Research ethics

Grand Rounds June 13, 2025: Fit for Purpose: Improving the Ethical Oversight of Pragmatic Clinical Trials (Stephanie Morain, PhD, MPH; Nancy Kass, ScD; Ruth Faden, PhD, MPH)

Posted on by Sophia Ramirez

Speakers

Stephanie Morain, PhD, MPH
Associate Professor, Berman Institute of Bioethics & Department of Health Policy & Management
Johns Hopkins University

Nancy Kass, ScD
Phoebe Berman Professor of Bioethics & Public Health
Berman Institute of Bioethics & Department of Health Policy & Management
Johns Hopkins University

Ruth Faden, PhD, MPH
Philip Franklin Wagley Professor of Biomedical Ethics
Berman Institute of Bioethics & Department of Health Policy & Management
Johns Hopkins University

Keywords

Comparative Effectiveness Research; Research Ethics; Oversight; Fit for Purpose

Key Points

  • There are 2 key problems with the ethical oversight of comparative effectiveness research (CER): insufficient evidence to guide key clinical decisions and challenges with ethical oversight for trials aimed at guiding those decisions.
  • The vast majority of clinical decisions are still made in the absence of high-quality evidence. For example, fewer than 10% of current recommendations in cardiology are based on the highest quality evidence; expert opinion, on the other hand, guides over 40% of recommendations.
  • There are challenges with ethical oversight in clinical trials, particularly when comparing existing therapies in widespread clinical use. The traditional approach to research ethics holds that research is conceptually different from care, undertaken for the sake of future patients. The oversight system, established in the 1970s, ensure that the risk/benefit ratio was acceptable; that people knew they were taking part in a study, and that it is not equivalent to care; and that people can voluntarily agree (or refuse) to take part.
  • But the reality isn’t so tidy: A clinical trial really might be someone’s “best treatment option.” In the meantime, clinical care has wasted billions of dollars delivering care that was unproven, unnecessary, or in error. Ongoing learning in healthcare settings is essential but must have sound ethical oversight.
  • Clinical research is not all the same; oversight must be matched (“fit”) to the specifics of the study. Sometimes it does, e.g. for studies of experimental, pre-market products, with high uncertainty. But one-size fits-all oversight can be problematic, e.g. for CER on approved products, and excessive oversight results in a greater-than-appropriate burdens for researchers and collaborating clinicians.
  • The team at the Berman Institute proposed a new model to improve the “fit for purpose” of research ethics oversight that might be feasible within current regulatory structures. There were two key considerations: participation’s impact on welfare and on autonomy. Oversight bodies should consider how much additional risk and burden is introduced with participation and studies shouldn’t restrict a decision that would have been available and meaningful to patients.
  • To achieve “fit for purpose” oversight, observational studies will require minimal oversight due to minimal increased risk compared to usual care, and no restriction of meaningful choice. Randomized trials will require case-by-case evaluation.

Discussion Themes

The origins of informed consent have their roots in paternalism, in which a physician makes all the judgement calls on behalf of a patient. Yet researchers and clinicians must make judgement calls about which of the many decision points involved in care are worth highlighting; to run through all of them risks losing an emphasis on those that have more serious implications.

The team noted that respect for autonomy (like other ethics commitments) is not absolute. It is bounded by other morally important duties, such as promoting welfare and seeking justice. In the clinical context, it’s also bounded by tradeoffs where patients have other interests.

November 29, 2021: New Article From the NIH Collaboratory Examines Use of Incentives and Payments in Pragmatic Clinical Trials

Posted on by Damon Seils
Head shot of Dr. Andrew Garland
Dr. Andrew Garland

Members of the NIH Collaboratory’s Ethics and Regulatory Core examined the use of incentives and payments to patients included in pragmatic clinical trials. Their findings and preliminary recommendations are published in the December issue of Clinical Trials.

Incentives and payments to patients are used in both pragmatic trials and conventional explanatory trials. However, because pragmatic trials typically evaluate interventions in the context of “real-world” clinical settings, the use of incentives and payments can raise logistical, ethical, and regulatory challenges.

Dr. Andrew Garland, a postdoctoral fellow at the Johns Hopkins Berman Institute of Bioethics who works in the Ethics and Regulatory Core, and who is the lead author of the article, reviewed 9 NIH Collaboratory Trials that used incentives and other payments to patients. Garland and coauthors Dr. Kevin Weinfurt and Dr. Jeremy Sugarman used these examples to describe how the standard conceptual framework for ethical payments and incentives may not always be appropriate for pragmatic trials.

Read the full report.

This work was supported within the NIH Collaboratory by the NIH Common Fund through a cooperative agreement from the Office of Strategic Coordination within the Office of the NIH Director. This work was also supported by the NIH through the NIH HEAL Initiative.

October 28, 2019: Latest Ethics and Regulatory Updates from NIH Collaboratory Trials Available

Posted on by Gina Uhlenbrauck

Six NIH Collaboratory Trials—ACP PEACE, EMBED, GGC4H, HiLo, Nudge, and PRIM-ER—have recently transitioned from the planning to implementation phase of their embedded pragmatic clinical trial (ePCT). During the transition, study teams reviewed and updated their ethics and regulatory meeting minutes from discussions with the Ethics and Regulatory Core. The minutes describe ethics and regulatory issues the trials have encountered, along with approaches the trials are using for informed consent, HIPAA, and monitoring and oversight:

Ethics and regulatory issues can pose challenges to embedded pragmatic trials because of the unique nature of clinical research conducted in the setting of routine clinical care. The Ethics and Regulatory Core provides assistance to study teams as they navigate the ethics and regulatory landscape of ePCTs.

October 15, 2019: Postdoctoral Fellowship in the Ethics and Regulatory Aspects of Pragmatic Clinical Trials at Johns Hopkins

Posted on by Gina Uhlenbrauck

The Johns Hopkins Berman Institute of Bioethics invites applications for a Postdoctoral Fellowship in the Ethics and Regulatory Aspects of Pragmatic Clinical Trials. This position includes pursuing independent research, working alongside faculty members involved with the ethics and regulatory aspects of large-scale pragmatic clinical trials (PCTs), and participating in the Hecht-Levi Postdoctoral Fellowship in Bioethics. The postdoctoral fellow is expected to pursue one or more projects addressing the ethics and regulatory aspects of PCTs in collaboration with Berman Institute faculty members. The Fellow will actively engage with the Ethics and Regulatory Core of the NIH Health Care Systems Research Collaboratory and the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) Resource Coordinating Center.

Qualifications: Applications are welcome from candidates who will have an MD, PhD, or JD or their equivalent by the start date of the fellowship. Applicants should not have completed their terminal degree more than 3 years before the start date of the appointment. Physicians should not have completed a formal residency training program more than 3 years by the start date of the appointment.

Start date: September 1, 2020.

Terms of Appointment: The fellowship is guaranteed for 1 year with the expectation of a second year of funding, contingent on review. Applicants may not be employed by another institution and are expected to be in residence for the duration of the appointment.

How to apply: For details on how to apply see: https://bioethics.jhu.edu/education-training/fellowships/#fellowship-pragmatic. Applications must be submitted by December 16, 2019.

September 28, 2018: Assessing and Reducing Risk of Re-identification When Sharing Sensitive Research Datasets (Greg Simon, MD, MPH, Deven McGraw, JD, MPH, Khaled El Emam, PhD)

Posted on by Gina Uhlenbrauck

Speakers

Gregory Simon MD, MPH
Investigator, Kaiser Permanente Washington Health Research Institute

Deven McGraw, JD, MPH, LLM
General Counsel & Chief Regulatory Officer, Ciitizen

Khaled El Emam, PhD
Department of Pediatrics, University of Ottawa
Children’s Hospital of Eastern Ontario Research Institute

Topic

Assessing and Reducing Risk of Re-identification When Sharing Sensitive Research Datasets

Keywords

Clinical trials; Research ethics; Data security; Data sharing; Sensitive research data; De-identified data

Key Points

  • The cycle of risk de-identification involves setting a risk threshold, measuring the risk, evaluating the risk, and applying transformations to reduce the risk.
  • The Safe Harbor method of de-identification (removal of 18 categories of data) is a legal minimum standard that does not take context into account, and may not be sufficient when sharing sensitive data publicly.
  • A higher standard for de-identification is the “Expert Determination” method, whereby an expert with contextual knowledge of the broader data ecosystem can determine whether the risk is “not greater than very small.”
  • With increasing concern about the risks of sensitive data sharing, it is important to be transparent with data participants and continue to build trust for data uses.

Discussion Themes

When is a dataset safe for sharing? What is the risk of re-identification, and how can we reduce the risk? Consider who you are releasing the data to and what other kinds of data might they have access to that could potentially lead to re-identification.

For more information on the de-identification of protected health information, visit the U.S. Department of Health and Human Services’s Guidance Regarding Methods for De-identification of Protected Health Information in Accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule.

The Health Information Trust Alliance de-identification framework identifies 12 criteria for a successful de-identification program and methodology.

Tags

#pctGR, #PragmaticTrials, #HealthData, @HealthPrivacy @Collaboratory1, @PCTGrandRounds

Report from NIH Collaboratory Workshop Examines Ethical and Regulatory Challenges for Pragmatic Cluster Randomized Trials

Posted on by Gina Uhlenbrauck

A new article by researchers from the NIH Collaboratory, published online this week in the journal Clinical Trials, explores some of the challenges facing physicians, scientists, and patient groups who are working to develop innovative methods for performing clinical trials. In the article, authors Monique Anderson, MD, Robert Califf, MD, and Jeremy Sugarman, MD, MPH, MA, describe and summarize discussions from a Collaboratory workshop on ethical and regulatory issues relating to pragmatic cluster-randomized trials.

Pragmatic Cluster-Randomized Trials

Many of the clinical trials that evaluate the safety and effectiveness of new therapies do so by assigning individual volunteers to receive either an experimental treatment or a comparator, such as an existing alternative treatment, or a placebo. However, this process can be complex, expensive, and slow to yield results. Further, because these studies often take place in specialized research settings and involve patients who have been carefully screened, there are  concerns that the results gathered from such trials may not be fully applicable to “real-world” patient populations.

For these reasons, some researchers, patients, and patient advocacy groups are interested in exploring different methods for conducting clinical trials, including designs known as pragmatic cluster-randomized trials, or CRTs. In a pragmatic CRT, groups of individuals (such as a clinic, hospital, or even an entire health system) are randomly assigned to receive one of two or more interventions being compared, with a focus on answering questions about therapies in the setting of actual clinical practice—the “pragmatic” part of “pragmatic CRT.”

Pragmatic CRTs have the potential to answer important questions quickly and less expensively, especially in an era in which patient data can be accessed directly from electronic health records. Just as importantly, that knowledge can then be fed back to support a “learning healthcare system” that is constantly improving in its approach to patient care.  However, while cluster-randomized trials are not themselves new, their widespread use in patient-care settings raises a number of potential challenges.

For example: in a typical individually randomized clinical trial, patients are enrolled in a study only after first providing written informed consent. However, in a CRT, the entire hospital may be assigned to provide a given therapy. In such a situation, how should informed consent be handled? How should patients be notified that research is taking place, and that they may be part of it? Will they be able to “opt out” of the research? What will happen to the data collected during their treatment? And what do federal regulations governing clinical trials have to say about this? These are just a few of the questions raised by the use of pragmatic CRTs in patient-care settings.

The NIH Collaboratory Workshop on Pragmatic Cluster-Randomized Trials

The NIH Collaboratory Workshop of Pragmatic CRTs, held in Bethesda, Maryland in July of 2103, convened a panel of experts in clinical trials, research ethics, and regulatory issues to outline the challenges associated with conducting  pragmatic CRTs and to explore ways for better understanding and overcoming them. Over the course of the intensive 1-day workshop, conference participants identified key areas for focused attention. These included issues relating to informed consent, patient privacy, oversight of research activities, insuring the integrity of data gathered during pragmatic CRTs, and special protections for vulnerable patient populations. The article by Anderson and colleagues provides a distillation of discussions that took place at the workshop, as well as noting possible directions for further work.

In the coming months and years, the NIH Collaboratory and its partners, including the National Patient-Centered Clinical Research Network (PCORnet), plan to build on this workshop experience. Together, they hope to explore these issues in greater detail and propose practical steps for moving forward with innovative clinical research methods, while at the same time maintaining robust protections for patients’ rights and well-being.

Jonathan McCall, MS, and Karen Staman, MS, contributed to this post.

Read the full text of the article here:

Anderson ML, Califf RM, Sugarman J. Ethical and regulatory issues of pragmatic cluster randomized trials in contemporary health systems. Clin Trials 2015 [e-Pub ahead of press].
doi:10.1177/1740774515571140 
For further reading:

Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: Increasing the value of clinical research decision making in clinical and health policy. JAMA 2003;290(12):1624-32. PMID:14506122; doi:10.1001/jama.290.12.1624.

The Ottawa Hospital Research Institute Ethical Issues in Cluster Randomized Trials Wiki.

Special Report: Ethical Oversight of Learning Health Systems. Hastings Center Report 2013;43(s1):S2–S44, Si–Sii.

Sugarman J, Califf RM. Ethics and regulatory complexities for pragmatic clinical trials. JAMA 2014;311(23):2381-2. PMID: 24810723; doi: 10.1001/jama.2014.4164.