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Is the COVID-19 Crisis a Reason to Delay Other Research? A Study of Beneficence

posted: June 22, 2020

Written by Dr. Michael Koren, MD, CPI, FAPCR

Due to the COVID-19 pandemic, many, but not all, of the tens of thousands of clinical trials conducted worldwide have been paused at the request of sponsors or governments. As a result, enrollment and patient visits have stopped due to the perception that these activities do not constitute essential services. As a group of “card-carrying” clinical research professionals, many members of the Academy of Clinicians in Clinical Research, including myself, have questioned the wisdom of this action. In the perspective piece that follows, I analyze the principles that clinical research professionals understand and espouse, and discuss how these principles might guide decisions about clinical trial continuity and adaptation to crisis.

Evidence-based medicine provides the intellectual and ethical underpinnings of modern health care. While this evidence comes in a variety of forms, clinical trials typically provide the most compelling data. The power of clinical trials lies in the deployment of methods and rules that limit biases and enhance our ability to uncover fundamental truths about the diagnosis and treatment of disease. No serious medical practitioner or thinker questions the role of clinical trials in improving health care outcomes.

The practice of medicine requires expert knowledge and insight that many of our patients will not easily understand. This imbalance of knowledge can lead to abuses, usually unintentionally. This knowledge imbalance applies to — perhaps particularly so — members of the clinical research enterprise who understand, through training and experience, certain esoteric aspects of the design and conduct of clinical research. To prevent this knowledge imbalance from leading to abuse, clinical research professionals embrace ethical principles. Many documents have enumerated and discussed these ethical principles, but the document most commonly cited that outlines the ethical framework for clinical research in the United States is the Belmont Report.

Belmont speaks to three ethical pillars: 1) Respect for Persons (originally described as “Autonomy”); 2) Beneficence; and 3) Distributive Justice. Each of these pillars supports equal weight and relies on the others to balance the competing priorities of conducting clinical research. For pillars 1 and 3, non-medically trained members on Institution Review Boards or governmental organizations working with physicians and other health care providers often have the qualifications and ability to analyze the standards, including the use of such tools as informed consent forms or research recruiting plans. However, the physician medical community, particularly in times of crisis, must take the lead in defining Beneficence.

What is Beneficence? Broadly speaking, Beneficence as an ethical principle follows from the ancient oath of physicians to “First Do No Harm.” Since antiquity, physicians have understood that the trust of our profession derives itself from making it clear that we will not exploit the knowledge gap between professional healers and the people desperately seeking cures and relief from affliction who do not possess the wherewithal to measure risks. In the modern context, Beneficence has evolved into a more nuanced idea. We understand that nearly all medical decisions involve analysis of the tradeoff between potential benefit and harm. Trained medical professionals execute these decisions constantly, whether it involves the necessity for a simple venipuncture or the design of a complex protocol for advanced cancer.

Clinical trials function as a core contributor to the process of continuously improving medical decision-making. They serve at the heart of deploying Beneficence. The results of clinical trials — whether positive or negative — provide an ongoing, ever-clearer North Star for clinicians, expert panels and medical policymakers. For this reason, the recent suspension of enrollment and visits for clinical trials as a non-essential or elective service during the COVID-19 crisis response struck a nerve. Important questions arose for many of us: How can clinical trials be both an essential guiding light to advance all of medicine and something considered elective during a medical crisis? Further, given our fundamental mission of weighing risks and benefits, we must also ask if interfering with non-COVID-19 medical research has done more harm than good.

When authorities halted research visits and other medical activities that they deemed “elective,” they had the best of intentions. These extreme measures may have seemed appropriate for a generational crisis, but the lessons of clinical research teach us the opposite. Depending on political views, people may react differently to President Trump’s disclosure of his use of hydroxychloroquine and the shelter-in-place lockdowns imposed by many governors as ways to mitigate the effects COVID-19. Putting politics aside, from a clinical researcher’s perspective, both actions constitute unproven, mechanistically questionable, and possibly unsafe measures. In the former case, using a drug without proven anti-viral activity and with possible adverse effects such as QT prolongation in a 73-year-old man would seem reckless. In the latter case, reducing freedom of movement and interfering with normal medical interactions could certainly contribute to upticks in cardiovascular disease (CVD), the nation’s leading killer. If lockdowns lead to poor food choices, less exercise and depression, the uptick in the rate of CVD could easily offset or exceed any COVID-19 public health benefits accruing from greater isolation based on Bayesian considerations.

We must also consider — as have Swedish health officials — that lockdowns can cause harm by preventing the development of herd immunity. Given the natural proclivity of corona viruses to mutate, a conceivable outcome of a lockdown could be to keep the public at greater risk for the effects of the most lethal strains of the virus while preventing less virulent strains from spreading and conferring immunity. We introduce this argument not to weigh in on a debate, but rather as a reminder that plausible scientific arguments exist for either benefit or harm, therefore medical scientists should not assume the direction of the outcome of an unproven intervention. We embed this idea into clinical research methodology by explicitly using two-tailed rather than one-tailed statistical testing so as to not assume the directionality of an effect as good or bad. This methodology embodies time-tested wisdom. The history of modern health research features many examples of very promising interventions, seemingly foolproof, that led to unexpected harm.

Pursuing Beneficence also manifests itself in clinical research as the idea that things proven to work should continue, even if they make comparisons of newer concepts more difficult. For this reason, we mandate the continuation of the standard of care in clinical trials. An active comparator trial of a new therapy or a placebo-controlled trial of a new drug in addition to an older, proven therapy meets ethical standards. A placebo-controlled trial that excludes a proven therapy does not.

Given our ethical imperative to preserve the standard of care, halting the process of clinical trials during the COVID-19 crisis wanders onto treacherous ethical grounds. We can assume that clinical trials, on average, improve health outcomes. We cannot say the same for the intervention to halt clinical trial visits and enrollment as a general course of action during the COVID-19 crisis. Without any evidence to support the health benefits of this draconian measure, pursuing Beneficence means favoring the maintenance those of activities.

From a practical standpoint, one can make arguments about whether a clinical trial should continue at a particular location at a particular time, and these discussions should include protocol and site-specific considerations. Fulfilling our obligation of Beneficence may indeed require tactical adjustments during a pandemic, but stopping all non-COVID-19 research worldwide goes well beyond this consideration. In most places, COVID-19 activity did not overwhelm the health care systems or require study teams to change their jobs. Further, the conduct of clinical trials usually takes place at centers with the ability to deploy appropriate hygienic and protective measures to minimize the risks of spreading infection. Consequently, infection/disease risks during general clinical research interactions should not exceed those of other deemed essential activities such as visiting the grocery store or pharmacy.

Moving forward, we hope that clinicians and policymakers understand the essential nature of clinical research in health care. As favorable trends emerge in the worldwide struggle to control COVID-19, we advocate for a quick re-opening of clinical trials in all therapeutic areas and a commitment to keep this research going unless the conduct of the research would clearly cause harm. As a clinical research community, we stand prepared to help our communities fight the scourges of COVID-19 and other afflictions by providing the evidence for evidence-based interventions.