As researchers and physicians race to investigate innovative therapeutics against the novel SARS-CoV-2 virus, unanswered questions remain regarding the ethics and design of clinical trials. Namely, what is the most ethically and scientifically rigorous approach to test unproven novel or repurposed therapeutic agents during a major public health emergency? Canonically, randomized controlled trials (RCTs) have represented the gold standard for evidence-based medicine. In this approach, the efficacy of an intervention is tested against a control intervention, generally the standard of care, with random assignment of patients to the two groups to avoid bias. While this framework, on its surface, seems most epistemically pure, it is important to recognize these trials will be taking place in the background of a catastrophic public health situation. As such, we need to balance individual and communal interests.
Many therapies, including remdesivir, chloroquine, hydroxychloroquine, azithromycin, and lopinavir-ritonavir, to name a few, have been proposed as potential therapies against COVID-19 based on in vitro and in silico models. While the conception of these drugs is based on medical theory, to create efficacious treatments, such medical theory must be married to empirical evidence, generated from observations and data. Due to their rigor, RCTs are unparalleled in combining medical and statistical theory to create progress in medicine.
By comparing groups that receive intervention to those in a control group, scientists are able to measure the effectiveness of that intervention on a pre-specified endpoint. Clinically robust endpoints for a COVID-19 trial include patient mortality and/or need for mechanical ventilation with ICU-level care. The need for a control group and randomization is imperative for minimizing bias and measuring efficacy. The randomization in these trials is ethical in those affected by COVID-19, as there is clinical equipoise between the treatments and standard of care, i.e., there is genuine uncertainty regarding the best therapy.
RCTs will be critical in finding a potential cure for COVID-19 and serve a broad communal interest. They must serve as the backbone of evidence for our treatment, as there is not yet a safe, proven treatment for COVID-19. While much promise has been touted regarding chloroquine, an anti-malarial drug, the evidence remains uncertain on its true efficacy. Examples abound of anecdotal evidence not panning out. For instance, in the 1970s, laetrile, a compound found in apricot pits, was touted for its anticancer benefits based on a case series. By 1978, more than 70,000 individuals in the U.S. were treated with it, only for a later retrospective analysis to find there was no definitive evidence of anticancer activity. With respect to COVID-19, poorly designed, and futile trials come with the opportunity cost of wasted data generation and at the expense of more credible interventions.
During the current pandemic, however, it is important to recognize that clinical trials are embedded in a complex web of social and economic factors. Not every patient will be able to enroll in a clinical trial, and for those that are enrolled, motives may not be purely altruistic, as there is past evidence to suggest participants in trials may be seeking some clinical benefit. The FDA’s recent guidelines for adaptive trials is vital in this regard. Adaptive methods vary, but the defining feature is that trial results from early participants can be used to adapt the treatment for later participants. These trials are attractive in emergency situations, as they are flexible with the main aim of minimizing harm to study participants, reducing the risks of research, and maximizing the benefits. Gilead Sciences, the company behind remdesivir, is currently using an adaptive trial design, which may produce results as soon as mid-April.
Finally, as in debates that surrounded early HIV trials, there is uncertainty regarding “compassionate” use of trial drugs and repurposed drugs that do not yet demonstrate efficacy. Agents used “compassionately” typically have evidence of safety, but there is no obligation for the data to contribute to evaluating the effectiveness of the drug. Some physicians believe that compassionate use drugs or repurposed drugs taken outside of a clinical trial interferes with research conduct and is a wasted opportunity to contribute to our collective knowledge. Such an approach discounts individual values, and the fear and anxiety that accompany a pandemic.
For instance, certain hospitals are using chloroquine and hydroxychloroquine off-label for ICU admissions of patients with COVID-19. To suggest patients and physicians should not attempt such therapies following a shared decision-making approach, is discordant with the AMA’s Principles of Medical Ethics, in which “a physician shall, while caring for a patient, regard responsibility to the patient as paramount.” The physician must assess each individual uniquely and, in certain circumstances, may deem the natural course of the SARS-CoV-2 virus is riskier than the intervention itself, especially in cases where the drugs have a long history of safety. The point is that without proven treatment options, therapeutic choices must be made on the basis of the patient-physician relationship until RCTs provide evidence one way or the other.
During the Ebola virus disease outbreak, the WHO issued guidelines for Monitored Emergency Use of Unregistered Interventions (MEURI), for diseases in which: 1) no proven effective treatments exist; 2) it is not possible to initiate clinical studies immediately; 3) there is informed consent; 4) and there is a positive risk-benefit analysis. This may be an effective framework to use in creating systematic documentation of clinical outcomes for the many drugs that may be repurposed in combating COVID-19. This method should not be used to circumvent clinical trials, but rather as another source to provide scientific information given the extreme circumstances.
The adaptive clinical trials being carried out will provide the best evidence for efficacious medications and appropriately balance communal with individual interests. Those in life-threatening situations that do not have access to a clinical trial may benefit from repurposed therapeutics, but should follow the WHO guidelines laid out for MEURI, given there is an adequate supply of those therapeutics. Such an approach navigates the tension between both individual and communal interests as well as the epistemic and ethical obligations of clinical trials.
John Paul Mikhaiel is a medical student.
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