Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. We first propose (...) a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs. (shrink)

Well-designed pragmatic clinical trials (PCTs) are critical for improving healthcare delivery and patient outcomes (Haff and Choudhry 2018), and the article written by Garland et al. (2023) advance...

SUPPORT, a study involving approximately 1,300 premature infants who were randomly assigned to treatment protocols that differed in whether they offered higher or lower levels of oxygen saturation, was purportedly an example of comparative effectiveness research performed in the intensive care unit. However, SUPPORT became highly controversial. One source of controversy involved the proper determination of “reasonably foreseeable risks.” Commentators debated whether randomization to contrasting restrictive strategies that are within existing standard‐of‐care treatments imposed additional “reasonably foreseeable risks” greater than what (...) study participants would have received outside of the research. A second controversial issue had to do with disclosures in informed consent documents. This article explores these issues.We argue that randomization to contrasting restrictive interventions lying at the outer ends of “standard‐of‐care” practices differs in important ways from unrestricted “standard‐of‐care” practices available outside of a proposed study; that research involving such randomization might pose additional “reasonably foreseeable risks” from what occurs in “standard‐of‐care” practices; and that for trials whose study designs are similar to the SUPPORT study, respect for persons requires the disclosure of information about the nature of the experimental procedures and their risks. (shrink)

Scholars have debated the role that altruistic considerations play—and should play—in recruitment and decision-making processes for clinical trials. Little empirical data are available to support their various perspectives. We analyzed 140 audiotaped pediatric informed consent sessions, of which 95 (68%) included at least one discussion of how participation in a cancer clinical trial might benefit: 1) the pursuit of scientific knowledge generally; 2) other children with cancer specifically; and 3) “the future” and other vaguely defined recipients. Clinicians initiated most (...) (80%) of these discussions of altruism. The enrollment rate of children in the clinical trial was high (83%) overall, but not higher among children whose parents were involved in an altruism-oriented discussion. These findings suggest that: (1) clinicians invoke a spectrum of altruistic considerations rather than a single monothematic notion of altruism, and (2) the effect of altruistic considerations on subsequent enrollment decisions is marginal. While further research on this topic is warranted, bioethical debate should strive to reflect the diversity of altruistic discourse in clinical research encounters and to place this discourse in the context of other, including nonaltruistic, considerations. (shrink)

The principle of clinical equipoise requires that, aside from certain exceptional cases, second generation treatments ought to be tested against standard therapy. In violation of this principle, placebo-controlled trials (PCTs) continue to be used extensively in the development and licensure of second-generation treatments. This practice is typically justified by appeal to methodological arguments that purport to demonstrate that active-controlled trials (ACTs) are methodologically flawed. Foremost among these arguments is the so called assay sensitivity argument. In this paper, I (...) take a closer look at this argument. Following Duhem, I argue that all trials, placebo-controlled or not, rely on external information for their meaningful interpretation. Pending non-circular empirical evidence that we can trust the findings of PCTs to a greater degree than the findings of ACTs, I conclude that the assay sensitivity argument fails to demonstrate that placebo-controlled trials are preferable, methodologically or otherwise, to active-controlled trials. Contrary to the intentions of its authors, the fundamental lesson taught by the assay sensitivity argument is Duhemian: the validity of all clinical trials depends on external information. (shrink)

In this issue of the American Journal of Bioethics, manuscripts focus on the obligations of clinicians and researchers in pragmatic clinical trials (Garland, Morain, and Sugarman 2023; Morain and L...

A resilient issue in research ethics is whether and when a placebo-controlled trial is justified if it deprives research subjects of a recognized treatment. The clinicians' moral duty to provide the best available care seems to require the use of ‘active’ controlled trials that use an established treatment as a control whenever such a therapy is available. In another regard, ACTs are supposedly methodologically inferior to PCTs. Hence, the moral duty of the clinical researcher to use the best methods (...) will favor PCTs. In this target article, I analyze the three reasons for believing that ACTs are inferior to PCTs namely: 1) ACTs lack ‘assay sensitivity’; 2) ACTs do not measure absolute effect size; and 3) ACTs require more participants; and I contend that none are acceptable. Consequently the tension between clinical and research ethics dissolves: the moral duty of the clinician to avoid PCTs is unopposed by methodological considerations. (shrink)

Randomised clinical trials provide the most valid means of establishing the efficacy of clinical therapeutics. Ethical standards dictate that patients and clinicians should not consent to randomisation unless there is uncertainty about whether any of the treatment options is superior to the others ("equipoise"). However, true equipoise is rarely present; most randomised trials, therefore, present challenging ethical dilemmas. Minimising the tension between science and ethics is an obligation of investigators and clinicians. This article briefly reviews several techniques for (...) addressing this issue and suggests that unbalanced randomisation, a technique rarely employed in current clinical trial practice, may be useful for enhancing the ethical design of human experimentation. (shrink)

The physician who upholds the Hippocratic oath is supposed to be loyal to his or her patients. This requires choosing only the therapy that the physician believes is best for the patient. However, knowing what is best requires randomized clinical trials. Thus, clinicians must be willing to recruit their patients to be assigned at random to one of two therapies in order to determine which is best based on the highest standards of pharmacological science.

It has been proposed that the urgency of having a vaccine as a response to SARS-CoV-2 is so great, given the potential health, economic and social benefits that we should override the established s...

Monitoring of clinical trials is important to ensure adherence to protocol, to safeguard the rights of research participants and to achieve compliance with principles of good clinical practice. Recent regulatory changes in India require Ethics Committees to keep an oversight of ongoing clinical trials including on-site monitoring. In this article, we share the experience of on-site monitoring of clinical trials by the Ethics Committee of a tertiary care, academic and research centre in India. We found a large (...) number of shortcomings in the areas of informed consent, adverse events, insurance and reimbursement, which would not have been detected by off-site document review. Interestingly, many shortcomings were also not detected by on-site monitoring arranged by clinical trial sponsors. We therefore conclude that on-site monitoring of ongoing clinical trials is a highly important activity for Indian Ethics Committees. (shrink)

Those researching HIV prevention measures for people who inject drugs face a dilemma. Regions where baseline HIV prevalence and onward transmission via injecting is sufficiently high to power HIV prevention trials are also those where repressive laws, policies and practices raise concerns about the ethics of research subject protection. Dawson et al, outlining criteria to address ethical challenges in HIV prevention research among PWID, recommend that all trial participants be offered sterile injecting equipment and urge additional strategies to limit (...) research and background risks.1 In light of ethical questions opened by recent clinical trials involving PWID, including several the authors cite favourably, these cautions are timely. Dawson et al urge weighing of costs and benefits of PWID participation in research trials as an essential part of the ethical calculus. Overdose is a particular risk in any trial that uses abstinence from opioids as a precondition for participation or as an outcome of interest, and a risk that institutional review boards and researchers frequently ignore. Given the increased likelihood of fatal overdose for those who return to injection following a period of abstinence, provision to all trial participants of naloxone—the overdose antidote …. (shrink)

To counter the pandemic caused by severe acute respiratory syndrome coronavirus 2, some have proposed accelerating SARS-CoV-2 vaccine development through controlled human infection trials. These trials would involve the deliberate exposure of relatively few young, healthy volunteers to SARS-CoV-2. We defend this proposal against the charge that there is still too much uncertainty surrounding the risks of COVID-19 to responsibly run such a trial.

Much has changed in maternal-fetal medicine since the early 2000s, when the previous ethical frameworks for fetal therapy trials were established. We applaud Hendriks and colleagues for taking on t...

Excluding women from participating in clinical drug trials might seem like a good thing. It may seem like a good way to protect women from the risks of being a research subject and a way to prevent fetal harm. However, the exclusion or inadequate representation of women in clinical trials may actually cause harm. Excluding women from clinical trials does not rule out the possibility of damage to offspring. Nor does it guarantee researchers or institutions freedom from (...) legal liability. The issue of women’s exclusion has received substantial attention in the USA but very little in Australia. (shrink)

American bioethics has served as a safety net for the rich and powerful, often failing to protect minorities and the economically disadvantaged. For example, minorities and the economically disadvantaged are often unduly influenced into participating in clinical trials that promise monetary gain or access to health care. This is a violation of the bioethical principle of “respect for persons,” which requires that informed consent for participation in clinical trials is voluntary and free of undue influence. Promises of access (...) to health care invalidate the voluntariness of informed consent not only because it unduly induces minorities and the economically disadvantaged to participate in clinical trials to obtain access to potentially life saving health care, but it is also manipulative because some times the clinical trial is conducted by the very institutions that are denying minorities and the economically disadvantaged access to health care. To measure whether consent is voluntary and free of undue influence, federal agencies should require researchers to use the Vulnerability and Equity Impact Assessment tool, which I have created based on the Health Equity Impact Assessment tool, to determine whether minorities and the economically disadvantaged are being unduly influenced into participating in clinical trials in violation of the “respect for persons” principle. (shrink)

Migrant workers in dormitories are an attractive source of clinical trial participants. However, they are a vulnerable population that has been disproportionately affected by the COVID-19 pandemic. Guidelines on recruiting vulnerable populations for clinical trials have long been established, but ethical considerations for migrant workers have been neglected. This article aims to highlight and explain what researchers recruiting migrant workers must be cognizant of, and offers recommendations to address potential concerns. The considerations raised in this article include: three types (...) of illiteracy, power dynamics, the risks associated with communal living and potential benefits to the migrant workers as well as researchers. No data are available. This article does not include original data. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Feminist Studies 41, no. 3. © 2015 by Feminist Studies, Inc. 509 Mytheli Sreenivas Birth Control in the Shadow of Empire: The Trials of Annie Besant, 1877–1878 In March 1877, two London activists provoked a debate about poverty and overpopulation that reverberated across metropole and colony. These activists, Annie Besant and Charles Bradlaugh, republished a book by the American physician Charles Knowlton that outlined methods to prevent conception. (...) TheFruitsofPhilosophy,which Bradlaugh and Besant provocatively subtitled An Essay on the Population Question, had been in limited circulation in Britain since 1833, but the book’s legality was called into question when its previous publisher was charged with obscenity in early 1877.1 Determined to establish the legal right to publish information about contraception, on March 23rd, 1877, Bradlaugh and Besant delivered copies of The Fruits of Philosophy to the police department, the city solicitor, and local magistrates, and they announced their intent to sell the book from their premises at the Freethought Publishing Company on Stonecutter Street in East London. The following day, a crowd filled the narrow space outside the publishing house, and the two activists sold hundreds of copies of Knowlton’s book. When no arrests were made, Besant and Bradlaugh renotified the authorities that they were selling a supposedly obscene book and were informed in turn that papers were 1. S. Chandrasekhar, “A Dirty, Filthy Book”: The Writings of Charles Knowlton and Annie Besant on Reproductive Physiology and Birth Control and an Account of the Bradlaugh-Besant Trial (Berkeley: University of California Press, 1981), 26. 510 Mytheli Sreenivas being prepared for their arrest and prosecution. On the 7th of April, 1877, Besant and Bradlaugh were arrested and taken into custody.2 In their subsequent trial, the two activists linked birth control advocacy to a Malthusian worldview. They argued that the urban working classes and the rural poor in Britain labored under the burden of overpopulation. Humanitarian concern for impoverished people, and not intent to promote obscenity, drove them to disseminate information about birth control. Besant and Bradlaugh were eventually acquitted on a legal technicality, and Bradlaugh moved on to other issues. Besant, however, was dissatisfied with The Fruits of Philosophy because its methods were outdated by the science of the day. She was determined to write a more up-to-date guide explaining contraceptive methods and went on to found a Malthusian League to disseminate birth control information. These events—the trial and Besant’s further campaigns promoting contraception —mark a watershed moment in the history of birth control activism.3 They would shape how reproduction came to be understood not as a private matter, but as a particular sort of social problem, whose implications reverberated from London to the empire in India and back again. To outside observers, Bradlaugh and Besant may have seemed an unlikely pair to set these events into motion. Bradlaugh, at age forty-four, had a long history of association with radical causes. A celebrated atheist and antimonarchical republican, he helped to shape a tradition of mid-nineteenth-century English radicalism that developed in the wake of Chartist decline. As a member of the National Reform League in the 1860s, he had participated in public demonstrations to extend the franchise. His leadership of the National Secular Society made him a popular lecturer among Freethinkers on issues of political democracy, anticlericalism, and occasionally on neo-Malthusianism.4 2. Anne Taylor, Annie Besant: A Biography (Oxford: Oxford University Press, 1992), 110–12. 3. The term “birth control” was coined in a meeting of Margaret Sanger and her associates in 1914, and thus would not have been in use in the late nineteenth century. The term contraception was not unknown, but had only limited circulation in scientific discourses. Nevertheless, I use both “birth control” and “contraception” interchangeably to mean methods to prevent conception. See Peter C. Engelman, A History of the Birth Control Movement in America (Santa Barbara, CA: Praeger, 2011), xviii. 4. Taylor, Annie Besant, 80–81. Mytheli Sreenivas 511 In comparison to Bradlaugh’s prominence, Besant was relatively unknown. Her public career began after a separation from her husband, the Anglican vicar Frank Besant. Perhaps the couple were ill-suited to each other from... (shrink)

In recent years, several cases about the legal personhood of nonhuman animals garnered global attention, e.g. the recognition of ‘basic rights’ for the Argentinian great apes Sandra and Cecilia. Legal scholars have embraced the animal turn, blurring the once sovereign boundaries between persons and objects, recognising nonhuman beings as legal subjects. The zoonotic origins of the Covid-19 pandemic stress the urgency of establishing ‘global animal law’ and deconstructing anthropocentrism. To this end, it is vital to also consider the extensive premodern (...) legal history that humans share with other animals. Over 200 so-called animal trials have been documented in premodern Europe. In these proceedings, certain nonhuman animals—particularly domestic pigs—were prosecuted, often resulting in their capital punishment or anathema. This paper takes a history of ideas approach to these historical instances where Western philosophy of law and philosophical anthropology intersect, problematising the notion that such trials constitute wholesome precedents of the kind of legal personhood presently debated in jurisprudence. My counter-hegemonic analysis of the legal prosecution and execution of several pigs in fifteenth-century France demonstrates that late mediaeval notions of criminality transcended the alleged human-nonhuman divide whilst reaffirming and reifying human distinctiveness. I propose that pig trials were local laboratories where Christian communities reflected upon the natural hierarchy of God’s creation. Ensuing the apparent breach of the prescribed boundaries of nature, these communities renegotiated and re-naturalised everyday interspecies sociability by utilising the offending animals to exemplify particular norms about what it means to be human, generally to the animals’ detriment. (shrink)

Background: Randomized controlled trials have been criticized for their inability to identify and differentiate the causal mechanisms that generate the outcomes they measure. One solution is the development of realist trials that combine the empirical precision of trials' outcome data with realism's theoretical capacity to identify the powers that generate outcomes. Main Body: We review arguments for and against this position and conclude that critical realist trials are viable. Using the example of an evaluation of the (...) educational effectiveness of virtual reality simulation, we explore whether Partial Least Squares Structural Equation Modelling can move statistical analysis beyond correlational analysis to support realist identification of the mechanisms that generate correlations. Conclusion: We tentatively conclude that PLS-SEM, with its ability to identify ‘points of action’, has the potential to provide direction for researchers and practitioners in terms of how, for whom, when, where and in what circumstances an intervention has worked. (shrink)

The recent Ebola outbreak in West Africa began in the spring of 2014 and has since caused the deaths of over 6,000 people. Since there are no approved treatments or prevention modalities specifically targeted at Ebola Virus Disease , debate has focused on whether unproven interventions should be offered to Ebola patients outside of clinical trials. Those engaged in the debate have responded rapidly to a complex and evolving crisis, however, and this debate has not provided much opportunity for (...) in-depth analysis. Additionally, the existing literature on access to unproven therapies has focused on contexts like HIV/AIDS and oncology, which are very different than the Ebola epidemic. In this paper, we examine the ethical issues surrounding access to unproven therapies in the context of the recent Ebola outbreak to yield new insights about this controversial and unsettled issue. We argue first that, in this context, the interests of patients in obtaining access to unproven therapies are not fully aligned.. (shrink)

Medical research involving human subjects can be risky and burdensome. Therefore, such research must be reviewed and approved by a Research Ethics Committee (REC). To guarantee the safety of the subjects, it is very important that these studies be conducted in accordance with the approved protocol. An important issue in this respect is whether studies include the requisite number of subjects based on the research question. The research question is unlikely to be answered reliably if the requisite number of subjects (...) is not met. In such cases, subjects are exposed to unnecessary risks and burdens. In this descriptive study, the authors evaluated how frequently studies are completed with the required number of subjects. Moreover, the authors identified the characteristics of research that does and does not include the required number of subjects. The results of this study show that a considerable proportion of studies (41/107) were terminated although they failed to recruit a sufficient number of subjects. Furthermore, the authors found that investigator-initiated studies have significantly (p=0.028) more problems in recruiting the requisite number of subjects than studies initiated by pharmaceutical companies. Potential solutions are discussed to reduce the number of studies that do not include a sufficient number of subjects. (shrink)

Hastings Center Report, Volume 52, Issue 3, Page 9-17, May–June 2022.

In their thoughtful and well-supported target article, Andrew Garland, Stephanie Morain, Jeremy Sugarman (2023) argue that clinicians have a duty to participate in pragmatic clinical trials. This d...

Research Ethics Committees (RECs) play a critical gatekeeping role in clinical trials. This role is meant to ensure that only those trials that meet certain ethical thresholds proceed through their gate. Two of these thresholds are that the potential benefits of trials are reasonable in relation to risks and that trials are capable of producing a requisite amount of social value. While one ought not expect perfect execution by RECs of their gatekeeping role, one should expect (...) routine success in it. This article reviews a range of evidence showing that substantial numbers of ethically tainted trials are receiving REC approvals. Many of the trials are early phase trials that evidence shows have benefits that may not be reasonable compared with their risks and many others are later trials that evidence shows may lack sufficient social value. The evidence pertains to such matters as methodologically inadequate preclinical studies incapable of supporting the inferences that REC members must make about the prospects for potential benefit needed to offset the risks in early phase trials and sponsorship bias that can cause improperly designed, conducted, analysed and reported later phase trials. The analysis of the evidence makes clear that REC practices need to be strengthened if they are to adequately fulfil their gatekeeping role. The article also explores options that RECs could use in order to improve their gatekeeping function. (shrink)

It is sometimes thought that randomized study group allocation is uniquely proficient at producing comparison groups that are evenly balanced for all confounding causes. Philosophers have argued that in real randomized controlled trials this balance assumption typically fails. But is the balance assumption an important ideal? I run a thought experiment, the CONFOUND study, to answer this question. I then suggest a new account of causal inference in ideal and real comparative group studies that helps clarify the roles of (...) confounding variables and randomization. 1Confounders and Causes2The Balance Assumption3The CONFOUND Study 3.1CONFOUND 13.2CONFOUND 24Disjunction C and the Ideal Study 4.1The ultimate ‘other cause’: C4.2The ideal comparative group study4.3Required conditions for causal inference5Confounders as Causes, Confounders as Correlates6Summary. (shrink)

BackgroundCommunity Advisory Boards (CAB) have become essential organs of involving communities in HIV clinical trials especially in developing countries. However, limited empirical evidence exists on the role of CABs in low and middle-income countries including Tanzania. This study aims at exploring the role of CABs in community-based HIV clinical trials conducted in Tanzania.MethodologyWe adopted a phenomenological approach to purposefully select HIV clinical trial stakeholders. These included CAB members, researchers and Institutional Review Board (IRB) members in Tanzania. We conducted (...) In-depth Interviews (IDIs) with ten participants and three Focus Group Discussions (FGDs) with eighteen participants. The data were thematically analyzed with the aid of MAXQDA software version 20.2.1.ResultsThe findings indicate that at every stage of implementation of a community-based HIV clinical trial, a functioning CAB is important for its success. This importance is based on contextualization of the informed consent process and protocol, managing rumours in the community, weighing trial risks and benefits, sensitizing the community, assisting participant recruitment, tracing and retention. However, being perceived as financial beneficiaries than community representatives emerged as a challenge to CAB members. ConclusionThe study empirically indicates the need for functioning CABs in every stage of implementation of community-based HIV clinical trials. The roles of which are interwoven in serving research goals and protecting the interests of the community and that of trial participants. (shrink)

BackgroundInformed consent, whose goal is to assure that participants enter research voluntarily after disclosure of potential risks and benefits, may be impossible or impractical in emergency research. In low resource settings, there is limited information on the experiences of the informed consent process for randomized clinical trials in the emergency care context. The objective of this study was to explore the experiences of the informed consent process and factors that motivated participation in two obstetrics and newborn care randomized clinical (...) trials (RCTs).MethodsThis was a qualitative study conducted among former participants of RCTs in the emergency obstetric care context, conducted at Kawempe National Referral Hospital, Uganda. It employed 30 in-depth interviews conducted from June 1, 2019 to August 30, 2019. Issues explored included attitudes about research, the purpose of the research in which they participated, motivations to take part in the study, factors that influenced enrolment decisions, and experiences of the informed consent process.ResultsRespondents felt that research was necessary to investigate the cause, prevention or complications of illness. The decisions to participate were influenced by hope for material or therapeutic benefit, trust in the healthcare system and influence of friends and family members. Many were satisfied with the informed consent process, though they did not understand some aspects of the research.ConclusionRespondents valued participation in RCTs in emergency obstetric and newborn care. Hope for benefit, altruism, desire to further scientific knowledge and trust in the investigators featured prominently in the motivation to participate. Both intrinsic and extrinsic factors were motivators for RCT participation. (shrink)

This paper discusses the so-called non-interference assumption (NIA) grounding causal inference in trials in both medicine and the social sciences. It states that for each participant in the experiment, the value of the potential outcome depends only upon whether she or he gets the treatment. Drawing on methodological discussion in clinical trials and laboratory experiments in economics, I defend the necessity of partial forms of blinding as a warrant of the NIA, to control the participants’ expectations and their (...) strategic interactions with the experimenter. (shrink)

"This collection is the first book-length examination of the various epistemological issues underlying legal trials. Trials are, among other things, centrally concerned with determining truth: whether a criminal defendant has in fact culpably committed the act of which they are accused, or whether a civil defendant is in fact responsible for the damages alleged by the plaintiff. But are trials truth-conducive? Assessing the value of trials as truth-seeking endeavors requires that we consider a host of underlying (...) social epistemological questions. The contributors to this volume address a number of these pressing questions, including but not limited to the following: How much credence should they give to eyewitness testimony? How should we balance the relative epistemic value of testimony offered by defense witnesses and prosecution witnesses? Are juries an effective means of arriving at justified beliefs about a defendant's guilt or innocence? When, if ever, is statistical information about a defendant's character relevant? What degree of certainty should we require to support a verdict of 'guilty'? How should standards of proof be interpreted for allegations that contain numerous discrete components? The Social Epistemology of Legal Trials will be of interest to scholars and upper-level students working on issues at the intersection of epistemology and philosophy of law"--. (shrink)