key: cord-1039111-igxfc1mp
authors: Mozersky, Jessica; Mann, Douglas L.; DuBois, James M.
title: The National Institute of Allergy and Infectious Diseases Decision to Stop the Adaptive COVID-19 Treatment Trial (ACCT-1): On Solid Ethical and Scientific Ground
date: 2020-05-26
journal: JACC Basic Transl Sci
DOI: 10.1016/j.jacbts.2020.05.002
sha: 50a8ddb78ab8bdc5b55733b721f7e4b87581ed0e
doc_id: 1039111
cord_uid: igxfc1mp

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On April 29, the NIH disclosed the preliminary findings of the Adaptive COVID-19

Treatment Trial (ACTT-1), the first clinical trial in the United States to evaluate an experimental treatment for COVID-19 (NCT04280705). ACTT was designed as an adaptive, randomized, stated that he believed that the NIAID likely took the right steps in making its decision to give remdesivir to the placebo patients, but raised concerns about using time to improvement, not death, as the measure of success, in the first place. He stated that "I don't find this endpoint very compelling, and to me the real issue is the decision to design the trial around the endpoint of time to recovery defined in the way they defined recovery….To me, the decisions that are this weighty ought to be based on clinically important endpoints." Dr. Steven Nissen, a well-known experienced clinical trialist and cardiologist at the Cleveland Clinic, did not believe that allowing placebo patients to take remdesivir was the correct decision. He stated that "I believe it is in society's best interest to determine whether remdesivir can reduce mortality, and with the release of this information doing a placebo-controlled trial to determine if there is a mortality benefit will be very difficult." He went on to say that he viewed the NIAID's decision as "a lost opportunity" (2) .

We believe that the controversies surrounding the NIAID's decision to terminate the states when a known effective treatment exists, new treatments must be tested against it except when "it is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention" (6) . Could one really say that withholding remdesivir after it was found to shorten time to recovery -the primary trial outcome participants were told about in the consent form -would not place hospitalized COVID-19 patients at an additional risk of "serious or irreversible harm as a result of not receiving the best proven intervention?" It is also worth noting that ACCT-1 was not designed nor powered for a mortality outcome. Moreover, during a period of pandemic, it is fair to assume that most hospitalized patients want to try something that is effective rather than continuing on placebo.

Clinical research necessarily involves balancing competing priorities and values such as producing generalizable knowledge that benefits society while minimizing harms and maximizing benefits to trial participants (3) . The principles articulated in the Declaration of Helsinki describe a common approach to balancing the goals of gaining new medical knowledge and protecting patients who enroll in clinical trials: Even in ordinary times, we cannot withhold a proven intervention when doing so risks harming patients. This alone could justify stopping a trial early. During times of pandemic, the urgent need for an initial proven intervention just strengthens the case for prioritizing patients' needs over ideal scientific endpoints.

Nevertheless, broadly recognized principles of public health ethics require that we infringe as little as possible against competing values or priorities such as knowledge regarding survival in clinical trials as we pursue a goal such as providing acutely ill patients with a proven intervention (7) . That is to say, even if we prioritize the protection of study participants and society's need for an initial proven intervention, we should support efforts to determine whether remdesivir reduces mortality to whatever extent is possible after dropping placebo controls.

Conceivably this can be done with remdesivir in the context of non-randomized clinical trials that use propensity matching of treated patients and untreated case-controls. Admittedly, the results will not be as definitive as an RCT and may represent a lost opportunity; however, this may be the type of scientific compromise that is both reasonable and required in the context of the public health crisis that we are currently facing, and will likely have to face again in the future. Many aspects of evidence-based medicine are based on less than perfect evidence, and we must never forget that the participants enrolling in a clinical trial during a deadly pandemic are first and foremost patients who trust their physicians to do what is best for them. As always, we welcome your thoughts on the ACCT-1 trial, either through social media (#JACC:BTS) or by email (jaccbts@acc.org).

COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities

Inside the NIH's controversial decision to stop its big remdesivir study

What makes clinical research ethical

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

Integrating Clinical Research into Epidemic Response: The Ebola Experience

World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects

Public health ethics: mapping the terrain