be able to narrow the knowledge gap and improve drug availability and safety for pregnant patients and their children. (shrink)

The target articles in this “Roe v. Wade” special issue of AJOB rightly point to multiple ethical harms of an imminent end to full federal protection for legal abortion in the United States, p...

In recent years, tremendous progress has been made toward recognizing the need for improved medical knowledge for pregnant people, a population group that has long been excluded from clinical trial...