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Invited Commentary
Cardiology
July 23, 2021

Reconfiguring the Cardiovascular Clinical Trial Enterprise in the United States

Author Affiliations
  • 1Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Netw Open. 2021;4(7):e2118176. doi:10.1001/jamanetworkopen.2021.18176

The cardiovascular clinical trial enterprise is in disarray globally, as brought into focus most poignantly by the COVID-19 pandemic.1-3 However, the crumbling clinical trial infrastructure, leading to inefficient trial execution, has been evident in the US for a much longer time. Despite the wealth of the nation and the presence of several hubs of drug and device innovation, for a variety of complex reasons spanning legal, regulatory, and cultural domains, enrollment in randomized clinical trials (RCTs) in the US remains suboptimal. Additionally, there are high degrees of financial cost per patient enrolled. This phenomenon is harmful for many reasons. It potentially leads to a lack of generalizability of findings from international RCTs to patients in the US. Over time, it will also lead to continued outsourcing of RCTs to other regions of the world and eventual loss of US leadership in RCTs.

In this issue of JAMA Network Open, Goyal et al4 have measured the start-up time needed to reach different trial milestones across various sites in North America in 9 large cardiovascular RCTs. They analyzed RCTs spanning from 2004 to 2017 that were coordinated by Duke Clinical Research Institute and examined the use of local vs central institutional review boards (IRBs). Their primary outcome of median start-up time from the study protocol delivery to the first patient enrollment decreased from 267 to 237 days over the study period (P < .001). Although this was a statistically significant difference, in absolute terms it was a relatively modest improvement.

More notably, for the top 10% of sites with respect to median start-up time, the metrics were much better: 107 days during the early study period, improving to 104 days in the latter part of the study (P = .04). Although that change was statistically significant, the absolute difference was very small. What was of interest, though, was that these top 10% of sites had start-up times that were less than half of the other 90% of sites. The most important finding from the study—and one that is immediately actionable—is that among the 37.5% of sites using a central IRB, the median time to overall start-up was 199 days vs 287 days (P < .001).

What, then, are the implications of this insightful study? First, for sites to take approximately three-quarters of a year from the time of study protocol delivery to enrolling their first patient is not a sustainable model. No intelligent, fiscally responsible industry sponsor or not-for-profit organization would invest in such an enterprise if there were feasible alternatives available elsewhere in the world. Time for regulatory approval at the site, contract execution, and activation of the site to authorize enrollment are all variables that can impede an RCT from starting at a site. Over the course of the study, modest improvements were noted in all these categories. Solutions to address each component of the delay may to some extent vary based on the site, although, as the authors propose, broader adoption of master service agreements between trial sponsors and sites could help streamline many processes.

Second, sites that are high performing with respect to the metric of start-up time may be better sites to concentrate research efforts and funding. This, of course, is dependent on these sites also being able to enroll a large number of patients, to provide thorough follow-up, and to maintain good adherence to the study protocol. It is probably the case that all these trial measures often overlap, but this is not guaranteed.5 Further research is needed to identify sites that shine in all these metrics, to try to bring other sites up to speed using best practices learned from those top sites. In the interim, it likely does make sense to focus resources on those sites that excel now. That approach does have the potential, however, to widen rather than narrow disparities in allocation of research resources to sites serving populations who already have disadvantages, such as patients from low-income neighborhoods, racial and ethnic minorities, and rural populations.6

Third, use of central IRBs seems like a relatively easy step to take to enhance clinical trial efficiency. As the saying among trialists goes, once you have seen one local IRB, you have seen one local IRB. To a given trial protocol, there tend to be several idiosyncratic responses from individual well-intentioned IRBs, with one IRB finding a particular issue, and another finding a totally different one. Making IRB approval more uniform, conducted by experts who have the time to devote to the task, could not only improve the efficiency of RCTs but also enhance rather than compromise patient safety. Many hospitals do not truly have the resources to staff an IRB appropriately, and many large academic centers may resist the suggestion to cede authority to a central IRB.

It would have been valuable to see whether the results of the present analysis pertain to noncardiovascular RCTs, but there is no reason to think that they would not. It would have also been of interest to see whether there was a difference between US and Canadian sites, as Canada has been more successful than the US with respect to enrollment metrics in recent years.

In conclusion, the authors have reported a critically important study that comes at a most opportune time when we are reconsidering many aspects of life. We can choose to act on these results and enhance RCT efficiency everywhere.7 This work should be viewed as highly relevant to more than just trialists: inefficient RCTs hurt patients, sites, investigators, trial sponsors, and regulators. The results should sound an alarm especially in the US. We cannot continue the same path that we have been on for the past 2 decades. Further white papers and calls to action on the sorry state of RCTs in the US are unlikely to manifest a meaningful change. As a simple first step, a switch from local to central IRB use could serve as a spark to invigorate once again what had been among the best RCT machinery in the world.

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Article Information

Published: July 23, 2021. doi:10.1001/jamanetworkopen.2021.18176

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Bhatt DL. JAMA Network Open.

Corresponding Author: Deepak L. Bhatt, MD, MPH, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115 (DLBhattMD@post.Harvard.edu).

Conflict of Interest Disclosures: Dr Bhatt reported serving on the advisory board for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, and Regado Biosciences; serving on the board of directors for the Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; being a Chair of the American Heart Association Quality Oversight Committee; serving on the data monitoring committees for the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; receiving honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); serving as Deputy Editor of Clinical Cardiology, Chair of the NCDR-ACTION Registry Steering Committee, and Chair of the VA CART Research and Publications Committee; receiving research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, and 89Bio; receiving royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); serving as site co-investigator for Abbott, Biotronik, Boston Scientific, Cardiovascular Systems, Inc, St. Jude Medical (now Abbott), and Svelte; serving as a trustee for the American College of Cardiology; and conducting unfunded research with FlowCo, Merck, and Takeda.

References
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Gaba  P, Bhatt  DL.  The COVID-19 pandemic: a catalyst to improve clinical trials.   Nat Rev Cardiol. 2020;17(11):673-675. doi:10.1038/s41569-020-00439-7 PubMedGoogle ScholarCrossref
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Goyal  A, Schibler  T, Alhanti  B,  et al. Assessment of North American clinical research site performance during the start-up of large cardiovascular clinical trials. JAMA Netw Open. 2021;4(7):e2117963. doi:10.1001/jamanetworkopen.2021.17963
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Bhatt  DL, Cavender  MA.  Are all clinical trial sites created equal?   J Am Coll Cardiol. 2013;61(5):580-581. doi:10.1016/j.jacc.2012.10.024 PubMedGoogle ScholarCrossref
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Cross  SH, Mehra  MR, Bhatt  DL,  et al.  Rural-urban differences in cardiovascular mortality in the US, 1999-2017.   JAMA. 2020;323(18):1852-1854. doi:10.1001/jama.2020.2047 PubMedGoogle ScholarCrossref
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Wang  X, Bhatt  DL.  COVID-19: an unintended force for medical revolution?   J Invasive Cardiol. 2020;32(4):E81-E82.PubMedGoogle Scholar
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