It was the spring of 2020 when the email came to our inboxes—a memo from our Institutional Review Board informing us that we were approved to begin conducting our pragmatic clinical trial with a wa...

Pragmatic clinical trials are a relatively new methodological approach to the execution of clinical research that can increase research efficiency and provide access to unique data. Some have suggested that the costs and delays associated with obtaining informed consent could make PCTs difficult or even impossible to execute. Alternative consent models have been proposed, some of which lower standards of disclosure, delay consent, or waive it altogether. We analyze the permissibility of changes to informed consent in (...) the context of Canadian research ethics policies, legislation, common law, professional codes of ethics, and professional standards of practice. We find that Canadian law and policy relating to informed consent clearly applies to any clinician who might be involved in a PCT. In addition, existing consent norms seem unable to accommodate alternative consent models for pragmatic research if such models would involve lowering the standard of disclosure. The strong emphasis on the primacy... (shrink)

Pragmatic clinical trials (PCTs) seek to show the effectiveness of treatments in routine, clinical practice (MacPherson 2004). However, a number of ethical challenges come to the fore when collater...

Garland, Morain, and Sugarman (2023) can be congratulated for their comprehensive and sharp analysis of physicians’ ethical duties with respect to pragmatic clinical trials (PCTs). PCTs embed resea...

Clinicians have good moral and professional reasons to contribute to pragmatic clinical trials (PCTs). We argue that clinicians have a defeasible duty to participate in this research that takes place in usual care settings and does not involve substantive deviation from their ordinary care practices. However, a variety of countervailing reasons may excuse clinicians from this duty in particular cases. Yet because there is a moral default in favor of participating, clinicians who wish to opt out of (...) this research must justify their refusal. Reasons to refuse include that the trial is badly designed in some way, that the trial activities will violate the clinician’s conscience, or that the trial will impose excessive burdens on the clinician. (shrink)

Pragmatic clinical trials offer important benefits, such as generating evidence that is suited to inform real-world health care decisions and increasing research efficiency. However, PCTs also present ethical challenges. One such challenge involves the management of information that emerges in a PCT that is unrelated to the primary research question, yet may have implications for the individual patients, clinicians, or health care systems from whom or within which research data were collected. We term these findings as?pragmatic (...) clinical trial collateral findings,? or?PCT-CFs?. In this article, we explore the ethical considerations associated with the identification, assessment, and management of PCT-CFs, and how these considerations may vary based upon the attributes of a specific PCT. Our purpose is to map the terrain of PCT-CFs to serve as a foundation for future scholarship as well as policy-making and to facilitate careful deliberation about actual cases as they occur in practice. (shrink)

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

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...

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...

The target articles in this issue advance our understanding of bioethical considerations in pragmatic trials (Garland, Morain, and Sugarman 2023; Morain and Largent 2023). Both articles appreciate...

We very much appreciate the helpful and generous commentaries in response to “Do Clinicians have a Duty to Participate in Pragmatic Clinical Trials?” (Garland, Morain, and Sugarman 2023). In that a...

Morain and Largent’s (2023) thorough and thoughtful article concludes that the partial-entrustment model of medical researchers’ ancillary-care obligations (Richardson and Belsky 2004; Belsky and R...

_341_ _Objectives: _In patients with multivessel disease both the detection of the culprit lesion and the exact allocation are important preconditions for sufficient treatment and improved outcome. In a vessel based approach the combination of quantitative coronary angiography and fractional flow reserve measured by a pressure wire should be advantageous compared to myocardial SPECT, as morphological and functional information is delivered simultaneously. Therefore our aim was to evaluate MS in the detection and allocation of hemodynamically significant stenoses obtained by the (...) combined gold standard QCA plus FFR in patients with multivessel disease. _Methods: _FFR and QCA of 95 vessels in 80 patients have been evaluated. Hemodynamically significant target lesions were defined as intermediate stenoses between 50 and 75% with an FFR. (shrink)

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged conventional (...) thinking about therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged conventional (...) thinking about therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

The volume of clinical research is increasing exponentially—far beyond our ability to process and absorb the results. Given this situation, it may be beneficial to consider reducing the flow at its source. In what follows, I will motivate and critically evaluate the following proposal: researchers should conduct fewer clinical trials. More specifically, I c onsider whether researchers should be permitted to conduct only clinical research of very high quality and, in turn, whether research ethics committees should (...) prohibit all other, lower-quality research, even when it might appear to meet some minimal ethical standard. Following a close analysis of the social-value requirement of ethical clinical research, I argue that this proposal is defensible. The problem identified in this paper has two parts, quantity and quality, and some clarification is needed about the latter because “quality” is a highly contested term in the medical literature. When some scholars advocate for high-quality trials, they mean large-scale, simple, explanatory randomized controlled trials. Others, including myself, have defended a different characterization of high-quality research that tends more toward pragmatic trial design and the use of methods other than RCTs. Pragmatic trials aim to provide evidence that directly supports clinical decision-making in “usual” care settings. Unlike explanatory trials, which aim to abstract away from particular settings and patients, in the hopes of creating ideal conditions for the success of an intervention, pragmatic trials deliberately pursue knowledge of high applicability, through the use of representative subjects, clinically important questions, flexible treatment protocols, patient-oriented outcome measures, and so on. I see applicability as a marker of high-quality research. The context in which research is meant to be applied should be the context in which new interventions are evaluated. (shrink)

Most phase III clinical trials today are explanatory. Because explanatory, or efficacy, trials test hypotheses under “ideal” conditions, they are not well suited to providing guidance on decisions made in most clinical care contexts. Pragmatic trials, which test hypotheses under “usual” conditions, are often better suited to this task. Yet, pragmatic, or effectiveness, trials are infrequently carried out. This mismatch between the design of clinical trials and the needs of health (...) care professionals is frustrating for everyone involved, and explains some of the challenges inherent in attempts to enhance knowledge translation and encourage evidence-based practice. The situation is more than simply frustrating, however; it is potentially unethical. Clinical trials must be socially valuable in order to (1) warrant the risks they impose on human research subjects and (2) fairly and efficiently assess new clinical interventions. Most bioethicists would agree that trials that have no social value, for instance, because their results do not have the potential to advance clinical care, should not be performed. What is less widely appreciated is that given limited research resources, trials that are more socially valuable should be preferred to trials that are less socially valuable when all else is equal. With respect to clinical trial design, I argue that while explanatory trials often have some social value, many have less social value than their pragmatic counterparts. On the basis of this general ethical assessment, I provide a preliminary defense of the position that clinical researchers should aim to conduct pragmatic trials, that is, that researchers face a burden of justification related to any idealizing elements added to trial designs. (shrink)

Garland and colleagues provide many compelling reasons for why clinicians ought to participate in pragmatic clinical trials (Garland et al. 2023), also known as effectiveness trials (Thorpe et al....

We studied changes in eligibility criteria--the largest impediment to patient accrual--in two samples of clinical trials. Trials from the NSABP (National Surgical Adjuvant Breast and Bowel Program) and POG (Pediatric Oncology Group) were analyzed. After eliminating duplications, the criteria in each protocol were enumerated and classified according to a novel schema. NSABP trials contained significantly more criteria than POG trials, and added precision criteria (making study populations homogeneous) at a faster rate than POG studies. The (...) difference between NSABP studies (explanatory trials) and POG studies (pragmatic trials) suggest that large numbers of eligibility criteria are not necessary for quality studies. We recommend that: (1) the inclusion/exclusion criteria distinction be abandoned; (2) eligibility criteria be explicitly justified; (3) the need for each criterion be assessed when new trials are planned; (4) criteria in phase III trials restricting patient accrual be minimized; and (5) further research be done to assess the impact of criteria on generalizability. (shrink)

. This article traces the intellectual history of scientific studies of intercessory prayer published in English between 1965 and the present by focusing on the conflict and discussion they prompted in the medical literature. I analyze these debates with attention to how researchers articulate the possibilities and limits medical science has for studying intercessory prayer over time. I delineate three groups of researchers and commentators: those who think intercessory prayer can and should be studied scientifically, those who are more skeptical (...) and articulate the limits of science around this topic, and those who focus primarily on the pragmatic applications of this knowledge. I analyze these contests as examples of what Thomas Gieryn calls “epistemic authority” as medical researchers engage in what he describes as “boundary‐work” or “the discursive attribution of selected qualities to scientists, scientific methods, and scientific claims for the purposes of drawing a rhetorical boundary between science and some less authoritative residual non‐science.” ). (shrink)

Pragmatic trials aim to directly inform health care decision-making through the collection of so-called ‘real world data’ from observations of comparative treatment effects in clinical practice. In order to ensure the applicability and feasibility of a pragmatic trial, design features may be necessary that deviate from standard research ethics requirements. Examples are traditional requirements to seek written informed consent and to perform extensive data and safety monitoring. Proposals for deviations from standard research ethics practice have resulted (...) in controversy about their ethical acceptability. One of the justifications for altered procedures is the allegedly high social value of pragmatic trials. In order to properly operationalize the concept in the ethical assessment of pragmatic trial designs, specification is warranted. We identified three determinants from common claims about a pragmatic trial's social value: the extent to which the research question has real world relevance, the trial design's ability to generate a real world answer and the probability of direct uptake of the results by decision-makers in practice. Subsequently, we discuss how these determinants should be applied to the practice of pragmatic trials, and to what extent they might be applicable to explanatory trials. (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...

The concept of practical, or pragmatic, clinical trials was introduced in the early 2000s, in parallel with the growing availability and use of electronic health data. Researchers and policymakers...

Background Pragmatic randomized controlled trials are designed to evaluate the effectiveness of interventions in real-world clinical conditions. However, these studies raise ethical issues for researchers and regulators. Our objective is to identify a list of key ethical issues in pragmatic RCTs and highlight gaps in the ethics literature. Methods We conducted a scoping review of articles addressing ethical aspects of pragmatic RCTs. After applying the search strategy and eligibility criteria, 36 articles were included and reviewed (...) using content analysis. Results Our review identified four major themes: 1) the research-practice distinction; 2) the need for consent; 3) elements that must be disclosed in the consent process; and 4) appropriate oversight by research ethics committees. 1) Most authors reject the need for a research-practice distinction in pragmatic RCTs. They argue that the distinction rests on the presumptions that research participation offers patients less benefit and greater risk than clinical practice, but neither is true in the case of pragmatic RCTs. 2) Most authors further conclude that pragmatic RCTs may proceed without informed consent or with simplified consent procedures when risks are low and consent is infeasible. 3) Authors who endorse the need for consent assert that information need only be disclosed when research participation poses incremental risks compared to clinical practice. Authors disagree as to whether randomization must be disclosed. 4) Finally, all authors view regulatory oversight as burdensome and a practical impediment to the conduct of pragmatic RCTs, and argue that oversight procedures ought to be streamlined when risks to participants are low. Conclusion The current ethical discussion is framed by the assumption that the function of research oversight is to protect participants from risk. As pragmatic RCTs commonly involve usual care interventions, the risks may be minimal. This leads many to reject the research-practice distinction and question the need for informed consent. But the function of oversight should be understood broadly as protecting the liberty and welfare interest of participants and promoting public trust in research. This understanding, we suggest, will focus discussion on questions about appropriate ethical review for pragmatic RCTs. (shrink)

Pragmatic randomized controlled trials are designed to evaluate the effectiveness of interventions in real-world clinical conditions. However, these studies raise ethical issues for researchers and regulators. Our objective is to identify a list of key ethical issues in pragmatic RCTs and highlight gaps in the ethics literature. We conducted a scoping review of articles addressing ethical aspects of pragmatic RCTs. After applying the search strategy and eligibility criteria, 36 articles were included and reviewed using content (...) analysis. Our review identified four major themes: 1) the research-practice distinction; 2) the need for consent; 3) elements that must be disclosed in the consent process; and 4) appropriate oversight by research ethics committees. 1) Most authors reject the need for a research-practice distinction in pragmatic RCTs. They argue that the distinction rests on the presumptions that research participation offers patients less benefit and greater risk than clinical practice, but neither is true in the case of pragmatic RCTs. 2) Most authors further conclude that pragmatic RCTs may proceed without informed consent or with simplified consent procedures when risks are low and consent is infeasible. 3) Authors who endorse the need for consent assert that information need only be disclosed when research participation poses incremental risks compared to clinical practice. Authors disagree as to whether randomization must be disclosed. 4) Finally, all authors view regulatory oversight as burdensome and a practical impediment to the conduct of pragmatic RCTs, and argue that oversight procedures ought to be streamlined when risks to participants are low. The current ethical discussion is framed by the assumption that the function of research oversight is to protect participants from risk. As pragmatic RCTs commonly involve usual care interventions, the risks may be minimal. This leads many to reject the research-practice distinction and question the need for informed consent. But the function of oversight should be understood broadly as protecting the liberty and welfare interest of participants and promoting public trust in research. This understanding, we suggest, will focus discussion on questions about appropriate ethical review for pragmatic RCTs. (shrink)

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)

Growing interest in embedded research approaches—where research is incorporated into clinical care—has spurred numerous studies to generate knowledge relevant to the real-world needs of patients and other stakeholders. However, it also has presented ethical challenges. An emerging challenge is how to understand the nature and extent of investigators’ obligations to patient-subjects. Prior scholarship on investigator duties has generally been grounded upon the premise that research and clinical care are distinct activities, bearing distinct duties. Yet this premise—and its corresponding (...) implications—are challenged when research and clinical care are deliberately integrated. After presenting three case studies from recent pragmatic clinical trials, we identify six differences between explanatory trials and embedded research that limit the application of existing scholarship for ascertaining investigator duties. We suggest that these limitations indicate a need to account for the implications of usual care and to move beyond a narrow focus on the investigator-subject dyad, one that better reflects the team- and institution-based nature of contemporary health systems. (shrink)

Pragmatic comparative effectiveness randomized controlled trials evaluate the effectiveness of one interventions under real-world clinical conditions. The results of ceRCTs are often directly generalizable to everyday clinical practice, providing information critical to decision-making by patients, clinicians, and healthcare policymakers. The PRECIS-2 framework identifies nine domains that serve to score a trial on a continuum between very explanatory to very pragmatic. According to the framework, pragmatic trials may have one or more of the following (...) features: there are fewer eligibility criteria for participants, in an... (shrink)

Randomized controlled trial trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions, whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic (...) class='Hi'>trials has grown substantially in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices. Semi-structured interviews with key stakeholders, across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials. We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications. (shrink)

This thesis addresses the tension in pragmatic cluster-randomized trials between their social value and the requirement to respect the autonomy of research participants. Pragmatic trials are designed to evaluate the effectiveness of treatments in real-world settings to inform clinical decision-making and promote cost-efficient care. These trials are often embedded into clinical settings and ideally include all patients who would receive the treatments under investigation as a part of routine care. Trialists increasingly adopt cluster-randomized (...) designs—in which intact groups, such as hospitals or clinics, are allocated randomly to study interventions—to simplify the inclusion of all patients. But including all-comers conflicts with the requirement to obtain written informed consent from research participants. Since informed consent is central to respecting patient autonomy, the question arises: how can the ends of autonomy and pragmatism be served simultaneously? Some philosophers argue that patients have an obligation to participate in clinical research and that this may negate consent requirements. I argue that while there may be grounds for a prima facie obligation for patients to participate in clinical research, no compelling argument has demonstrated that the obligation is enforceable. Others assert that broad application of a waiver of consent will facilitate the conduct of pragmatic cluster-randomized trials. I demonstrate that this proposal sharply conflicts with the historical origins of the waiver. I articulate a novel moral foundation for the use of a waiver of consent and show that when trials evaluate treatments delivered directly to patients, the autonomy interests at stake for participants are too substantial to permit its use. My solution draws a distinction between consent requirements in existing policy and consent as an autonomous authorization. As many pragmatic cluster-randomized trials are conducted in primary care settings with no research staff, I argue that patient autonomy can be promoted and protected using clinical-style consent, in which health providers seek verbal informed consent from patients and document it in the electronic health record. This approach has been associated with high rates of recruitment and, thus, may satisfy both requirements for social value and respect for autonomy. (shrink)

As the_number of clinical trials continues to grow, there is an increasing need for education and training in the field. The clinical research climate is less forgiving of errors and oversights and therefore requires more knowledge of regulations and requirements. This brand new edition details new laws and regulations in protecting children participating in clinical trials and how a new focus on privacy of individual health information in the United States has changed how medical records (...) are handled. Includes a manual for investigators, research nurses and study coordinators with minimal experience or who are new to clinical research An easy-to-read and open text design using ‘sidebars’ of examples and information boxes related to the main text Includes a list of Frequently Asked Questions and Glossary Duke Clinical Research Institute is the world’s largest academic clinical research organisation and is well known and respected within the clinical research community. (shrink)

In this essay, we defend the design of the Salk polio vaccine trial and try to put some limits on the role schemata should play in designing clinical research studies. Our presentation is structured as a response to de Freitas and Pietrobon who identified the CONSORT statement as a schema that would have, had it existed at the time, ruled out the design of the Salk polio vaccine trial of 1954 in favor of a completely randomized controlled clinical (...) trial. We argue that large-scale public health interventions often require evidence beyond simple efficacy, the limit of what an RCT can provide, and that the design actually adopted for the Salk trial represented a reasonable—albeit imperfect—compromise. This is of more than historical interest in that many contemporary studies are of the scale and scope to require a more pragmatic, rather than explanatory, approach to study design. (shrink)

This systematic review identifies and critically evaluates instruments that have been developed to measure clinical trial informed consent comprehension in non-cognitively-impaired adults.Literature searches were carried out on Medline (Ovid), PsycInfo, CINHAL, ERIC, ScienceDirect, and Cochrane Library for English language articles published between January 1980 and September 2008. Instruments were excluded if they focused on consent onto paediatric trials, the construct under study was primarily capacity or competency, or the instrument was developed specifically for psychiatric or cognitively-impaired populations. Instruments (...) selected for review were evaluated against the following criteria: (1) method of item generation; (2) type and format of test items; (3) administration and interpretation of test results; and (4) psychometric properties.Three instruments met our defined inclusion criteria: the Deaconess Informed Consent Comprehension Test (DICCT), the Quality of Informed Consent (QuIC) questionnaire and the Brief Informed Consent Protocol (BICEP). Each instrument varied in terms of content measured. Significantly, these are the first standardized instruments developed to assess comprehension in non-cognitively-impaired adults. Yet, each instrument had its own set of limitations such as the lack of generalizability and the absence of details pertaining to how test results should be used to guide clinical decision-making.Standardized clinical trial informed consent comprehension assessments have been developed to identify gaps in research participants' understanding and ensure that respect for patient autonomy is satisfied. (shrink)

The article presents the advantages and limitations of adaptive clinical trials for assessing the effectiveness of medical interventions and specifies the conditions that contributed to their development and implementation in clinical practice. I advance two arguments by discussing different cases of adaptive trials. The normative argument is that responsible adaptation should be taken seriously as a new way of doing clinical research insofar as a valid justification, sufficient understanding, and adequate operational conditions are provided. The (...) second argument is historical. The development of adaptive trials can be related to lessons learned from research in cases of urgency and to the decades-long efforts to end the productivity crisis of pharmaceutical research, which led to the emergence of translational, personalized, and, recently, precision medicine movements. (shrink)

Heterogeneous treatment effects represent a major issue for medicine as they undermine reliable inference and clinical decision-making. To overcome the issue, the current vision of precision and personalized medicine acknowledges the need to control individual variability in response to treatment. In this paper, we argue that gene-treatment-environment interactions (G × T × E) undermine inferences about individual treatment effects from the results of both genomics-based methodologies—such as genome-wide association studies (GWAS) and genome-wide interaction studies (GWIS)—and randomized controlled trials (...) (RCTs). Then, we argue that N-of-1 trials can be a solution to overcome difficulties in handling individual variability in treatment response. Although this type of trial has been suggested as a promising strategy to assess individual treatment effects, it nonetheless has limitations that limit its use in everyday clinical practice. We analyze the existing variability within the designs of N-of-1 trials in terms of a continuum where each design prioritizes epistemic and pragmatic considerations. We then support wider use of the designs located at the pragmatic end of the explanatory-pragmatic continuum. (shrink)

The outsourcing of clinical trials to Latin America by the transnational innovative pharmaceutical industry began about twenty years ago. Using archival information and field work in Argentina, Brazil, Costa Rica, Mexico and Peru, the authors discuss the regulatory contexts and the ethical dimensions of human experimentation in the region. More than 80% of all clinical trials in the region take place in these countries, and the European Medicines Agency has defined them as priority countries in Latin (...) America. The authors raise questions about the quality of data obtained from the trials and the violation of human rights during their implementation. Their findings are presented in this volume, the first in-depth analysis of clinical trials in the region.. (shrink)

As a consequence of the COVID-19 pandemic, the number of decentralized clinical trials, trials conducted in whole or in part at locations other than traditional clinical trial sites, significantly increased. While these trials have the potential advantage of access, participant centricity, convenience, lower costs, and efficiency, they also raise a number of important ethical and practical concerns. Here we focus on a number of those concerns, including participant safety, privacy and confidentiality, remote consent, digital access (...) and proficiency, and trial oversight. Awareness of these ethical complexities will help foster the development of processes and cooperative solutions to promote safe, ethical trials going forward, optimized to decrease burden and increase access for all participants. (shrink)

Procedures for the selection of subjects for participation in randomized clinical trials--usually formalized as eligibility criteria in the study protocol--have both scientific and ethical implications. In this thesis, I undertake an examination of eligibility criteria at three stages in the genesis and dissemination of medical knowledge: clinical trial protocol, interpretation by investigators, and reporting of study results.In the first chapter, ethical issues in subject selection are reviewed and the main study questions are presented. In the second chapter, (...) the results of an examination of eligibility criteria in two sets of clinical trials, one sponsored by the NSABP, the other sponsored by POG, covering a twenty-year time span are presented. The POG trials had far fewer eligibility criteria than the NSABP studies, suggesting that large numbers of criteria may not be necessary for high quality research. In the third chapter, the impact of subjective eligibility criteria on enrollment and investigator uncertainty is explored. Subjective criteria were associated with more variable enrollment decisions and greater uncertainty. Such criteria represent a threat to the validity, conduct and interpretation of trials and, therefore, should only be included when carefully justified. The fourth chapter examines the accuracy of the reporting of eligibility criteria in sets of corresponding study protocol, methods paper, journal article, and Clinical Alert. Important information is lost at each step in the dissemination of study results. Unnecessary criteria ought to be dropped at a trial's inception; all other criteria must be reported faithfully. The fifth chapter attempts to provide a comprehensive philosophical account of just selection procedures for clinical research using the political philosophy of Michael Walzer. The sixth, and last, chapter, discusses explanatory and pragmatic approaches to clinical trial design, overlapping scientific and ethical concerns related to eligibility criteria, and questions for further study. (shrink)

Pragmatism is a distinctive approach to clinical research ethics that can guide bioethicists and members of institutional review boards (IRBs) as they struggle to balance the competing values of promoting medical research and protecting human subjects participating in it. After defining our understanding of pragmatism in the setting of clinical research ethics, we show how a pragmatic approach can provide guidance not only for the day-to-day functioning of the IRB, but also for evaluation of policy standards, such (...) as the one that addresses acceptable risks for healthy children in clinical research trials. We also show how pragmatic considerations might influence the debate about the use of deception in clinical research. Finally, we show how a pragmatic approach, by regarding the promotion of human research and the protection of human subjects as equally important values, helps to break down the false dichotomy between science and ethics in clinical research. (shrink)

The European framework surrounding clinical trials on medicinal products for human use is going to change as demonstrated by the large debate at European institutional level. One of the major challenges is to overcome the lack of harmonisation of clinical trial procedures among countries. This aspect is gaining more and more importance, considering the increasing number of multicentre and multinational studies. In this work, the actual European rules governing the Clinical Trial Application have been analysed throughout (...) the different steps including the registration of the trial in the European database; the preparation of documents to be submitted and their contents; the preparation of documents related to the information and consent process; the submission to competent bodies. Specific issues related to paediatric research and trials involving non EU/EEA countries have been addressed as well. Results reveal that the European legislation offers a well defined set of European rules covering different aspects of a Clinical Trial Application. However, these are not suitable to meet the challenges from multicentre and multinational clinical studies. A stronger set of rules, such as is available in a composite European Regulation has been adopted and is expected to harmonise practices and enable sponsors to carry out well conducted trials. But will the new regulation overcome the existing criticisms of Directive 2001/20/EC? (shrink)

Embedded pragmatic clinical trials (PCTs), like other types of randomized comparative-effectiveness research (CER) studies, are sometimes conducted without informed consent. Indeed, authors of both...

This article describes our efforts to screen and enrol clinical trial participants conscientiously in the COVID-19 pandemic setting. We present the standard screening and enrolment process prior to, and our process of adapting to, the pandemic. Our goal was to develop a way to screen and enrol people for clinical trials that was both equitable and effective. In addition, we outline the steps our research department took to ensure that ethical, clinical and logistical factors were considered (...) when matching a patient to a clinical trial. (shrink)

It is not uncommon for multiple clinical trials at the same institution to recruit concurrently from the same patient population. When the relevant pool of patients is limited, as it often is, trials essentially compete for participants. There is evidence that such a competition is a predictor of low study accrual, with increased competition tied to increased recruitment shortfalls. But there is no consensus on what steps, if any, institutions should take to approach this issue. In this (...) article, we argue that an institutional policy that prioritises some trials for recruitment ahead of others is ethically permissible and indeed prima facie preferable to alternative means of addressing recruitment competition. We motivate this view by appeal to the ethical importance of minimising the number of studies that begin but do not complete, thereby exposing their participants to unnecessary risks and burdens in the process. We then argue that a policy of prioritisation can be fair to relevant stakeholders, including participants, investigators and funders. Finally, by way of encouraging and helping to frame future debate, we propose some questions that would need to be addressed when identifying substantive ethical criteria for prioritising between studies. (shrink)

The relationship between the ethical standards for the governance of clinical trials and market forces can be complex and problematic. This article uses India as a case study to explore this nexus. From the mid-2000s, India became a popular destination for foreign-sponsored clinical trials. The Indian government had sought to both attract clinical trials and ensure these would be run in line with internationally accepted ethical norms. Reports of controversial medical research, however, triggered debate (...) about the robustness and suitability of India's regulatory system. In response to civil society pressure and interventions by the Supreme Court, the Indian government proposed additional measures aimed at strengthening protections for clinical trial participants. Whilst the reforms can be seen as a victory for human rights activists, they have also been criticised as being overly burdensome for sponsors. Indeed, their announcement prompted an exodus of clinical trials from India. Fearful of losing business to ‘rival’ countries, the Indian government is revisiting some of its proposals. The Indian example suggests that research ethics frameworks and national policies for economic development are increasingly intertwined. Host countries are in theory free to improve the lot of research participants, but doing so may make them appear less attractive to foreign sponsors, who can simply shift their activities to more industry-friendly jurisdictions. Although these economic pressures are unlikely to lead to a regulatory ‘race to the bottom’, they may limit host countries' ability to enact socially desirable reforms. (shrink)