The coronavirus pandemic has created an urgent need for therapeutics. Early reports of potential efficacy of hydroxycloroquine led to swift public embrace and presidential endorsement, even as public health leaders called for restraint prior to widespread use of these medications. [1] While flickers of hope for effective treatment may lift public morale, widespread adoption of unproven therapies can have dangerous health and economic consequences. Traditional pathways for evaluating new treatments through randomized trials hinge on establishing and maintaining equipoise at a broad public health level, but also at the bedside where wrenching decisions are made in real-time. [2,3] But preserving clinical equipoise may seem contradictory to the physician’s role in times of uncertainty, a tension that becomes particularly salient as the stakes increase. We explore the tenuous nature of clinical equipoise for coronavirus treatment. We then provide specific policy recommendations that can be implemented now to help preserve equipoise and facilitate scientific advancement of safe and effective treatments while honoring physicians’ obligations to patients.

Uncontrolled adoption of approved medications for off-label indications poses a serious threat to preserving the equipoise needed for future clinical trials. Equipoise—that is, whether physicians making bedside decisions genuinely maintain uncertainty regarding whether a given option is helpful or harmful—can erode rapidly for several reasons. [3] These include biologic plausibility, financial incentives, patient demands (either informally or through coordinated advocacy), and providers’ desires to help patients in need. The art of medicine demands that physicians continuously calibrate the estimated risks and benefits of clinical interventions based on available data. Caring for individual patients in the face of uncertainty is fundamental to physician’s professional identity and ethics. When faced with a deteriorating patient, randomizing patients within clinical trials may feel like abandoning the expected role of sagely adjudication just at the time of greatest need.

The coronavirus pandemic has brought this dilemma into stark focus: When patients are critically ill, the ability to maintain equipoise fades rapidly in direct proportion to illness, so that the possibility of benefiting individual patients increasingly appears to outweigh potential harms. For high-risk cases, patients or their surrogates may decline randomization and instead receive the therapy through compassionate use, and clinicians similarly may be reluctant to rely on a coin flip rather than their own judgement. This creates circular reasoning justifying the erosion of equipoise by claims that randomized trials can’t be done, and soon enough an unproven treatment that still, scientifically, deserves equipoise can become, by community adoption, the standard of care.

The world needs swift, decisive evaluation of repurposed medications and newer agents that are not available off-label, and hundreds of trials for potential therapies for covid have already begun. But failure to maintain equipoise has grave implications for our ability to assess treatment options. First, enrollment in randomized trials may be slowed or biased, delaying completion of meaningful studies. Physicians may be more willing to randomize healthier patients, where the stakes appear lower, and since many of these patients would likely recover without intervention, the trial may appear to suggest no benefit to treatments that would have been demonstrated to be effective had they been evaluated in higher risk populations, as we have previously demonstrated in a satirical fashion through publication of the PARACHUTE Trial. [4]  We believe this “parachute phenomenon,” which hinges only on the strong belief that a treatment is beneficial and not on its true efficacy, may be playing out in real time. 

The exuberant embrace of untested treatments may lead to toxicities (including among otherwise healthy people), create scarcities for patients who may have approved indications for the same drugs, and distract public and clinical attention from the real work of developing treatment. For instance, shortly after US President Donald Trump announced his belief in the effectiveness of hydroxycholoroquine, an American man was killed and his wife made critically ill due to the consumption of chloroquine phosphate, even as patients with lupus and rheumatoid arthritis—for which hydroxychloroquine has been proven efficacious—started to describe shortages of the medication. [5] Additionally, precious time and resources may be wasted as industry starts preparing supply chains or re-configuring manufacturing to produce mass quantities of a drug that may not be effective. Lastly, cycles of hope and disappointment will lead to widespread frustration and fatigue, and erode public trust in both clinical decision-making and scientific progress.

Some advocate for a compromise that allows clinicians to use unproven treatments at their own discretion while enrolling these patients in a registry. Data on their clinical course could then be compared with contemporaneous or historic control populations. While this approach may be useful for characterising drug safety, reliance on real-world evidence in this context may not produce reliable conclusions because of the fast-changing environment in which drugs are being used off-label. While allowing physicians to prescribe medications based on their best judgment may be aligned with patients’ desires and our own professional ethics, it will not support the development of definitive effectiveness that is critically needed to combat the rapidly spreading contagion.  

The coronavirus era demands immediate design and adoption of institutional policies, shaped by clear national guidance, to preserve equipoise and allow focused randomized trials to enroll and yield data as quickly as possible. The locus of control should be institutions, rather than state or federal requirements, to allow for integration with local institutional review boards and other institutional practices dictating medication usage. A model for such policies might be the way in which many hospitals strictly limit access to certain antibiotics, requiring approval from a specialist stewardship committee prior to release from pharmacy. These approaches take both the control and burden away from bedside decision-making, as is done for other ethical quandaries such as allocation of ventilators. [6] Physicians are obligated to care for the patient in front of them, whereas by definition enrolling these patients in trials primarily helps society and may or may not turn out to have helped or harmed the patient. Only strongly enforced guidance can help resolve this tension in the service of all patients.

We also call for widespread commitment among clinicians to restrict use of purported coronavirus treatments outside of clinical trial. This must be paired with a reduction of barriers for pooling patient-level data to maximize knowledge generation and, in doing so, honour the selflessness of patients or families who agree to participate. National guidance should include best practices for innovative trial designs that will further minimize the need to randomize patients to “nothing”, including crossover trials, unbalanced randomization, or factorial designs evaluating multiple interventions such that most patients have the opportunity to be receive some experimental intervention in addition to supportive care. Federal commitments to incentivize trials of generic medications may be particularly important if existing antivirals appear promising in early studies.

In the midst of an epochal pandemic, the tireless dedication of medical professionals to their patients has never been more evident.  This selflessness demands an equally steadfast commitment to maintaining equipoise, letting our patients become participants in research and our partners in the service of scientific progress.  

Daniel B. Kramer ^1,2

Dhruv S. Kazi ^1,2

Robert W. Yeh ^1,2

On Behalf of the PARACHUTE Trial Investigators

1 Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston MA

2 Harvard Medical School, Boston MA

Competing interests: DK is supported in part by the Greenwall Faculty Scholars Program in Bioethics. DK and RY also report serving as a consultant to the Circulatory Systems Advisory Panel of the Food and Drug Administration. 

Acknowledgement: The authors thanks Bernard Lo, MD, for his review of a prior draft of this manuscript.

References:

1. Associated Press. Malaria Drugs’ Promise for Coronavirus Spurs Hope, Shortages.  New York Times, March 23, 2020. Available at: https://www.nytimes.com/aponline/2020/03/23/health/bc-us-med-virus-outbreak-malaria-drug-evidence.html?searchResultPosition=6.  Accessed March 27, 2020. 
2. Bausch DG. One Step Closer to an Ebola Virus Vaccine. N Engl J Med 2017;376(10):984-85. doi: 10.1056/NEJMe1414305 [published Online First: 2014/11/27]
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5. Haelle T.  Man Dead From Taking Chloroquine Product After Trump Touts Drug For Coronavirus.  Forbes.com, March 23, 2020. https://www.forbes.com/sites/tarahaelle/2020/03/23/man-dead-from-taking-chloroquine-after-trump-touts-drug-for-coronavirus/#682ba90b72e9.  Accessed March 27, 2020. 
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