Federal human subject protection regulations have gone a long way to protect the safety of clinical trial participants. However, research professionals say that these regulations view clinical research as a highly controlled system somewhat separate from medical practice.1 This results in medical decision-makers not having high-quality evidence to make the choices in treating patients, they say. “As the field of clinical research has evolved to address this gap, it has become challenging to apply the current regulatory and ethical paradigms.” They say this is particularly evident among an increasing number of “pragmatic” clinical trials. Pragmatic trials are designed to reflect real-world medical care by recruiting broad populations of patients, embedding the trial into the usual healthcare setting, and leveraging data from health systems to produce results that can be readily used to improve patient care, according to the Patient-Centered Outcomes Research Institute (PCORI) in Washington, DC.

Pragmatic clinical trials have their own ethical and regulatory challenges. For example, some of these trials may use cluster randomization in which groups, rather than individuals, are randomized. Questions surrounding pragmatic clinical trials include what constitutes research versus a quality improvement initiative under current regulatory guidelines; how should the criteria for determining what is minimal-risk research be appropriately applied; and when is a waiver or alteration of informed consent ethical and justified?1

The research community is making more attempts to respond to some of the challenges. The National Institutes of Health (NIH) Health Care Systems Research Collaboratory, established by the NIH’s Common Fund in 2012, has supported the design and rapid execution of pragmatic clinical trial “Demonstration Projects” that address questions of major public health importance and engage healthcare delivery systems in research partnerships. These projects help to establish best practices and provide proof of concept for innovative designs in pragmatic clinical research, the NIH Collaboratory says. Along with the pragmatic trial design in the projects, electronic health records are used as the core collection instrument, and at least two integrated health systems have to be collaborating.

From their experience working with the first range of Demonstration Projects, Jeremy Sugarman, professor of bioethics and medicine and deputy director of the Johns Hopkins Berman Institute of Bioethics, and cardiologist Robert Califf, deputy commissioner for Medical Products and Tobacco at FDA, mapped out the 10 ethical and regulatory issues for an article in the June 18, 2014, issue of the Journal of the American Medical Association.2 “[R]esearch that evaluates elements of usual medical practice may encounter ethical and regulatory challenges,” they write. “But unless significant progress is made toward efficient functional approaches to these issues, the evidence gap for clinical practice will remain.”

With support from the National Patient-Centered Clinical Research Network (PCORnet) — a coordinated, interoperable “network of networks” comprising 13 Clinical Data Research Networks (CDRNs) and 21 Patient-Powered Research Networks (PPRNs), the NIH Collaboratory also sponsored a series of articles resulting from a multidisciplinary workshop that was held. These articles were published in the October 2015 issue of Clinical Trials and addressed the ethical and regulatory challenges to pragmatic clinical trials.3 The journal articles, written by authors from the fields of clinical research and patient advocacy, as well as clinicians, bioethicists, and regulatory experts, covered the following topics:

• Exploration of the ethical and regulatory issues in pragmatic clinical trials
• Gatekeepers for pragmatic clinical trials
• Harmonization and streamlining of research oversight for pragmatic clinical trials
• Oversight on the borderline: Quality improvement and pragmatic research
• Harms, benefits, and the nature of interventions in pragmatic clinical trials
• Ethical responsibilities toward indirect and collateral participants in pragmatic clinical trials
• Considerations in the evaluation and determination of minimal risk in pragmatic clinical trials
• Use of altered informed consent in pragmatic clinical research
• The ethics and regulatory landscape of including vulnerable populations in pragmatic clinical trials
• The FDA and pragmatic clinical trials of marketed medical products
• Privacy and confidentiality in pragmatic clinical trials
• Data monitoring committees for pragmatic clinical trials

Sugarman and Califf edited the issue and wrote the overview of the articles. “We’re facing a serious gap in terms of the scientific evidence we need to better guide decisions about medical treatments,” said Califf in a statement.4 “The problem is ensuring that we can converge upon an ethical and regulatory framework that’s appropriate for the kinds of research that will be essential in the coming era of patient-centered precision medicine.”

“These articles address a number of areas that for years have been marked by uncertainty, even for experts,” Sugarman said. “What we have tried to do here is clarify some of the most pressing issues and point toward some possible solutions.”

NIH offers podcast on pragmatic clinical trials

On May 10, 2016, the NIH Collaboratory revisited the topics above in a public webcast of the workshop, Ethical and Regulatory Issues of Pragmatic Clinical Trials.5 Panelists from the Demonstration Projects spoke, along with experts in the areas of informed consent, vulnerable populations, IRBs, data monitoring committees, and privacy issues.

In opening remarks, Catherine Meyers, director of the Office of Clinical and Regulatory Affairs at NIH’s National Center for Complementary and Integrative Health, said the NIH Collaboratory has supported 10 Demonstration Projects so far, nine of which successfully launched the “full implementation stage of the pragmatic clinical trial.” Besides the Demonstration Projects, the NIH Collaboratory also supports the Coordinating Center of the NIH Collaboratory, based at the Duke Clinical Research Institute in Durham, NC. The center has a task order of three discrete areas, Meyers said. The first is to support planning and implementation of clinical trials funded in the program. The second is to provide leadership and expertise for all aspects of clinical trials, and the third is to make tools and resources available to the broader research community.4

In his remarks, Sugarman said that each of the Demonstration Projects was wrestling with a variety of regulatory and ethics issues. “We soon realized that the only way to overcome some of the barriers being faced or apparent barriers to doing the research was to conduct multi-stakeholder consultations.” These consultations included the principal investigator (PI), members of the PI’s research team, the chair or director (or both) of the relevant IRBs, representatives of the Office for Human Research Protections (OHRP), representatives of the NIH, and others who would be involved in trying to figure out the right path for the trial moving forward.  The meetings were held as the projects moved from development to implementation. “We saw a lot of changes, Sugarman said. 

The number one issue encountered with the Demonstration Projects has been that of informed consent, he said. “One of the things we heard from many of the Demonstration Projects is that traditional approaches to informed consent, that sort of very ritualistic process with long documents and waving of pens and paper that they were so accustomed to, may be inappropriate in the context of pragmatic clinical trials,” he said. The reasons related to the risk of the project, whether life would differ anyway, and if the trial integrity would be undermined in the case of a selection bias. However, the stakeholders found that there were limited data on alternative approaches. Speaking as an ethics matter, he said, were there means of getting the informed consent such as having a conversation, putting up a sign, or something in between? “We almost have no or limited experience knowing what those effects might be.” Sugarman also spoke about risk determination, nature of interventions, identifying research participants, FDA-regulated products, IRBs, research and quality improvement, vulnerable subjects, data monitoring, and privacy in relation to pragmatic clinical trials.

The all-day workshop tackled panel discussions such as options for altered consent and the importance of minimal risk determination, oversight of pragmatic clinical trials — IRBs and data and safety monitoring boards, privacy issues for pragmatic clinical trials, vulnerable populations, and expert Q&A. One attendee spoke critically of the NIH Collaboratory. “It’s clear that the Collaboratory projects have succeeded at the expense of devoting an enormous amount of time, energy, thought, and quite frankly cost in order to be able to accommodate what in many cases are very straightforward minor changes in clinical practice, the kind that any organization could make of its own accord without any kind of oversight,” the commenter said. “And to layer that kind of investment on PCORnet’s goal of doing 10 times as many studies at a tenth the cost I think will render that infeasible.”

It will mean PCORnet will have to do studies more like collaborative studies, costing millions of dollars instead of half a million dollars, he continued. “My take is this has been a brilliant exposition of how you can put enormous resources into dealing with a fundamentally inappropriate regulatory and oversight regime for standard kind of practice research.” When asked for clarification, the commenter said that the “extra overhead involved in the regulatory and ethics compliance will be a substantial disincentive to what would otherwise be a substantial number of PCORnet trials.”

Valerie Bonham, senior attorney for the Office of the General Counsel, NIH’s Public Health Division, pointed to where we are in the history of the scientific enterprise and the history of human volunteers and human engagement in human research. “As an optimist, it strikes me that there’s an opportunity to if not significantly change the regulatory structure … to really help push it along by continuing to highlight it in this context,” she said.

 “To me it brings back the fundamental question of what is the fundamental difference between research and learning, trying to learn in a clinical setting, and what sets them apart, and should they be set apart,” another commenter said. “It’s not clear to me that I’ve heard an answer to that yet throughout this day, which has been fascinating.”

“I don’t think anyone wants to make an argument that we want in any way to undermine the ethical nature of the clinical enterprise or the research enterprise by the rethinking of how we learn,” Sugarman said. “I mean, we have fundamental understandings about what it means to treat patients well and to not harm them in the process, to treat them fairly and to respect them. And how those play out in different settings differs slightly about what we call it and how new something is, and how much we know about it.

“We sometimes need data to teach us to do the right thing,” he continued. “With the same humility about not knowing whether the right answer is A or B or A, B, C, D or E for the same condition, we sometimes don’t know and will need to find ways of gathering those data. We obviously want to do it in the least burdensome way, but we never want to be saying that we don’t want to protect the rights and welfare of people and that we don’t want to treat them fairly.”

Of course there are regulatory burdens that may be associated because we only have either/or boxes right now, Sugarman said. “But it’s through learning and through experience that we can try to incrementally change that.”

References

1. Rethinking Clinical Trials. Available at: http://sites.duke.edu/rethinkingclinicaltrials/tools-for-research/ethical-and-regulatory-issues-in-pragmatic-clinical-trials/#Project. Accessed June 30, 2016.
2. Sugarman J, Califf RM. Ethics and regulatory complexities for pragmatic clinical trials. JAMA 2014;311:2381-2382.
3. Clinical Trials. October 2015 Available at http://ctj.sagepub.com/content/12/5.toc. Accessed June 30, 2016.
4. PCORnet. NIH Health Care Systems Research Collaboratory offers new perspective on clinical research. Sept. 15, 2015 Available at http://www.pcornet.org/2015/09/nih-health-care-systems-research-collaboratory-offers-new-perspectives-on-clinical-research/. Accessed June 30, 2016.
5. NIH Videocasting and Podcasting , Ethical and Regulatory Issues of Pragmatic Clinical Trials Workshop. May 10, 2016. Available at https://videocast.nih.gov/Summary.asp?File=19676&bhcp=1. Accessed June 30, 2016.

By Sue Coons, MA

This article was reprinted from Research Practitioner, Volume 17, Number 4, July-August 2016.