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

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.

NIH Finalizes Policy on Genomic Data Sharing


The National Institutes of Health has issued a final NIH Genomic Data Sharing (GDS) policy to promote data sharing as a way to speed the translation of data into knowledge, products, and procedures that improve health while protecting the privacy of research participants. The NIH news release contains highlights of the policy.

The GDS policy is an extension of and replaces the Genome-Wide Association Studies (GWAS) data sharing policy. A key tenet of the policy is the expectation that researchers obtain the informed consent of study participants for the potential future use of their de-identified data for research and for broad sharing. NIH has similar expectations for studies that involve the use of de-identified cell lines or clinical specimens.

NIH officials finalized the GDS policy after reviewing public comments on a draft released September 2013. Starting January 25, 2015, the policy will apply to all NIH-funded, large-scale human and non-human projects that generate genomic data. This includes research conducted with the support of NIH grants and contracts and within the NIH Intramural Research Program. A report from members of the NIH Genomic Data Sharing policy team appears in the August 27, 2014, advance online issue of Nature Genetics.


PCORI Executive Director Dr. Joe Selby to Speak on Regulatory Issues Concerning Big Data


The meeting of the Secretary’s Advisory Committee for Human Research Protections (SACHRP) scheduled for July 21-22, 2014, will include a session on “Regulatory Issues Concerning Big Data.” Joe Selby, MD, MPH, executive director of the Patient-Centered Outcomes Research Institute (PCORI), will speak, along with leaders from the NIH and FDA. The session is scheduled for 1:30-3:45 pm on Monday, July 21.

SACHRP provides recommendations on human subjects protection to the Secretary of the U.S. Department of Health and Human Services and reviews activities of the Office for Human Research Protections (OHRP). Other topics to be covered during the two-day meeting include informed consent comprehension, the return of research results to human subjects, and ethical/regulatory issues in interventional social media research.

The meeting is available to the public and will be videocast live.

View the meeting agenda
View the live webcast (available July 21-22, 2014)

A link to materials from the meeting will be provided in an update to this post when available.


Collaboratory Investigators Publish Article on Ethical and Regulatory Complexities for Pragmatic Clinical Trials in JAMA


“Ethics and Regulatory Complexities for Pragmatic Clinical Trials,” a Viewpoint article by Jeremy Sugarman, MD, MPH, MA, and Robert Califf, MD, was published online in JAMA today. In the article, the authors draw on early experiences from two large networks conducting pragmatic clinical trials, the NIH Collaboratory and the National Patient-Centered Clinical Research Network (PCORnet), to describe 10 ethical and regulatory complexities facing this new field of research. Topics covered include informed consent, risk determination, the role of gatekeepers, and institutional review board review and oversight, among others, as well as the ongoing need for further discussion and research as a key part of efforts aimed at creating a learning healthcare system.

Dr. Sugarman is chair of the Regulatory/Ethics Core of the NIH Collaboratory and deputy director for medicine of the Johns Hopkins Berman Institute of Bioethics. Dr. Califf is the principal investigator of the NIH Collaboratory Coordinating Center and director of the Duke Translational Medicine Institute.


SACHRP Meeting to Discuss Research Consent Issues


The Department of Health & Human Services’ Secretary’s Advisory Committee on Human Research Protections (SACHRP) has announced that it will be holding a 2-day public meeting centering on consent issues in clinical research.

Part of the meeting will be devoted to discussion of consent issues in the context of cluster randomized trials. Unlike “typical” clinical trials that randomly assign an individual research volunteer to receive one of two treatment options, or a treatment vs. a placebo, a cluster randomized trial (or CRT) randomly assigns groups of people to an intervention. These groups can include clinics, hospitals, city blocks, or whole healthcare systems. Because CRTs randomize groups rather than individuals, obtaining consent from the people involved in such research can present a number of challenging issues.

Meeting participants will also discuss a variety of other topics related to the application of regulations governing research conduct in the current era, as well as potential changes to such regulations.

The meeting, which will include programmed presentations as well as a period for public comment, will be held in Washington, DC, on March 12-13, 2014, at the U.S. Department of Health and Human Services, 200 Independence Avenue SW., Hubert H. Humphrey Building, Room 800. A full program of the meeting’s events is available here, and additional description and context are available from the Federal Register.


Changes to Informed Consent in the Era of Learning Healthcare Systems


In 2007, a seminal report from the Institute of Medicine (IOM) threw a sharp spotlight on a series of problems facing the broader U.S. healthcare system:

Evidence on what is effective, and under what Cover page of IOM report - The Learning Healthcare Systemcircumstances, is often lacking, poorly communicated to decision makers, or inadequately applied, and despite significant expenditures on health care for Americans, these investments have not translated to better health.

—The Learning Healthcare System (IOM Workshop Summary), 2007

The IOM report called for a new approach to closing the existing gaps in patient care, one that would create a system in which patient care, quality improvement efforts, and clinical research would exist as integrated components within a virtuous cycle of feedback—the “learning healthcare system.” (The original report, plus a series of related reports [PDF], can be read for free online at the National Academies Press website.)

In the years since The Learning Healthcare System was first published, researchers, healthcare providers, health systems, and governmental and regulatory agencies have all struggled with the monumental task of building such a system. One aspect that has presented a particularly complex set of challenges centers on the issue of informed consent. The principle of informed consent—the idea that all patients have the right to make a fully informed decision, free from coercion or other undue pressure, about whether or not to participate in research—is a foundational tenet of clinical research ethics. However, some of the tools that are widely considered to be critical to the success of achieving a workable learning healthcare system, such comparative effectiveness studies and cluster-randomized trials, are difficult or even impossible to conduct under existing models of individual informed consent.

Recent efforts from the Ottawa Consensus Statement Group and a series of articles published in an issue of the Hastings Center Report have explored explored informed consent in such circumstances. These are now joined by a pair of articles published in the February 20, 2014 issue of the New England Journal of Medicine. In the first, Faden and colleagues outline a case for streamlining or even dispensing with individual informed consent in certain kinds of randomized comparative-effectiveness or quality improvement studies that present a minimal risk of harm to patients [1]. The authors also describe the larger framework that would provide transparent and accountable oversight of such studies, as well as overseeing the integration of findings from such research into the patient-care process.

The second article, by Kim and Miller, presents a different vision for informed consent,  the “Integrated Consent Model” [2]. Unlike Faden and colleagues, the authors argue for preserving the element of informed consent for all randomized pragmatic research, even in circumstances considered to pose minimal risk to patients. Kim and Miller suggest that such a model, in which the prospect of participating in research is offered as part of the general clinical discussion about treatment options and documented by the physician, will satisfy ethical imperatives for informing patients while remaining sufficiently streamlined to meet the demands of pragmatic clinical research. They also argue that an “integrated consent” approach could be accommodated under existing regulations.

Regardless of whether either or both of these perspectives can be incorporated into the emerging learning healthcare system, the larger questions surrounding informed consent are  garnering significant interest, as evidenced by the response to the Department of Health and Human Service’s 2011 call for public comment on a proposal to modify rules governing clinical research. And with the proliferation of new technologies and trial designs that use data extracted directly from patient’s electronic health records (such as the NIH Collaboratory Trials coordinated through the NIH Collaboratory) and the emergence of innovative networks devoted to pragmatic patient-centered research, the need for a solution both protects patients and enables vitally needed research will only continue to grow.

For additional perspective on the recent publications in the New England Journal of Medicine, see "Research Permissions–Angels on the Head of a Pin, or the Key Issue to Decipher?" by NIH Collaboratory PI Dr. Rob Califf.

References


1. Faden RR, Beauchamp TL, Kass NE. Informed consent, comparative effectiveness, and learning health care. N Engl J Med 2014;340:766-768. 10.1056/NEJMhle1313674.

2. Kim SYH, Miller FG. Informed consent for pragmatic trials — The integrated consent model. N Engl J Med 2014; 370:769-772. doi: 10.1056/NEJMhle1312508.