Special Issue of Clinical Trials
This page provides background and links to a series of 12 articles on the ethics and regulatory challenges in pragmatic clinical trials. Each article in the special issue of Clinical Trials describes an issue in detail (e.g., privacy, informed consent) and, where possible, attempts to provide guidance for future pragmatic clinical trials. The project was supported by the NIH Collaboratory, with additional support from the Patient-Centered Outcomes Research Institute.
A special series of Grand Rounds presentations will feature topics from the special issue presented by the authors on the third Friday of each month.
On this page
- Background
- NIH Collaboratory and PCORnet Writing Project
- Clinical Trials Special Issue (with summary and link for each article)
Background
There is historical and ongoing controversy regarding the ethical conduct of research involving human subjects. Throughout the 20th century, several studies designed to gain medical knowledge were carried out at the cost of harm to marginalized or vulnerable populations [1]. Recognition of these abuses led to the articulation of ethical principles for clinical research and development of regulations to ensure the protection of human subjects. The Belmont Report outlines three fundamental ethical principles for human subjects research: respect for persons, beneficence, and justice [2]. These principles serve as the foundation for federal research regulations, which are codified as 21 CFR 50 (FDA regulations on the protection of human subjects) and 45 CFR 46 (the Common Rule). See the chapters on regulatory issues and informed consent for further background information.
Though these policies set in place important protections, they viewed clinical research as a highly controlled system somewhat separate from medical practice. This divide has resulted in a failure to provide decision-makers with high-quality evidence to make the best choices in medical practice [3-5]. As the field of clinical research has evolved to address this gap, it has become challenging to apply the current regulatory and ethical paradigms. This is evident among an increasing number of pragmatic clinical trials, which study clinically relevant alternatives (often approved or accepted treatments) in representative populations at the point of clinical care [5,6].
In contrast to traditional clinical trials that study new therapies in highly controlled settings, pragmatic clinical trials rely on streamlined processes to measure outcomes in heterogeneous populations in real-world clinical settings [6]. Some pragmatic trials use cluster randomization, in which groups (e.g., clinics, hospitals, cities) are randomized rather than individuals. Because of these differences, the application of ethical principles and regulations to pragmatic clinical trials is complex [7,8]. Questions 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. As observed in the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT), there can be risks and ethical controversy even in studies comparing standard or accepted treatment options.
There have been some attempts to respond to some of the ethical and regulatory challenges faced in the conduct of pragmatic clinical trials, and more broadly, in a healthcare system that integrates research with clinical care. For example, the Ottawa Ethics of Cluster Randomized Trials Consensus Group issued a statement with recommendations for the ethical design and conduct of cluster randomized trials [9]. Issues specific to pragmatic cluster randomized trials were discussed in a subsequent workshop convened by the NIH Health Care Systems Research Collaboratory [7]. Kass and colleagues have argued that the distinction between clinical practice and research is increasingly blurred as our healthcare system advances toward a learning healthcare system [10] and current regulations and ethical principles do not account for this changing landscape. They proposed a new ethics framework for the learning healthcare system [11,12], which has been discussed and debated [13,14].
Part of the changing research environment involves a shift toward patient-centeredness [15]. Patient-centered outcomes research engages patients throughout the research process in determining what research questions are important, providing input during study design and conduct, and planning the dissemination and implementation of results [16,17]. In keeping with patient-centered research principles, engaging patients in shaping ethical and regulatory guidelines for clinical research would promote autonomy and show respect for persons [18].
NIH Collaboratory and PCORnet Writing Project
Recognizing that there are unresolved ethical and regulatory issues critical to the conduct of pragmatic clinical trials [7,8], the NIH Health Care Systems Research Collaboratory and the National Patient-Centered Clinical Research Network (PCORnet) invited a group of stakeholders, including ethicists, clinical trialists, institutional review board professionals, and patient representatives, to address a set of 11 priority issues. The goal was to produce academic manuscripts that would thoroughly review the topics; identify best practices and provide guidance for future pragmatic clinical trials where possible; and describe issues that remain to be resolved. Work groups initiated discussions over teleconferences and then convened at 1.5-day face-to-face meetings with time for cross-group discussions; 78 attendees from 50 organizations were in attendance. The culmination of this effort is a special issue in Clinical Trials, as outlined below.
Clinical Trials Special Issue
Complete issue available online
- Exploring the ethical and regulatory issues in pragmatic clinical trials
Califf RM, Sugarman J. Clin Trials 2015;12:436-441. doi: 10.1177/1740774515598334.
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- Gatekeepers for pragmatic clinical trials
Whicher DM, Miller JE, Dunham KM, Joffe S. Clin Trials 2015;12:442-448. doi: 10.1177/1740774515597699.
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- Harmonization and streamlining of research oversight for pragmatic clinical trials
O’Rourke PP, Carrithers J, Patrick-Lake B, Rice TW, Corsmo J, Hart R, Drezner MK, Lantos JD. Clin Trials 2015;12:449-456. doi: 10.1177/1740774515597685.
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- Oversight on the borderline: quality improvement and pragmatic research
Finkelstein JA, Brickman AL, Capron A, Ford DE, Gombosev A, Greene S, Iafrate RP, Kolaczkowski L, Pallin S, Pletcher MJ, Staman KL, Vazquez MA, Sugarman J. Clin Trials 2015;12:457-466. doi: 10.1177/1740774515597682.
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- Harms, benefits, and the nature of interventions in pragmatic clinical trials
Ali J, Andrews JE Jr, Somkin CP, Rabinovich CE. Clin Trials 2015;12:467-475. doi: 10.1177/1740774515597686.
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- Ethical responsibilities toward indirect and collateral participants in pragmatic clinical trials
Smalley JB, Merritt MW, Al-Khatib SM, McCall D, Staman KL, Stepnowsky C. Clin Trials 2015;12:476-484. doi: 10.1177/1740774515597698.
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- Considerations in the evaluation and determination of minimal risk in pragmatic clinical trials
Lantos JD, Wendler D, Septimus E, Wahba S, Madigan R, Bliss G. Clin Trials 2015;12:485-493. doi: 10.1177/1740774515597687.
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- Use of altered informed consent in pragmatic clinical research
McKinney RE Jr, Beskow LM, Ford DE, Lantos JD, McCall J, Patrick-Lake B, Pletcher MJ, Rath B, Schmidt H, Weinfurt K. Clin Trials 2015;12:494-502. doi: 10.1177/1740774515597688.
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- The ethics and regulatory landscape of including vulnerable populations in pragmatic clinical trials
Welch MJ, Lally R, Miller JE, Pittman S, Brodsky L, Caplan AL, Uhlenbrauck G, Louzao DM, Fischer JH, Wilfond B. Clin Trials 2015;12:503-510. doi: 10.1177/1740774515597701.
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- The Food and Drug Administration and pragmatic clinical trials of marketed medical products
Anderson ML, Griffin J, Goldkind SF, Zeitler EP, Wing L, Al-Khatib SM, Sherman RE. Clin Trials 2015;12:511-519. doi: 10.1177/1740774515597700.
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- Privacy and confidentiality in pragmatic clinical trials
McGraw D, Greene SM, Miner CS, Staman KL, Welch MJ, Rubel A. Clin Trials 2015;12:520-529. doi: 10.1177/1740774515597677.
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- Data monitoring committees for pragmatic clinical trials
Ellenberg SS, Culbertson R, Gillen DL, Goodman S, Schrandt S, Zirkle M. Clin Trials 2015;12:530-536. doi: 10.1177/1740774515597697.
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Bibliography
1. Kahn JP, Mastroianni AC, Sugarman J. Beyond consent: seeking justice in research. New York: Oxford University Press, 1998.↑
2. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. April, 1979. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html. Accessed December 9, 2014.↑
3. Kessler R, Glasgow RE. A proposal to speed translation of healthcare research into practice: dramatic change is needed. Am J Prev Med 2011;40:637-644. PMID: 21565657. doi: 10.1016/j.amepre.2011.02.023.↑
4. Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet 2005;365:82-93. PMID: 15639683. doi: 10.1016/S0140-6736(04)17670-8.↑
5. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624-1632. PMID: 14506122. doi: 10.1001/jama.290.12.1624.↑
6. Califf RM, Sugarman J. Exploring the ethical and regulatory issues in pragmatic clinical trials. Clin Trials 2015;12:436-441. doi: 10.1177/1740774515598334.↑
7. Anderson ML, Califf RM, Sugarman J. Ethical and regulatory issues of pragmatic cluster randomized trials in contemporary health systems. Clin Trials 2015;12:276-286. PMID: 25733677. doi: 10.1177/1740774515571140.↑
8. Sugarman J, Califf RM. Ethics and regulatory complexities for pragmatic clinical trials. JAMA 2014;311:2381-2382. PMID: 24810723. doi: 10.1001/jama.2014.4164.↑
9. Weijer C, Grimshaw JM, Eccles MP, et al. The Ottawa Statement on the ethical design and conduct of cluster randomized trials. PLoS Med 2012;9:e1001346. PMID: 23185138. doi: 10.1371/journal.pmed.1001346.↑
10. Kass NE, Faden RR, Goodman SN, et al. The research-treatment distinction: a problematic approach for determining which activities should have ethical oversight. Hastings Cent Rep 2013;43:S4-S15. doi: 10.1002/hast.133.↑
11. Faden RR, Beauchamp TL, Kass NE. Informed consent, comparative effectiveness, and learning health care. N Engl J Med 2014;370:766-768. doi: 10.1056/NEJMhle1313674.↑
12. Faden RR, Kass NE, Goodman SN, et al. An ethics framework for a learning health care system: a departure from traditional research ethics and clinical ethics. Hastings Cent Rep 2013;43:S16-S27. doi: 10.1002/hast.134.↑
13. Kim SY, Miller FG. Informed consent for pragmatic trials—the integrated consent model. N Engl J Med 2014;370:769-772. PMID: 24552326. doi: 10.1056/NEJMhle1312508.↑
14. The Hastings Center. Ethical Oversight of Learning Health Care Systems. Available at: http://www.thehastingscenter.org/LearningHealthCareSystems/. Accessed August 5, 2015.↑
15. Sacristan JA. Clinical research and medical care: towards effective and complete integration. BMC Med Res Methodol 2015;15:4. PMID: 25575454. doi: 10.1186/1471-2288-15-4.↑
16. Frank L, Basch E, Selby JV, et al. The PCORI perspective on patient-centered outcomes research. JAMA 2014;312:1513-1514. PMID: 25167382. doi: 10.1001/jama.2014.11100.↑
17. Gabriel SE, Normand SL. Getting the methods right—the foundation of patient-centered outcomes research. N Engl J Med 2012;367:787-790. PMID: 22830434. doi: 10.1056/NEJMp1207437.↑
18. Lantos JD. U.S. Research Regulations: Do They Reflect the Views of the People They Claim to Protect? Ann Intern Med 2015;162:731-732. doi: 10.7326/M15-0632.↑
Originally published on September 15, 2015.
Updated October 1, 2015.
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