What's a Hospital to Do?Equipoise, Pandemics and Single-site Clinical Trials Todd B. Seto I learned a lot about clinical trials over the past year. Some things were unexpected, and challenged the validity and feasibility of implementing research during a pandemic. Some things were anticipated, based on long-standing differences in philosophies of care and the bureaucracy of research regulations. Some things were reaffirming, and reminded me of the importance of scientific discourse and how much I enjoy my job and working with my colleagues. I learned the most during the spring, when initial reports of potential COVID-19 therapies were largely observational and poorly designed. We tried—and failed—to join multi-center clinical trials that were forming to study new therapies. Rather than waiting, we designed and ran our own single-center randomized clinical trials, basing our protocol on recommendations from the WHO and anticipating that we could eventually contribute our data to larger collaborative efforts and meta-analyses. Our first studies were randomized controlled trials of hydroxychloroquine (NCT04345692) and tocilizumab (NCT04412772) for hospitalized patients with COVID-19 that started on March 26, 2020 and June 2, 2020 respectively. The most unexpected lesson should have been better anticipated. Equipoise does not mean the same thing to all people, particularly among [End Page 24] physicians who highly value autonomy and in the midst of the anxiety and uncertainty of a growing pandemic. For some of us, clinical equipoise—when there is professional disagreement among the community of expert practitioners as to the preferred treatment—was sufficient to justify enrolling patients into randomized clinical trials. For others, it was not. Rather, individual equipoise—when a health care provider is uncertain as to the preferred treatment—was the standard. Seemingly entrenched on the extremes of two sides, it was hard for our clinicians to find common ground. Thus, discussions on the merits of hydroxychloroquine quickly shifted to disagreement on the role of physician autonomy vis-à-vis the broader professional community, the meaning of "evidence-based," the obligations of physicians to their patients, and the ethics of randomized controlled trials during pandemics. Recognizing the importance of open discussion and transparency, we convened a COVID-19 therapeutics advisory group, with broad representation by front-line clinicians, pharmacy and research staff. Although the group was unable to reconcile the tension between clinical and individual equipoise, there was still broad support for the clinical trials as long as access to the study drugs were not restricted to study participants. Interestingly, nearly all study eligible patients were ultimately offered the opportunity to participate in our studies. The most anticipated lesson I learned was both the most frustrating and satisfying. As we started our clinical trials, it was apparent that the bureaucracy of research regulation and compliance, built over decades to minimize institutional risk and maximize human subjects protection, was poorly suited to match the rapidly evolving clinical milieu of the early pandemic. As the COVID-19 community incidence steadily increased and the hospitalization rate started to rise, we knew that waiting months for IRB approval and weeks for Medicare Coverage Analyses (MCA) and financial start-up would be too slow. Also, it was a shock when we were reminded that our institution, as the sponsor of this single-center study, had to pay for the cost of the study drugs—manageable for hydroxychloroquine but less so for tocilizumab, particularly without external funding support or the ability to bill insurance. Scientifically and fiscally responsible, it seemed as if we were being "punished" for doing the right thing—offering these medications as part of a randomized controlled trial rather than usual care. However, we were fortunate to have institutional support to pursue our studies. Our hospital IRB committee held ad hoc meetings to help expedite our study reviews; our MCAs were prioritized and completed within 48 hours; our hospital leadership agreed to internally fund all study-related costs; and it took 7 days to go from conceptualizing our hydroxychloroquine study to enrolling our first patient. It was rewarding to see our research administrative team recognize its role in our institution's response to COVID-19. On a larger scale and looking back over the past year...
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Mar 11, 2021
José Manuel Pérez De La Lastra + 3
Open Access
