Ethics and Clinical Trials

Selected resources from The Hastings Center.

Bioethics Briefings:

Clinical Trials

Clinical trials are specifically designed to test the safety and efficacy of interventions in humans and are preceded by laboratory and animal research. A randomized controlled trial is a type of clinical trial comparing two or more interventions. RCTs are the principal method for demonstrating the safety and efficacy of new interventions. Clinical trials must be approved by an institutional review board to ensure participants’ rights are protected. Read our briefing to consider: What are the ethical issues in clinical trials?

From Hastings Bioethics Forum:

From Hastings Center Report:

Reevaluating the Ethical Issues in Porcine-to-Human Heart Xenotransplantation

First published: 13 October 2022

Abstract

A major limiting factor with heart allotransplantation remains the availability of organs from deceased donors. Porcine heart xenotransplantation could serve as an alternative source of organs for patients with terminal heart failure. A first-in-human porcine xenotransplantation that occurred in January 2022 at the University of Maryland Medical Center provided an opportunity to examine several ethical issues to guide selection criteria for future xenotransplantation clinical trials. In this article, the authors, who are clinicians at UMMC, discuss the appropriate balancing of risks and benefits and the significance, if any, of clinical equipoise. The authors also review the alleged role of the psychosocial evaluation in identifying patients at an elevated risk of posttransplant noncompliance, and they consider how the evaluation’s implementation might enhance inequities among diverse populations. The authors argue that, based on the principle of reciprocity, psychosocial criteria should be used, not to exclude patients, but instead to identify patients who need additional support. Finally, the authors discuss the requirements for and the proper assessment of informed and voluntary consent from patients being considered for xenotransplantation.

Xenotransplantation Clinical Trials and the Need for Community Engagement

First published: 13 October 2022

Abstract

There are several ethical concerns facing first-in-human clinical trials involving xenotransplantation. Who should participate in these trials? If we limit trial participation to those who have exhausted other treatment options, how can we avoid therapeutic misconception? How should we balance the desire for long-term monitoring of trial participants against the well-established principle that research participants have the right to withdraw from research? Finally, how should we balance concerns about equitable access to these trials with deep mistrust of the scientific community? In particular, should xenotransplant clinical trials attempt to address well-known inequities in clinical trial participation by race and ethnicity? In this commentary, I argue that clinical investigators and regulators have an obligation to engage with underrepresented communities to develop answers to these questions.

Facilitating Ukrainian Refugees’ Continued Participation in Clinical Trials

First published: 28 June 2022

Abstract

Russia’s invasion of Ukraine and the ongoing armed conflict are having a hugely damaging effect on health services and the health infrastructure in Ukraine. Hundreds of clinical trials have been halted, leaving patients without access to treatment and jeopardizing the development of promising new drugs. There is a lack of clarity on dealing with protocol deviations and other disruptions caused by war. This article proposes guidance on facilitating Ukrainian refugees’ continuation in clinical trials. The safety of study participants should be the main priority and guide every decision, regardless of any potential consequences for an ongoing trial. This commentary outlines policy recommendations regarding participants’ reenrollment, the handover of participants and data to new principal investigators, and the consent process as well as the sponsor’s obligations related to translation, data transfer, and support for Ukrainian investigators. To ensure data integrity, investigators should carry out risk assessments of the further use of refugees’ data.

Toward Meeting the Obligation of Respect for Persons in Pragmatic Clinical Trials

First published: 28 June 2022

Abstract

Research ethics oversight systems have traditionally emphasized the informed consent process as the primary means by which to demonstrate respect for prospective subjects. Yet how researchers can best fulfill the ethical obligations of respect for persons in pragmatic clinical trials (PCTs)—particularly those that may alter or waive informed consent—remains unknown. We propose eight dimensions of demonstrating respect in PCTs: (1) engaging patients and communities in research design and execution, (2) promoting transparency and open communication, (3) maximizing agency, (4) minimizing burdens and promoting accessibility, (5) protecting privacy and confidentiality, (6) valuing interpersonal interactions with clinicians and study team members, (7) providing compensation, and (8) maximizing social value. While what respect requires in the context of PCTs will vary based on the nature of the PCT in question, the breadth of these dimensions demonstrates that respect obligations extend beyond informed consent processes.

Setting Risk Limits and Ensuring Fairness in Learning Health Care

First published: 28 June 2022

Abstract

Historical abuses resulted in the segregation of clinical research and clinical care. While this approach has protected participants, it is extremely inefficient, leading commentators to propose (re)integrating research and care into learning health care systems. Previous commentators have argued that, in these systems, it could be appropriate to condition care on patients’ consent to participation in research, but only when the added research risks are minimal. In the article “Compulsory Research in Learning Health Care: Against a Minimal Risk Limit,” Robert Steel agrees about making research participation a condition for receiving care in these systems, but he argues that the limit to minimal risks is unfounded, and he offers compelling reasons to think that, in principle, permitting greater research risks could be fair and consistent with individual rights. Unfortunately, the nature of current institutions suggests that this approach is unlikely to be implemented fairly. We conclude that, to ensure fair learning health care systems, research and care may need to be reformed in more fundamental ways.

Allocation of Opportunities to Participate in Clinical Trials during the Covid-19 Pandemic and Other Public Health Emergencies

First published: 15 December 2021

Abstract

Covid-19 raised many novel ethical issues including regarding the allocation of opportunities to participate in clinical trials during a public health emergency. In this article, we explore how hospitals that have a scarcity of trial opportunities, either overall or in a specific trial, can equitably allocate those opportunities in the context of an urgent medical need with limited therapeutic interventions. We assess the three main approaches to allocating trial opportunities discussed in the literature: patient choice, physician referral, and randomization/lottery. As, we argue, none of the three typical approaches are ethically ideal for allocating trial opportunities in the pandemic context, many hospitals have instead implemented hybrid solutions. We offer practical guidance to support those continuing to face these challenges, and we analyze options for the future.

Alzheimer’s and Aducanumab: Unjust Profits and False Hopes

First published: 22 June 2021

Abstract

Accelerated approval of aducanumab for mild Alzheimer’s by the U.S. Food and Drug Administration on June 7, 2021, has generated substantial medical, scientific, and ethical controversy. That approval was contrary to the nearly unanimous judgment of the FDA’s Advisory Committee that little reliable evidence existed of significant benefit, even though the drug did reduce β-amyloid. Three major ethical problems were created by this approval: (1) Medicare resources would be unjustly squandered, given the drug’s $56,000 annual price and the 3.1 million older potential American patients needing the drug; (2) physicians will feel ethically compelled to provide the drug to desperate, insistent patients, given FDA approval and in spite of side effects of brain bleeds and brain swelling; (3) and false hopes are generated for patients. A needed corrective by the federal government would reduce reimbursement to the bare cost of producing the drug (plus only a modest profit) until a phase IV trial has been successfully completed.

Does a Public Health Crisis Justify More Research with Incarcerated People?

First published: 23 March 2021

Abstract

Covid-19 has infected thousands and killed hundreds in prisons, jails, and immigration detention facilities across the United States. Responding to this crisis, leading medical researchers have called for expanding opportunities for people in prison to participate in vaccine trials. These calls, like current regulations, focus on individualized risk assessments around consent, coercion, and harm, while ignoring the unnaturalness of deprivation conditions in U.S. prisons. We need new frameworks of analysis that refocus on structural, rather than individual, risk assessments. Integrating structural perspectives—including skepticism of claims of scarcity, avoidance of representational distortions, and attention to institutional agency—into our existing, overly individualistic frameworks might permit the design of more ethical research projects involving people who are incarcerated. Still, the unnatural deprivations of incarceration might be so great that research subjects might need to be removed from prison entirely in order to ethically participate in research.

The Social Risks of Science

First published: 14 December 2020

Abstract

Many instances of scientific research impose risks, not just on participants and scientists but also on third parties. This class of social risks unifies a range of problems previously treated as distinct phenomena, including so-called bystander risks, biosafety concerns arising from gain-of-function research, the misuse of the results of dual-use research, and the harm caused by inductive risks. The standard approach to these problems has been to extend two familiar principles from human subjects research regulations—a favorable risk-benefit ratio and informed consent. We argue, however, that these moral principles will be difficult to satisfy in the context of widely distributed social risks about which affected parties may reasonably disagree. We propose that framing these risks as political rather than moral problems may offer another way. By borrowing lessons from political philosophy, we propose a framework that unifies our discussion of social risks and the possible solutions to them.

The Ethical Limits of Children’s Participation in Clinical Research

First published: 28 August 2020

Abstract

This essay reflects on arguments by Paul Ramsey, in The Patient as Person: Explorations in Medical Ethics (1970) and elsewhere, that continue to challenge policy-makers and those doing clinical and translational research involving children. Ramsey argued that parents cannot morally authorize their child’s participation in research unless the research is designed to benefit the child. He acknowledged that abiding by this position could have adverse impacts on improving child health, and he concluded, in a 1976 Hastings Center Report piece, that researchers must “sin bravely.” Many philosophers and theologians, including Richard McCormick, have argued against Ramsey. The Ramsey-McCormick debate played out in the bioethics literature and, by invitation, at the deliberations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which was tasked with developing an ethics framework and policies for human subjects protections. Although in its final recommendations, the commission sided with McCormick, the strict limitations on risks and harms to which a child can be exposed were clearly influenced by Ramsey.

Hans Jonas and the Ethics of Human Subjects Research

First published: 18 February 2020

Abstract

In the 1960s, human experimentation and public funding of research increased significantly, and with the rise of the modern teaching hospital, the distinction between clinical care and experimentation became more and more blurred. Yet little in the way of meaningful government regulation existed in the United States prior to 1970. In 1966, Paul Freund, the president of the American Academy of Arts and Sciences, appointed an interdisciplinary working group to consult on the issues being raised by human experimentation. Contributions from the group were published in a 1969 issue of Daedalus titled Ethical Aspects of Experimentation with Human Subjects. In the lead essay, Hans Jonas challenged then-conventional understandings of the moral problems posed by research involving humans and argued for an alternative moral framework. To Jonas, it mattered whether the physician was trying to make the patient well rather than trying to find out how to improve the health of future patients.

Bystander Ethics and Good Samaritanism: A Paradox for Learning Health Organizations

First published: 20 August 2019

Abstract

In 2012, a U.S. Institute of Medicine report called for a different approach to health care: “Left unchanged, health care will continue to underperform; cause unnecessary harm; and strain national, state, and family budgets.” The answer, they suggested, would be a “continuously learning” health system. Ethicists and researchers urged the creation of “learning health organizations” that would integrate knowledge from patient-care data to continuously improve the quality of care. Our experience with an ongoing research study on atrial fibrillation—a trial known as IMPACT-AFib—gave us some insight into one of the challenges that will have to be dealt with in creating these organizations. Although the proposed educational intervention study placed no restrictions on what providers and health plans could do, the oversight team argued that the ethical principle of beneficence did not allow the researchers to be “bystanders” in relation to a control group receiving suboptimal care. In response, the researchers designed a “workaround” that allowed the project to go forward. We believe the experience suggests that what we call “bystander ethics” will create challenges for the kinds of quality improvement research that LHOs are designed to do.

Of Drowning Children and Doubtful Analogies

First published: 20 August 2019

Abstract

In this issue of the Hastings Center Report, James Sabin and his colleagues ask what responsibility investigators in a learning health organization have to patients when research—particularly research of which patients might be unaware—illuminates problematic aspects of the patients’ care. Sabin and his colleagues were confronted by this question in the midst of designing a randomized controlled trial that sought to determine if an educational intervention targeted at patients with atrial fibrillation and their clinicians reduces underuse of oral anticoagulants. Worried about harm that might befall patients in the control group and fearing that they would be negligent bystanders if they knew these patients were at risk and did nothing, the investigators adopted a “workaround.” But the “workaround,” I suggest, was not a solution to the negligent bystander problem. Nor was it a solution to the problem as I would alternatively frame it—how to address instances of suboptimal patient care identified through research within learning health organizations.

Clinical Trial Portfolios: A Critical Oversight in Human Research Ethics, Drug Regulation, and Policy

First published: 20 August 2019

Abstract

Regulators rely on clinical trials for drug approval and labeling decisions. Health systems and clinicians rely on the evidence from trials to determine treatment, and patients rely on it to decide which courses of care to undertake. Many of these stakeholders presume that the careful review of individual studies is enough to address the ethical and scientific questions that arise in clinical trials. In what follows, however, we demonstrate that explicit consideration of trial portfolios—series of trials that are interrelated by a common set of objectives—is crucial. the ethical acceptability and evidentiary probity of individual trials can change depending on the characteristics of the portfolios in which they are embedded. Second, how trial portfolios are composed, how well they are coordinated, and how efficiently they use information determines the balance of risks and benefits they present as well as their different prospects for generating socially valuable information; these three factors also raise distinct questions of justice.

Assessing the Psychological Impact of Genetic Susceptibility Testing

First published: 03 July 2019

Abstract

The expanded use of genetic testing raises key ethical and policy questions about possible benefits and harms for those receiving disease-risk information. As predictive testing for Huntington’s was initiated in a clinical setting, survey research posing hypothetical test scenarios suggested that the vast majority of at-risk relatives wanted to know whether they carried a disease-causing mutation. However, only a small minority ultimately availed themselves of this opportunity. Many at-risk individuals concluded that a positive test result would be too psychologically overwhelming. A substantial literature suggests that individuals are often more resilient than anticipated in coping with many different health-related stresses. Much of my own work in the field has been through the Risk Evaluation & Education for Alzheimer’s Disease study (REVEAL), a series of randomized clinical trials assessing the impact of genetic susceptibility testing on asymptomatic individuals at risk for Alzheimer’s disease. Our experience in developing and implementing four successive, multisite trials provides some potentially useful lessons for the field. More people will be asking for their personal genetic information. Better understanding will help us decide when access is appropriate and how best to disclose results in a manner that supports adjustment to test findings and promotes use of genetic information to improve human health.

Beecher Reconsidered

First published: 03 July 2019

Abstract

In 1962, Harvard professor of anesthesiology Henry Beecher wrote to Senator Estes Kefauver about certain additions to the federal Food and Drug Act then being considered. According to The Antibiotic Era, the Maryland congressman Samuel Friedel had introduced language that would require informed consent in clinical research. Beecher joined a number of other distinguished medical scientists warning that such a requirement would “cripple” American medical research. A year before, Beecher had protested the U.S. Army’s inclusion of the Nuremberg Code in its contracts. Beecher’s commitment to a medical ethics of virtue rather than one of oversight suggests that he was a far more interesting person than the cardboard cutout so often vaguely referenced in bioethics as an icon of the rights of human subjects. His thinking about research ethics was rooted in his post-World War II laboratory work with LSD.

Federal Right to Try: Where Is It Going?

First published: 18 April 2019

Abstract

Policy-makers, bioethicists, and patient advocates have been engaged in a fierce battle about the merits and potential harms of a federal right-to-try law. This debate about access to investigational medical products has raised profound questions about the limits of patient autonomy, appropriate government regulation, medical paternalism, and political rhetoric. For example, do patients have a right to access investigational therapies, as the right-to-try movement asserts? What is government’s proper role in regulating and facilitating access to drugs that are still in development? In this review, we analyze the history of the right-to-try movement, review the arguments put forth by supporters and opponents of the legislation, and consider the movement’s consequences. Two possible scenarios may emerge. One is that the right-to-try pathway may fail to meaningfully increase patient access to investigational products. Alternatively, certain companies may attempt to rely on the federal right-to-try legislation to sell investigational products, taking advantage of the provision that allows for direct costs, as there is currently no clear mechanism for enforcement or monitoring of cost calculations.

The Critical Role of Medical Institutions in Expanding Access to Investigational Interventions

First published: 18 April 2019

Abstract

The U.S. federal government provides two tracks for eligible patients to obtain access outside clinical trials to investigational interventions currently under study for potential clinical benefits: the Food and Drug Administration’s expanded access pathway and the pathway created by the more recent Right to Try Act. In this issue of the Hastings Center Report, with a critical focus on patients, industry, and the research enterprise, Kelly Folkers and colleagues frame the inherent challenges that these pathways are meant to solve and have also inadvertently created. But an additional key focus is how the relevant situations should be managed at the bedside and how the system risks both inefficient and inequitable access to options at the institutional level. Although either pathway could be helpful to patients, the challenges of having the pathways coexist are greater than the sum of their parts. Individual clinicians represent the front line of the regulatory and eligibility challenges of expanded access and right to try, making clinical education a critical component of a comprehensive approach to using them well. But it is medical institutions that must take the lead on supporting access to investigational options in the most equitable and effective manner possible.

IRB Becomes E&HR

First published: 21 February 2019

Abstract

In January 2019, under the new name Ethics & Human Research, The Hastings Center relaunched its forty-year-old journal that focuses on the ethical, regulatory, and policy issues related to research with humans. Formerly called IRB: Ethics & Human Research, E&HR has the same editorial team, led by the Hastings scholar Karen Maschke, and is meant to continue the work of IRB but will also feature a greater range of scholarship on issues in science and health care that have implications for research with humans. While E&HR is formally a continuation of IRB, it feels like a new journal. It is similar in design and format to its sister journal, the Hastings Center Report, and it has a closely linked channel for publication and distribution. Like HCR, it is published through John Wiley & Sons in both paper and electronic formats. Its home on the Wiley Online Library is https://onlinelibrary.wiley.com/journal/25782363.

Pregnant Women Can Finally Expect Better

First published: 21 February 2019

Abstract

A decade of advocacy for the inclusion of pregnant women in the clinical research agenda is starting to pay off. In September, the United States Task Force on Research Specific to Pregnant Women and Lactating Women issued its advice to the secretary of Health and Human Services on addressing gaps in knowledge and research on safe and effective therapies for pregnant women and lactating women. The task force is pushing for major reforms. If its recommendations are taken up, we can anticipate a significant shift in pregnancy research in the United States. This will affect pregnant women, clinicians caring for them, researchers, and institutional review boards.

The Social Value Requirement in Research: From the Transactional to the Basic Structure Model of Stakeholder Obligations

First published: 26 December 2018

Abstract

The history of research ethics includes ethical norms that do not neatly fit into a rubric of “human subjects protections” but that are nevertheless seen as fundamental ethical dictates. Among these norms is the so-called social value requirement for clinical research. Recently, however, the ethical foundation for the social value requirement has come under criticism. I seek to clarify the terms of this foundational debate. I contend that much of this discussion—both critiques of the social value requirement as well as recent defenses—is predicated on a framework of research ethics that I refer to as the “transactional model of stakeholder obligations.” I argue that this model does not fully capture the ethical considerations that ought to inform the design and conduct of clinical research, and I introduce and defend an alternative framework that I call the “basic structure model of stakeholder obligations.” The basic structure model is grounded in a claim that clinical research plays a direct role in establishing the justice or injustice of our social organization and should therefore be governed more explicitly by justice-based considerations. As such, the model explicitly accounts for the fundamentally social nature of the research enterprise itself. In addition to defending the basic structure model, I show how it provides a more stable foundation for the social value requirement, and I consider some worries about whether the model may be too demanding in practice.

Locating the Source(s) of the Social Value Requirement(s)

First published: 26 December 2018

Abstract

In this issue of the Hastings Center Report, Danielle Wenner looks at a few prominent analyses of the social value requirement for clinical research, claiming that they are all based on what she calls a transactional model of research ethics. She argues that the transactional model fails to provide a secure foundation for the social value requirement, and then, appealing to John Rawls, she argues that a more secure foundation lies in the principles of social justice. Wenner’s attempt to locate the source of the social value requirement raises important questions regarding its scope and strength. To determine what the social value requirement requires, we need to know why it’s a requirement. Does the social value requirement apply to all trials or only to a subset? Is it a necessary condition on ethical research or an important consideration that can conflict with, and sometimes be defeated by, other considerations? Wenner’s attempt to answer these questions is obscured by the fact that she mistakenly regards a minority view of research ethics as the mainstream view. Once we correct for that, her analysis of the foundation of the social value requirement provides a valuable opportunity to consider how the ethics of research as an institution might supplement or alter the ethics of individual clinical trials.

Difficulties with Applying a Strong Social Value Requirement to Clinical Research

First published: 26 December 2018

Abstract

In an insightful article published in this issue of the Hastings Center Report, Danielle Wenner criticizes what she describes as transactional approaches to the social value requirement in clinical research and defends a “basic structure approach.” Transactional approaches understand social value obligations as arising from transactions (or relationships) between research subjects, investigators, sponsors, and other parties. The basic structure approach, by contrast, understands social value obligations as stemming from the demands of Rawlsian social justice. According to Wenner, “The primary justification for the social value requirement lies not in the ethics of free and fair transactions but rather in the goals of the clinical research enterprise and the nature of its impacts on society. The requirement is justified because it ensures that biomedical progress occurs in a manner constrained by considerations of justice.” In this commentary, I will not critique the basic structure approach per se but will raise some concerns that arise when oversight committees, such as institutional reviews boards, attempt to apply it to proposed studies involving human subjects.

Real-World Evidence, Public Participation, and the FDA

First published: 24 November 2017

Abstract

For observers of pharmaceutical regulation and the Food and Drug Administration, these are uncertain times. Events in late 2016 raised concerns that the FDA’s evidentiary standards were being weakened, compromising the agency’s ability to adequately perform its regulatory and public health responsibilities. Two developments most directly contributed to these fears—the approval of eteplirsen, a treatment for Duchenne muscular dystrophy, against the recommendations of both FDA staff and an advisory committee and the December 2016 signing of the 21st Century Cures Act, which encouraged greater use by the FDA of “real-world” evidence not obtained through randomized controlled trials. The arrival of the Trump administration—with its deregulatory, industry-friendly approach—has only amplified concerns over the future of the FDA. It is too early to know whether the recent developments are truly harbingers of an FDA less likely to prevent unsafe or ineffective products from reaching the market. But elements in the two events—the role of patient narratives in deliberations regarding eteplirsen and the enthusiasm for real-world evidence in the 21st Century Cures Act—raise critical issues for the future of evidence in the FDA’s work. The rigorous, inclusive approach under way to consider issues related to real-world evidence provides a model for a similarly needed inquiry regarding public participation in FDA decision-making.

The Real-World Ethics of Adaptive-Design Clinical Trials

First published: 24 November 2017

Abstract

From the earliest application of modern randomized controlled trials in medical research, scientists and observers have deliberated the ethics of randomly allocating study participants to trial control arms. Adaptive RCT designs have been promoted as ethically advantageous over conventional RCTs because they reduce the allocation of subjects to what appear to be inferior treatments. Critical assessment of this claim is important, as adaptive designs are changing medical research, with the potential to significantly shift how clinical trials are conducted. Policy-makers are swiftly moving to encourage greater use of adaptive designs. In 2016, the newly enacted 21st Century Cures Act instructed the Food and Drug Administration to help product sponsors incorporate adaptive methods into proposed clinical trial protocols and applications for investigational drugs and also biological products. In this article, we review the ethical justifications commonly offered for adaptive designs, explore these arguments in the context of actual trials, and contend that clinical equipoise is a useful standard for adaptive-trial ethics. We distinguish between theoretical and clinical equipoise and explain why ethical arguments related to adaptive trials tend to focus on the former. Yet we contend that theoretical equipoise can be an unreliable standard for adaptive ethics. While we contend that clinical equipoise is the most critical principle for the primary ethical concerns posed by adaptive trials, we suggest ethical approaches to deal with some additional concerns unique to adaptive designs.

Are Transplant Recipients Human Subjects When Research Is Conducted on Organ Donors?

First published: 02 August 2017

Abstract

Interventional research on deceased organ donors and donor organs prior to transplant holds the promise of reducing the number of patients who die waiting for an organ by expanding the pool of transplantable organs and improving transplant outcomes. However, one of the key challenges researchers face is an assumption that someone who receives an organ that was part of an interventional research protocol is always a human subject of that same study. The consequences of this assumption include the need for oversight by an institutional review board and for research-level informed consent from transplant recipients, all within the complex practical realities of the organ donation and transplantation process in the United States. The current national focus on this issue provides an opportunity to think critically about the policy goals of the human subjects regulations and their application to the nascent field of deceased organ donor intervention research. We propose that for donor research where the transplant recipient does not fall under the definition of human subject, the clinical consent model—rather than the consent model used for human research subjects—best facilitates the policy objectives of balancing clinical innovation, transparency, and protection of patients in an ethically responsible and legally compliant manner.

First published: 24 May 2017

Abstract

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.

Space for the Prisoner’s Point of View

First published: 16 March 2017

Abstract

The lead article in this issue discusses a potentially free metaphorical space—that of decision-making—within the confines, tangible and intangible, of life in jail or prison. By interviewing prisoner-participants from six clinical studies, Paul Christopher and colleagues sought to find out how these men and women would answer open-ended questions about their decision to enroll in the research. What the interviewers heard was that none saw themselves as having been inappropriately pressured to do so. In fact, a significant percentage of the prisoners described being dissuaded from participating in the studies. The authors therefore advise that unfair exploitation poses the more relevant research risk to contemporary prisoners in the United States than does coercion, and they encourage investigations into whether prisoners are unfairly restricted or discouraged from joining clinical studies.

Although Keramet Reiter makes no reference to etymology in her commentary responding to the article, her argument suggests that the roots of “coerce”—the Latin for “shut up” or “enclose”—remain relevant. Reiter argues that, under current conditions, the people shut up in prisons in the United States cannot make an unfettered choice to join a clinical trial.

Reprioritizing Research Activity for the Post-Antibiotic Era: Ethical, Legal, and Social Considerations

First published: 16 March 2017

Abstract

Many hold that the so-called golden era of antibiotic discovery has passed, leaving only a limited clinical pipeline for new antibiotics. A logical conclusion of such arguments is that we need to reform the current system of antibiotic drug research—including clinical trials and regulatory requirements—to spur activity in discovery and development. The United States Congress in the past few years has debated a number of bills to address this crisis, including the 2012 Generating Antibiotic Incentives Now Act and the 2016 21st Century Cures Act. Experts have also sought to advance antibiotic development by encouraging greater use of trials with noninferiority hypotheses, which are thought to be easier to conduct. The goal underlying these proposals is to stave off the post-antibiotic era by expanding the pharmaceutical armamentarium as quickly as possible. But although new antibiotic agents are necessary to combat the long-term threat of drug-resistant disease, we argue that these research policies, which effectively lower the bar for antibiotic approval, are ethically problematic. Rather, given broader public health considerations related to the full lifecycle of antibiotic use—including development of resistance—we should reject an overly permissive approach to new antibiotic approval and instead set the bar for regulatory approval at a point that will naturally direct research resources toward the most transformative chemical or social interventions.

Enrolling in Clinical Research While Incarcerated: What Influences Participants’ Decisions?

First published: 16 March 2017

Abstract

As a 2006 Institute of Medicine report highlights, surprisingly little empirical attention has been paid to how prisoners arrive at decisions to participate in modern research. With our study, we aimed to fill this gap by identifying a more comprehensive range of factors as reported by prisoners themselves during semistructured interviews. Our participants described a diverse range of motives, both favoring and opposing their eventual decision to join. Many are well-recognized considerations among nonincarcerated clinical research participants, including a desire for various forms of personal benefit, altruism, and concern about study risks and inconveniences. However, a number of influences seem unique to prisoners. Participants did not report that they were not coerced into enrolling, and they have even been under pressure not to enroll. However, many sought to enroll in order to obtain access to better health care, raising a concern about whether they were unfairly exploited.

Coercion and Access to Health Care

First published: 16 March 2017

Abstract

In this issue of the Hastings Center Report, Paul Christopher and colleagues describe a study of why prisoners choose to enroll in clinical research. The article represents an important methodological and policy contribution to the literature on prisoner participation in research and medical experimentation. Given the methodological and ethical debates to which this research seeks to make an empirical contribution, the careful manner in which the study was conducted and the transparency with which the authors describe the research is especially noteworthy. In sum, I respect the research steps the authors took. However, I disagree with their conclusions about both the absence of coercion for prisoner clinical research participants and the merits of applying risk-benefit models to govern prisoner research participation.

An Argument for Fewer Clinical Trials

First published: 06 October 2016

Abstract

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 (RECs) 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.

First published: 10 March 2016

Abstract

On September 8, 2015, the Department of Health and Human Services issued a Notice of Proposed Rule Making to revise the Federal Policy for the Protection of Human Subjects, widely known as the “Common Rule.” The NPRM proposes several changes to the current system, including a dramatic shift in the approach to secondary research using biospecimens and data. Under the current rules, it is relatively easy to use biospecimens and data for secondary research. This approach systematically facilitates secondary research with biospecimens and data, maximizing the capacity for substantial public benefit. However, it has been criticized as insufficiently protective of the privacy and autonomy interests of biospecimen and data sources. Thus, the NPRM proposes a more restrictive regime, although more so for biospecimens than data. Both the status quo and the NPRM’s proposal are critically flawed.

First published: 19 February 2019

Abstract

The view that research with competent adults requires valid consent to be ethical perhaps finds its clearest expression in the Nuremberg Code, whose famous first principle asserts that “the voluntary consent of the human subject is absolutely essential.” In a similar vein, the United Nations International Covenant on Civil and Political Rights states that “no one shall be subjected without his free consent to medical or scientific experimentation.” Yet although some formulations of the consent principle allow no exceptions, others hold that informed consent is not always strictly necessary for ethical research. The U.S. federal regulations known as the “Common Rule,” which govern research with human subjects, lists several conditions for waiving consent. However, neither guidance documents on the ethics of clinical research nor the literature in bioethics contains a general justification of research without consent. The purpose of this paper is to advance a justificatory framework that will explain why research without consent is permissible in paradigmatic cases and that can be useful in analyzing cases about which there is (or is likely to be) disagreement. We argue that research without consent can be justified on two grounds: if it stands to infringe no right of the participants and obtaining consent is impracticable, or if the gravity of the rights infringement is minor and outweighed by the expected social value of the research and obtaining consent is impracticable.

Confronting Biospecimen Exceptionalism in Proposed Revisions to the Common Rule

First published: 20 January 2016

Abstract

On September 8, 2015, the Department of Health and Human Services issued a Notice of Proposed Rule Making to revise the Federal Policy for the Protection of Human Subjects, widely known as the “Common Rule.” The NPRM proposes several changes to the current system, including a dramatic shift in the approach to secondary research using biospecimens and data. Under the current rules, it is relatively easy to use biospecimens and data for secondary research. This approach systematically facilitates secondary research with biospecimens and data, maximizing the capacity for substantial public benefit. However, it has been criticized as insufficiently protective of the privacy and autonomy interests of biospecimen and data sources. Thus, the NPRM proposes a more restrictive regime, although more so for biospecimens than data. Both the status quo and the NPRM’s proposal are critically flawed.

Whatever Happened to Human Experimentation?

First published: 14 December 2015

Abstract

Several years ago, the University of Minnesota hosted a lecture by Alan Milstein, a Philadelphia attorney specializing in clinical trial litigation. Milstein, who does not mince words, insisted on calling research studies “experiments.” “Don’t call it a study,” Milstein said. “Don’t call it a clinical trial. Call it what it is. It’s an experiment.” Milstein’s comments made me wonder: when was the last time I heard an ongoing research study described as a “human experiment”? The phrase is now almost always associated with abuses. Asking a prospective subject to sign up for a medical experiment would probably get roughly the same response as asking him or her to sign up for a police interrogation.

It wasn’t always this way. In the early days of American bioethics, scholars used the word “experimentation” in the same neutral way that they later began to use “research study” and “clinical trial.”

First published: 10 November 2015

Abstract

The Common Rule governs research on human subjects and attempts to balance respect for individual decision-making with efficiency when research risks are low. The regulations allow research to be conducted without consent if the data or biospecimens collected in a study are deidentified, and consent can be waived for identifiable data and biospecimens if the risks of the research are minimal and consent is deemed impracticable. These approaches have been widely used for research using clinical databases and residual clinical and research biospecimens, and they have proven remarkably successful over the past twenty-five years, if success is measured by a lack of adverse events. But the landscape is changing.

What Counts as Equipoise?

First published: 05 May 2015

Abstract

A commentary on “SUPPORT: Risks, Harms, and Equipoise,” by Robert M. Nelson; “The Controversy over SUPPORT Continues and the Hyperbole Increases,” by Alan R. Fleischman; and “SUPPORT and the Ethics of Study Implementation,” by John D. Lantos and Chris Feudtner, all in the January-February 2015 issue.

Muddled Measures of Risks and Misremembered Reasons

First published: 05 May 2015

Abstract

A commentary on “Were There ‘Additional Foreseeable Risks’ in the SUPPORT Study?,” by Henry J. Silverman and Didier Dreyfuss; “SUPPORT: Risks, Harms, and Equipoise,” by Robert M. Nelson; “The Controversy over SUPPORT Continues and the Hyperbole Increases,” by Alan R. Fleischman; and “SUPPORT and Comparative Effectiveness Trials: What’s at Stake?,” by Lois Shepherd, all in the January-February 2015 issue.

The Potential Harms and Benefits from Research on Medical Practices

First published: 05 May 2015

Abstract

A commentary on “SUPPORT and the Ethics of Study Implementation: Lessons for Comparative Effectiveness Research from the Trial of Oxygen Therapy for Premature Babies,” by John D. Lantos and Chris Feudtner, in the January-February 2015 issue.

Ongoing Controversy over SUPPORT

First published: 19 January 2015

Abstract

It has been a couple of years now since debate erupted over the study known as the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, which sought to gauge the risks and benefits of different blood oxygen levels currently targeted in the care of premature infants. Both articles in this issue of the Hastings Center Report try to take the debate to a new level, but as expressed in the title of one of three commentaries on the articles, the controversy shows no signs of abating.

Should All Research Subjects Be Treated the Same?

First published: 19 January 2015

Abstract

One of the founding principles of research ethics is that subjects should be treated equally. In the words of the Belmont Report, “equals ought to be treated equally.” This principle does not imply that all subjects should be treated exactly the same. Rather, subjects who are similar in relevant respects should receive similar treatment. Clinical status is clearly relevant to determining how subjects should be treated. Greater resources should be devoted to subjects who have worse diseases. In contrast, fame is irrelevant. Subjects should not receive greater resources simply because they are famous. A more challenging question, one that pervades clinical research yet has received almost no attention in the literature, is whether subjects’ level of scientific importance is relevant to determining how much support they should receive.

SUPPORT: Risks, Harms, and Equipoise

First published: 19 January 2015

Abstract

The debate about the ethics of the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) often focuses on the assumptions made by the different parties involved, failing to note the lack of a necessary connection between those assumptions and the main criticism of the study—that the parents appear to have been poorly informed. The fact that the target ranges of oxygen saturation (SpO2) used in SUPPORT were within the range recommended as an appropriate “standard of care” does not mean that the infants randomized to one of two restricted SpO2 ranges received the same treatment they would have received outside of the trial. The corresponding observation that randomization altered the potential harms to which an individual infant was exposed does not mean that the risks of being in SUPPORT were greater than or in addition to the risks associated with usual care. The argument that parents should have been better informed about these potential harms does not entail the (incorrect) assumption that neonatal clinicians make individualized treatment decisions rather than follow a standardized protocol when adjusting the level of oxygen a preterm infant receives. The fact that parents are unaware of the trade-off clinicians make between these potential harms when establishing such a protocol does not justify the failure to adequately inform parents about the purpose of SUPPORT and the risks and harms that were involved.

The Controversy over SUPPORT Continues and the Hyperbole Increases

First published: 19 January 2015

Abstract

Two articles in this issue of the Hastings Center Report address the continuing controversy over the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT). This controversy is part of a larger discussion about the appropriate regulatory framework for protecting human research participants in comparative effectiveness research (CER), a group of studies that aims to compare two “usual” or “standard” treatments in order to provide evidence of which treatment is most effective.

Were There “Additional Foreseeable Risks” in the SUPPORT Study? Lessons Not Learned from the ARDSnet Clinical Trials

First published: 19 December 2014

Abstract

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.

SUPPORT and the Ethics of Study Implementation: Lessons for Comparative Effectiveness Research from the Trial of Oxygen Therapy for Premature Babies

First published: 19 December 2014

Abstract

The Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) has been the focal point of many different criticisms regarding the ethics of the study ever since publication of the trial’s findings in 2010 and 2012. In this article, we focus on a concern that the technical design and implementation details of the study were ethically flawed. While the federal Office Human Research Protections focused on the consent form, rather than on the study design and implementation, OHRP’s critiques of the consent form reveal views about the study design and implementation that we believe are fundamentally flawed. These criticisms about the design and implementation of SUPPORT, if generalized, become relevant concerns about these aspects of many comparative effectiveness research studies.

Our analytical approach will be to use SUPPORT as a prime example of comparative effectiveness research and show why it challenges some prevailing assumptions about the riskiness of research. We will address five aspects of the study design and implementation: 1) randomization, 2) treatment by protocol, 3) choice of endpoints, 4) lack of a “standard care” control group, and 5) the use of altered oximeters. Examining these aspects will allow us to answer two specific central questions. The first is a methodological question with ethical implications: was the study designed in such a way as to answer the primary study question? The second question is whether the study design added or decreased risk to the babies enrolled in the study compared to babies who were not in the study.

Reducing Health Disparities and Enhancing the Responsible Conduct of Research Involving LGBT Youth

First published: 17 September 2014

Abstract

Although there is clearly a need for evidenced-based behavioral or biomedical prevention or treatment programs for suicide, substance abuse, and sexual health targeted to members of the LGBT population under the age of eighteen, few such programs exist, due in substantial part to limited research knowledge. Ambiguities in regulations that govern human subjects protections and the related inconsistencies in institutional review board (IRB) interpretations of regulatory language are the key reason for the lack of rigorous clinical trial evidence to support treatment choices and prevention approaches to reducing health disparities for this population. Given the socially sensitive nature of suicide, substance abuse, and HIV and STI research in general and LGBT research specifically, in the absence of empirical data to guide their decisions, IRBs must often rely on subjective judgments of minimal risk, which can lead to overestimation of the magnitude and probability of psychological, social, and informational harms that might arise from LGBT youth participation in clinical trials. In addition, more than other youth, LGBT adolescents whose families are unaware of their sexual orientation or gender identity or whose families have victimized them on account of it may be reluctant to participate in studies that require guardian permission. This, in turn, intensifies problems of recruitment and unbiased sampling. However, many IRBs are reluctant to apply federal regulations permitting waiver of guardian permission under conditions in which such permission is clearly not “feasible” or “reasonable” to require. Consequently, many investigators have excluded LGBT individuals under eighteen years of age in health intervention research proposals because of anticipated or actual difficulties obtaining IRB approval. This situation is in conflict with current ethical discourse focusing on the right of youths to participate in trials that will protect them from receiving developmentally untested, inappropriate, and unsafe treatments. In this article, we describe these barriers and recommendations for providing LGBT youth safe and fair access to health research.

First published: 09 January 2014

Abstract

Issues associated with consent to clinical trials have attracted considerable attention recently, spurred in part by controversies over alleged inadequacies in the consent process. Professor Jansen’s interesting essay is unusual in two ways. First, it raises issues about the conceptualization of one set of problems in informed consent (which Jansen subsumes under the term “therapeutic error”) and, more critically, about the methods and the data used to assess them. Second, she is unique in using the findings of academic experimental psychology to critique the empirical findings. This produces a thoughtful and original critique of the process of informed consent to research that, nonetheless, we believe, yields a model that does not reflect the reality of clinical research.

First published: 20 December 2013

Abstract

When patients enrolled in early-phase cancer treatment trials are asked later to explain their decision to participate, they often reveal unrealistically high expectations for therapeutic benefit from participation. This phenomenon has given rise to a complex and ongoing debate over the quality and validity of informed consent to these trials. Bioethicists and researchers must better understand these expectations and why research participants so often have them. This article presents a new explanation for this phenomenon by drawing on social psychology research on mindsets and, in particular, on a distinction between deliberative and implementation mindsets.

Cluster Randomized Trials: Another Look

First published: 20 December 2013

Abstract

The type of research known as cluster randomized trials raises ethical questions not readily answered within the standard understanding of research ethics. What distinguishes a CRT is that it randomizes at the level of social groups rather than at the level of individual research participants: in a CRT, the regimen under study might be assigned to a village, hospital, or school. The organizational schemes of CRTs raise an assortment of fundamental ethical problems. In certain CRTs, the question of whether it is possible to obtain individual informed consent is central. Also, if the intervention is offered at the level of a sizable social group, there is usually no realistic possibility for individuals to opt out of the trial. Other ethical questions raised by CRTs have to do with identifying the subjects of research, and indeed with whether “research” is occurring at all.

How a Clinical Trial Registry Became a Symbol of Misinformation

First published: 18 November 2013

Abstract

In 1971, President Richard Nixon declared a “war against cancer,” stating that “the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease.” Nixon signed the National Cancer Act, and shortly thereafter the first national registry listing all ongoing clinical trials for cancer therapies was published by the National Cancer Institute. The registry was proposed by Mary Lasker (“a patroness and advocate of clinical research”) to help doctors find open trials in which to enroll their patients and to help researchers maintain a steady supply of research participants. The registry appeared to be a win for doctors, patients, researchers, and pharmaceutical companies alike. However, it ended up exposing corrupt practices and tensions between ethics, the corporate need for profits, and public health goals. How did this happen?

The Research-Treatment Distinction: A Problematic Approach for Determining Which Activities Should Have Ethical Oversight

First published: 11 January 2013

Abstract

The rise of quality improvement research and comparative effectiveness research in health care settings constitutes progress toward the goal of what the Institute of Medicine has called a “learning healthcare system,” in which we are “drawing research closer to clinical practice by building knowledge development and application into each stage of the healthcare delivery process.” As clinical research and clinical practice move closer to a deliberately integrated system, the distinction between the two is increasingly blurred, although the sharp distinction in U.S. regulations and research ethics literature remains in place. In the 1970s and for two decades thereafter, this distinction was helpful: for some forms of research, it sheds light on which activities require ethical oversight. Research that is closely integrated with health care—notably, health delivery research—was then uncommon, however. That is no longer the case, and regulations and research ethics need to change to accommodate the new landscape.

In this paper, we argue that conceptual, moral, and empirical problems surround the received view that we can and should draw sharp distinctions between clinical research and clinical practice. We start with the history of the research-practice distinction in the reports of a U.S. national commission and in U.S. federal regulations, and then offer a critical assessment of five characterizations of research that have been used in policy documents and the scholarly literature to try to make a sharp distinction between research and practice. We challenge the clarity and the tenability of these characterizations as a way of distinguishing research from practice. We argue that the received view of the research-practice distinction leads to overprotection of the rights and interests of patients in some cases and to underprotection in others. We contend that a new ethical foundation needs to be developed that facilitates both care and research likely to benefit patients, and that provides oversight that, rather than being based on a distinction between research and practice, is commensurate with risk and burden in both realms.

The Unbelievable Rightness of Being in Clinical Trials

First published: 11 January 2013

Abstract

Much of what Ruth Faden and colleagues say squarely meshes with the ideas of the U.S. Department of Health and Human Services about reforming the system for protecting research subjects. Having said that, I want to turn to a very different part of the research universe, the elephant in the room, as it were: the world of interventional randomized clinical trials. Under the current regulatory system, these research subjects receive substantial protections. Most importantly, they are generally enrolled only after they give their informed consent. The rationale for this approach is that research subjects are denied the core ethical protection provided to patients: there is no requirement that everything done to them be in their best interests. Faden and colleagues appear to be proposing to eliminate this informed consent requirement for a significant range of such trials.

A Closer Look at the Bad Deal Trial: Beyond Clinical Equipoise

First published: 27 March 2012

Abstract

Some commentators have recently proposed that “clinical equipoise,” although widely accepted, is not necessary for morally acceptable research on human subjects. If this concept is rejected, however, we may find that trials not in the best medical interests of their subjects—”bad deal trials”—could be justified. To avoid exploiting participants, we must find a way to distribute the risks fairly, even if it means embracing radical changes in the way clinical research is conducted.

Goodbye to All That: The End of Moderate Protectionism in Human Subjects Research

First published: 06 March 2012

Abstract

Federal policies on human subjects research have performed a near-about face. In the 1970s, policies were motivated chiefly by a belief that subjects needed protection from the harms and risks of research. Now the driving concern is that patients, and the populations they represent, need access to the benefits of research.

Can Research and Care Be Ethically Integrated?

First published: July 2011

Abstract

Medical ethics assumes a clear boundary between clinical research and clinical medicine: one produces knowledge for the benefit of future patients, while the other provides optimal care to individuals right now. It also assumes that the two cannot be integrated without sacrificing the needs of the current patient to those of future patients. But integration could allow us to provide better care to everyone, now and in the future.

Comparing Drug Effectiveness at Health Plans: The Ethics of Cluster Randomized Trials

First published: September 2008

Abstract

“Cluster randomized trials,” in which groups of patients are randomly assigned to different therapeutic interventions, provide a powerful way of evaluating drugs. CRTs have not been widely used, in good part because of concerns about whether patients must give informed consent to participate in them. A better understanding of how CRTs fit into clinical practice resolves the concerns.

Research in the Physician’s Office: Navigating the Ethical Minefield

First published: March 2008

Abstract

Dr. Smith is an internist in private practice who works at an inner-city clinic affiliated with a university hospital. He is also a member of the university faculty. Many of Dr. Smith’s patients have type 2 diabetes mellitus and struggle with health care and other costs. Thinking about opportunities to better serve his patients and advance his career, Dr. Smith considers conducting clinical research in his office.

ACME is a respected pharmaceutical company that for decades has engaged in research, development, and production of widely used drugs. Several of ACME’s oral agents for type 2 diabetes will soon go off patent. In an effort to retain its market share in this class of drugs, ACME wants to complete clinical trials expeditiously and obtain approval for its new oral hypoglycemic medicine. The company approaches Dr. Smith to be a coinvestigator in its multicenter clinical trial.

Moral Standards for Research in Developing Countries From “Reasonable Availability” to “Fair Benefits”

First published: May 2004

Abstract

Commentators have argued that when research conducted in a developing country shows an intervention to be effective, the intervention must be made “reasonably available” to the host population after the trial. But this standard is sometimes too stringent, and sometimes too lenient. It offers a benefit, but not necessarily a fair benefit.

A Critique of Clinical Equipoise: Therapeutic Misconception in the Ethics of Clinical Trials

First published: May 2003

Abstract

A predominant ethical view holds that physician-investigators should conduct their research with therapeutic intent. And since a physician offering a therapy wouldn’t prescribe second-rate treatments, the experimental intervention and the best proven therapy should appear equally effective. “Clinical equipoise” is necessary. But this perspective is flawed. The ethics of research and of therapy are fundamentally different, and clinical equipoise should be abandoned.

PHASE I CANCER TRIALS: A Collusion of Misunderstanding

First published: July 2000

Abstract

Physician-investigators face the daunting task of enrolling desperate patients into Phase I cancer trials that are not meant to be therapeutic. Patients doggedly regard the trials as therapeutic, and researchers tend to collaborate in their confusion by glossing the trials’ true purposes and noting the occasional benefit that subjects accidentally receive. The disparity between hope and fact must be redressed by degrees, from many angles at once.

Special Issues

Special Issue: The Intersection of Research Fraud and Human Subjects Research: A Regulatory Review, edited by Barbara E. Bierer and Mark Barnes

Volume 44, Issue s3

First published: July 2014

Abstract

Over the past three decades, two separate federal regulatory structures have emerged, each seeking to assure separate aspects of the integrity and ethics of research conducted using federal funding. One set of regulations is described in the Public Health Service Policies on Research Misconduct and relates to research misconduct, defined as consisting of fabrication of data or results, falsification of data and results, or plagiarism, in accordance with the federal-wide definition adopted by the Office of Science and Technology Policy. The second set of regulations, set forth in the Department of Health and Human Services regulations on the protection of human subjects (known as the “Common Rule”), prescribes a set of ethical and procedural protections for research involving human subjects.

These two sets of research regulations are distinguished from each other by having different foci of enforcement, priorities of protection, oversight officials, oversight procedures, seizure of evidence, standards of proof, expectations of privacy, and appeal procedures for researchers who are subject to adverse findings and penalties. These differences are significant and fundamental. They complicate the process of compliance for institutions and researchers, who are expected to adhere to both sets of standards for the same federally funded research activities in research with human subjects. Compliance is especially complicated when suspected violations of both sets of standards must be investigated and resolved concurrently. This document represents an effort to provide institutions and individuals with practical suggestions as they try to comply with both sets of regulations.

Ethics & Human Research:

Read here.

Ethics & Human Research (formerly IRB: Ethics & Human Research) aims to foster critical analysis of issues in science and health care that have implications for human biomedical and behavioral research, including developments that bring new challenges to existing ethical, regulatory, and policy frameworks governing research with humans in the United States and elsewhere. Six issues of the research ethics journal are published each year, containing an assortment of commentaries, case studies, peer-reviewed scholarly articles, and book reviews.

From Hastings Center Bioethics Timeline:

1946: Guatemala Syphilis Studies 

The Syphilis Study Section of the National Institutes of Health-approved grants for Public Health Service researchers to study intentional infection with syphilis, gonorrhea, and chancroid, followed by treatment with newly available penicillin. The studies, involving more than 1,300 Guatemalan soldiers, prisoners, and mental patients, began in 1946 and ended in 1948. The studies remained buried in the archives until 2010. See timeline 2011.

1946: AMA Adopts Principles for Permissible Human Experimentation

The Judicial Council of the American Medical Association (AMA), at the behest of researcher Andrew C. Ivy, approved three requirements for human subjects research: voluntary consent of the subject, prior animal experimentation to determine risk, and proper medical management of the experiment. These requirements were intended to buttress claims about conventions of experiments involving humans in light of the Nuremberg Doctors’ Trial

1946: United States v. Karl Brandt et al. 

An American military tribunal presides at the trial of 23 high ranking Nazi doctors and administrators. These individuals were charged with war crimes, crimes against humanity, and medical experiments, without consent, on prisoners of war, civilians of occupied countries, and others, which included murder, brutality, torture, atrocities, and other inhuman acts.  

1947: Nuremberg Code

The judges in the Nuremberg Doctors Trial issue requirements for “Permissible Medical Experiments” with which to judge the Nazi doctors. The document outlines ten principles. The first and most widely cited principle states that “the voluntary consent of the human subject is absolutely essential.” The document, which has come to be called the Nuremberg Code, has been hailed as the most important document in the history of the ethics of medical research.

1955: Jonas Salk and the Polio Vaccine 

In 1954, Jonas Salk (1914-1995), with funding from the National Foundation for Infantile Paralysis, launched a massive clinical trial of his new vaccine against polio. Before this trial in which more than 1.8 million American children between the ages of six and nine participated, Salk tested the vaccine on institutionalized, mentally incapacitated children. Parents of the “Polio Pioneers” signed a form “requesting that their child participate” in the trial. On April 12, 1955, Thomas Francis, Salk’s mentor and the director of the trial, reported that the vaccine was safe and 90% effective in protecting against paralytic poliomyelitis. The success of the vaccine prompted extraordinary support for medical science and vaccination among the American public.

D. Oshinsky, Polio: An American Story (Oxford University Press, 2005).

1956: Hepatitis Experiments at Willowbrook

Dr. Saul Krugman begins experiments at Staten Island’s Willowbrook State School in which developmentally disabled children are given active hepatitis virus in order to study the disease. It lasts until 1970 and becomes one of the most infamous research scandals of the era.

1961: Social Responsibility in Pediatric Research

Conference on “Social Responsibility in Pediatric Research” held by the Law-Medicine Research Institute at Boston University. This meeting was one of several meetings, organized by the LMRI and funded by the National Institutes of Health, to investigate clinical research practices.

1961: Thalidomide

Francis Kathleen Oldham Kelsey, a reviewer for the U.S. Food and Drug Administration refuses to approve an application filed in 1960 by William S. Merrill Company to market a German drug, thalidomide, in the United States citing a letter in the British Medical Journal reporting cases of peripheral neuritis—nerve damage in the hands and feet—among patients treated with thalidomide. “The burden of proof that the drug is safe . . . lies with the applicant,” Kelsey wrote to the company on May 5, 1961.

1962: Publication of Maurice Pappworth’s Human Guinea Pigs: A Warning

British physician Maurice Pappworth publishes an article in the literary magazine Twentieth Centuryon human experimentation. He raised similar issues about lack of informed consent that would later be raised by Henry Beecher in the United States. The two “whistleblowers” corresponded with and supported each other’s efforts; both referenced violations of the informed voluntary consent requirement of the Nuremberg Code in their critiques of current research ethics violations.

The Jewish Chronic Disease Hospital is accused in Brooklyn Supreme Court of injecting cancer cellsinto noncancer patients without their consent. This experiment, run by Memorial-Sloan Kettering oncologist Chester Southam, is one of those cited in Henry Beecher’s 1966 exposé of ethically questionable research.

1964: The Declaration of Helsinki

The World Medical Association issues the Declaration of Helsinki, its recommendations guiding doctors performing clinical research. The Declaration supplemented the Nuremberg Code’s landmark defense of research subjects’ rights, which, by mandating the informed voluntary consent of research subjects, inadvertently precluded research on children and others incapable of consenting. The Declaration clarified these issues for researchers permitting surrogate consent and similar accommodations to the realities of clinical research.

1965: Letter Questioning Tuskegee Study

Detroit physician Irwin Schatz writes to the U.S. Public Health Service questioning the morals of the Tuskegee Study of Untreated Syphilis in the Negro Male, but his letter is ignored. Seven years later, there would be widespread outrage when details of the study went public.

1966: Publication of Henry Beecher’s Ethics and Clinical Research

Henry K. Beecher, a Harvard anesthesiologist, publishes a seminal article on research involving human subjects in the New England Journal of Medicine. This article describes 22 “unethical or questionably ethical studies” conducted by American and European researchers. These included, for example, a clinical experiment in the 1960s at the Willowbrook State School in which healthy mentally retarded children were infected with hepatitis, and the injection of cancer cells into patients at the Jewish Chronic Disease Hospital.

H. K. Beecher, “Ethics and Clinical Research,” New England Journal of Medicine 274, no. 24 (1966): 1354-60.

1966: Judicial Council of the American Medical Association Issues “Ethical Guidelines for Clinical Investigation”

At the 1966 Annual Convention of its House of Delegates, the American Medical Association endorsed the ethical principles set forth in the 1964 Declaration of Helsinki of the World Medical Association concerning human experimentation. These principles are consistent with those already included in the Principles of Medical Ethics of the AMA.

1966: Animal Welfare Act

The Animal Welfare Act is signed into law. It is the only Federal law in the United States that regulates the treatment of animals in research, exhibition, transport, and by dealers. Other laws, policies, and guidelines may include additional species coverage or specifications for animal care and use, but all refer to the Animal Welfare Act as the minimum acceptable standard. The Act is enforced by the USDA, APHIS, and Animal Care.

1972: Tuskegee Syphilis Study Revealed

The study of “Untreated Syphilis in the Negro Male” was begun by the U.S. Public Health Service in 1932. In the mid-1960s, Peter Buxton, a PHS venereal disease investigator in San Francisco, found out about the Tuskegee study and expressed concerns to his superiors that it was unethical. The PHS formed a review committee but ultimately opted to continue the study with the goal of tracking participants until all had died so that autopsies could be performed and project data could be analyzed. Buxton then leaked the story to a reporter friend who passed it on to a fellow reporter. Jean Heller of the Associated Press broke the story in July 1972, prompting public outrage and forcing the study to shut down.

J. Heller, “Syphilis Victims in U.S. Study Went Untreated for 40 Years,” New York Times, July 26, 1972.

1972: Publication of Jay Katz, Alexander Capron, and Eleanor Glass’s Experimentation with Human Beings: The Authority of the Investigator, Subject, Professions, and State in the Human Experimentation Process

This extraordinary compendium of information about cases of questionable research ethics offered authoritative source of information on the subject in the formative years of the field of bioethics.

J. Katz, A. Capron, and E. Glass, Experimentation with Human Beings: The Authority of the Investigator, Subject, Professions, and State in the Human Experimentation Process. New York: Russell Sage Foundation, 1972. https://www.russellsage.org/publications/experimentation-human-beings

1973: Final Report of the Tuskegee Syphilis Study Ad Hoc Advisory Panel Is Submitted to the U.S. Public Health Service

The Advisory Panel described the study as ethically unjustified and recommended that a permanent national board be established with authority to regulate federally supported research involving human subjects.

https://biotech.law.lsu.edu/cphl/history/reports/tuskegee/complete%20report.pdf

1974: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, the first public national body to shape bioethics policy in the United States, was created as Title II of the National Research Act, which was signed into law by President Richard Nixon. The Commission, which was formed in the aftermath of the Tuskegee Syphilis Study, was charged with identifying ethical principles to be followed when conducting biomedical and behavioral research on humans and with establishing guidelines for the conduct of such research.

https://bioethicsarchive.georgetown.edu/pcsbi/history.html

1979: The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research

This publication by the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research introduced three basic principles for assessing the ethics of research on human subjects: respect for persons (researchers are to respect subjects as autonomous agents and thus seek informed voluntary consent from them), beneficence (researchers’ duty to mitigate harm to research subjects and promote their welfare) and justice (researchers’ duty not to exploit vulnerable populations by choosing subjects because they are convenient or compliant). These principles transformed the concept of consent in morality and law. In precedents dating to the Duke of York’s laws of 1665, consent had served to alleviate researchers’ responsibility for inflicting injury, death, or other harms, on anyone not consenting to participate in an experiment. The Belmont Principles changed the focus from harm prevention to subjects’ rights to be respected as autonomous agents.

https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/index.html

https://bioethics.georgetown.edu/library-materials/archives/belmont-report-anniversary-and-oral-history/

1979: The Hastings Center Launches IRB: Ethics & Human Research

The first publication dedicated to discussion of human subjects research ethics. Renamed and expanded to become Ethics and Human Researchin 2019.

Ethics & Human Research

1980: Bayh-Dole Act Enacted

This act permits researchers to patent inventions developed with government funds and thereby incentivizing the growth of the biopharmaceutical industry.

https://autm.net/about-tech-transfer/advocacy/legislation/bayh-dole-act

1981: U.S. Food and Drug Administration Revises Human Subjects Regulations

The FDA revises its regulations relating to experiments involving human subjects.

https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/fda-policy-protection-human-subjects

1983: Comité National d’Ethique Commissioned

France becomes the first country in continental Europe to establish a National Consultative Ethics Committee for Life Sciences and Health. In conjunction with the new Council for International Organizations of Medical Sciences (CIOMS) guidelines, this served as a stimulus for local hospitals to establish committees to review research on human subjects. Laws regulating these committees were enacted in 1988.

https://www.ccne-ethique.fr/

1983: Proposed International Guidelines for Biomedical Research Involving Human Subjects

Issued by the Council of International Organizations of Medical Science (CIOMS) and the World Health Organization (WHO), the CIOMS guidelines modified the World Medical Association’s 1964 Declaration of Helsinki to address the outbreak of HIV/AIDs and to address the biopharmaceutical industry’s multinational field trials on human subjects, focusing on those conducted in the developing world.

http://www.frqs.gouv.qc.ca/documents/10191/186011/CIOMS+ethics+guidelines.pdf/3a3307e9-65f7-4fb1-b7d8-b69c977df155

1984: Publication of Ronald Bayer, Carole Levine, and Thomas Murray’s Guidelines for Confidentiality in Research on AIDS

In this article, published in The Hastings Center journal IRB: Ethics and Human Research, the authors recommend two dozen guidelines for institutional review boards to use when reviewing research proposals involving people with HIV/AIDS, a group vulnerable to social stigmatization and discrimination. The guidelines are “designed to provide the basis for the cooperation of the research community and the subjects of AIDS research” in order to “afford the fullest degree of protection for confidentiality compatible with sound scientific research.”

https://www.jstor.org/stable/3564421?seq=1#metadata_info_tab_contents

1987: Publication of Benjamin Freedman’s Equipoise and the Ethics of Clinical Research

Freedman first defined and elaborated the use of the term “equipoise” in research–the position of uncertainty that justifies ethically prospective clinical trials. The concept would become an essential element of research ethics.

Freedman, B., “Equipoise and the Ethics of Clinical Research,” New England Journal of Medicine317 (1987): 141-45.

https://pubmed.ncbi.nlm.nih.gov/3600702/

1989: Research Ethics Federal Regulatory Developments

The year 1989 was marked by several research ethics federal regulatory developments. U.S. public health agencies amended their definitions of misconduct and established new requirements of scientific integrity to be assured through scientific integrity review. The National Institutes of Health established requirement for responsible conduct of research education for graduate students on training grants. These newly promulgated definitions and requirements heightened the responsibilities of those researchers funded through NIH to adherence to the established research ethics regimen and placed a responsibility on research universities to educate the scientists in training similarly funded.

https://www.niehs.nih.gov/research/resources/bioethics/timeline/index.cfm

1990: First Human Gene Therapy Clinical Trial

The first gene therapy trial included two girls with adenosine deaminase (ADA) deficiency, a genetic immunological disease, and was done at the National Institutes of Health Clinical Center by W. French Anderson, MD, Kenneth Culver, MD, and Michael Blaese, MD, through the National Heart, Lung, and Blood Institute and the National Cancer Institute. Virally delivered therapy would be reexamined after the death of University of Pennsylvania research subject Jesse Gelsinger in 1999, though research in genetically altering somatic cells as a promising treatment has accelerated since the discovery of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats) and other related interventions.

https://www.genengnews.com/magazine/269/making-history-with-the-1990-gene-therapy-trial/

1991: Publication of the “Common Rule”

The Federal Policy for the Protection of Human Subjects (“Common Rule”) was published.  It was codified in regulations. The HHS regulations, 45 C.F.R., part 46, have four subparts: (A) the Federal Policy or “Common Rule,” (B) additional protections for pregnant women, (C) additional protections for prisoners, and (D) additional protections for children.

https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html

1994: Advisory Committee on Human Radiation Experiments

The Advisory Committee on Human Radiation Experiments (ACHRE) was created in 1994 by President Clinton to investigate and report on the use of federally funded research using ionizing radiation on human subjects. Ruth Faden, PhD, MPH, led the committee in its ethical review of experiments conducted in conjunction with atmospheric atomic testing, intentional releases, and other population exposures. The committee made findings about the human radiation experiments: their number and purpose, the likelihood that they produced harm, and how human radiation experimentation contributed to advances in medicine, as well as the ethics and regulations of the era, and made recommendations for actions that must be taken to ensure that the ends of national security and the advancement of medicine will “proceed only through means that safeguard the dignity, health, and safety of the individuals and groups who may be put at risk in the process.” These included changes in the current federal system for the protection of the rights and interests of human subjects through “changes in institutional review boards; in the interpretation of ethics rules and policies; in the conduct of research involving military personnel as subjects; in oversight, accountability, and sanctions for ethics violations; and in compensation for research injuries.” The report adds to the legacy of retrospective reviews of research such as the 1972 panel review of the Tuskegee research by the U.S. Assistant Secretary for Health and Scientific Affairs, among others.

Advisory Committee on Human Radiation Experiments (1994-95); report (1995)

https://bioethicsarchive.georgetown.edu/achre/

https://bioethicsarchive.georgetown.edu/achre/final/

1995: The SUPPORT Trial on End-of-Life Care & Dying Well in the Hospital: The Lessons of SUPPORT

A two-year prospective observational study (phase I) with 4301 patients followed by a two-year controlled clinical trial (phase II) with 4804 patients and their physicians randomized to the intervention group or control group in five teaching hospitals in the United States that showed substantial shortcomings in care for seriously ill hospitalized adults (phase I) and failure of intervention to improve care or patient outcomes (phase II). This was followed by a foundational document on end-of-life care practices, 12 commenters discuss the implications of the SUPPORT study.

The SUPPORT Principal Investigators. “A Controlled Trial to Improve Care for Seriously Ill Hospitalized Patients. The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT),” Journal of the American Medical Association 274, no. 20 (1995): 1591-98.

E. H. Moskowitz and J. Lindemann, “Dying Well in the Hospital: The Lessons of SUPPORT,”special report, Hastings Center Report25, no. 6 (1995): S2-S36.

https://pubmed.ncbi.nlm.nih.gov/7474243/

1997: Publication of Peter Lurie and Sidney Wolfe’s “Unethical Trials of Interventions to Reduce Neonatal Transmission of Human Immunodeficiency Virus in Developing Countries”

Peter Lurie and Sidney Wolfe report that after research demonstrates reduced HIV transmission to newborn infants, the standard of care for HIV-positive pregnant women becomes the regimen used in the AIDS Clinical Trials Group (ACTG) Study 076. However, in developing countries, the potential cost of the ACTG regimen prevents access. Follow-up research studies in developing countries often do not provide patients with antiretroviral drugs or use placebos in the control groups. The article highlights that researchers often ask the wrong question by not assessing the effectiveness of less expensive interventions, do not appreciate the ethically challenged use of placebos, and fail to appreciate the implications of using a standard of care that does not conform to the standard of care in the sponsoring country.

P. Lurie and S. Wolfe, “Unethical Trials of Interventions to Reduce Neonatal Transmission of Human Immunodeficiency Virus in Developing Countries,”New England Journal of Medicine337, no. 12 (1997): 853-56.

https://www.researchgate.net/profile/Peter_Lurie/publication/13926523_Unethical_Trials_of_Interventions_to_Reduce_Perinatal_Transmission_of_the_Human_Immunodeficiency_Virus_in_Developing_Countries/links/575339bb08ae17e65ec678be/Unethical-Trials-of-Interventions-to-Reduce-Perinatal-Transmission-of-the-Human-Immunodeficiency-Virus-in-Developing-Countries.pdf/

1999: Case of Jesse Gelsinger

Jesse Gelsinger, age 18, develops respiratory failure and dies after receiving experimental new gene therapy. In a wrongful death lawsuit against the researchers, the University of Pennsylvania and Children’s Hospital of Philadelphia, numerous problems are identified. The Gelsinger case leads to efforts to promote ethical conduct of clinical research and to better protect patient safety in trials. The case highlights the uncertainty of genotoxicity as a risk that needs to be communicated in the informed consent process and the possible introduction of bias in presenting information about a research trial when an investigator or institution has a conflict of interest.

https://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html/

https://www.nature.com/news/gene-therapy-trials-must-proceed-with-caution-1.20186/

2000: NIH and OHRP-Training in Research Ethics

The National Institutes of Health (NIH) and the Office for Human Research Protections (OHRP), situated within the U.S. Department of Health and Human Services (HHS), require all people conducting or overseeing human subjects research have some training in research ethics. OHRP provides guidance for the protection of the rights, welfare, and well-being of human subjects involved in research conducted or supported by the HHS. OHRP oversees and ensures compliance with a set of regulations for Institutional Review Boards (IRB) that cover human test subjects in research, including those pertaining to the “Common Rule” (see Publication of the Common Rule in the 1991 timeline entry). OHRP’s regulatory compliance activities include suspension of research experiments when violations are identified. Within OHRP, the Division of Education and Development (DED) provides education for IRBs, gives guidance on research ethics, and advises the HHS Secretary on issues of medical ethics. The educational section of the OHRP website supports the IRB and research communities in their efforts to protect human subjects in research. Much of DED’s educational materials are for public use and distribution.

https://www.hhs.gov/ohrp/

OHRP suspends Johns Hopkins Research license for Fed funded research

2002: Publication of: Integrity in Scientific Research: Creating an Environment That Promotes Responsible Conduct

The Committee on Assessing Integrity in Research Environments, the National Research Council, and the Institute of Medicine develop a report that stresses the important role that research institutions play in providing an integrity-rich environment. Recommendations included the following:

  • Funding agencies should establish research grant programs to identify, measure, and assess the factors that influence integrity in research.
  • Research institution should (a) develop and implement a comprehensive program designed to promote integrity in research, (b) implement effective educational programs that enhance the responsible conduct of research, (c) evaluate and enhance the integrity of their research environments using a process of continuous quality improvement including self-assessment and external peer review, and (d) include institutional self-assessment of integrity in research as part of existing accreditation processes whenever possible.
  • Office of Research Integrity (ORI) should establish and maintain a public database of institutions that are actively pursuing or employing institutional self-assessment and external peer-review of integrity in research.

https://www.nap.edu/catalog/10430/integrity-in-scientific-research-creating-an-environment-that-promotes-responsible

https://www.ncbi.nlm.nih.gov/pubmed/24967480/

2004: Publication of Ruth Macklin’s Double Standards in Medical Research in Developing Countries

Macklin provides a policy-based argument that research populations in the developing world must, whenever possible, receive treatment and benefits equal to those enjoyed by their counterparts in the developed world. The book takes ethical guidelines that inform policy to focus on the practical application for the conduct of research. 

R. Macklin, Double Standards in Medical Research in Developing Countries (New York: Cambridge University Press, 2004).

2008: Publication of Benjamin Freedman’s Equipoise and the Ethics of Clinical Research

Freedman first defined and elaborated the use of the term “equipoise” in research–the position of uncertainty that justifies ethically prospective clinical trials. The concept would become an essential element of research ethics.

Freedman, B., “Equipoise and the Ethics of Clinical Research,” New England Journal of Medicine317 (1987): 141-45. https://pubmed.ncbi.nlm.nih.gov/3600702/

2018: Revised Common Rule

Seventeen federal agencies had published final revisions to the “Common Rule” governing human subjects research in 2017, but these eventually come to be called the “2018 Common Rule Requirements,” and actual implementation is delayed until 2019. The rules specifically exempt some activities from consideration as human subjects research (e.g., public health surveillance and activities like oral histories, journalistic and biographical investigations, and historical scholarship) and streamline IRB review processes, among other changes.

https://www.hhs.gov/ohrp/regulations-and-policy/regulations/finalized-revisions-common-rule/index.html