All clinical trials raise certain ethical issues. “But trials conducted during epidemics are especially difficult, both ethically and practically,” says Charles Weijer, MD, PhD, professor of philosophy and medicine at Western University in London, Ontario, Canada.

Dozens of potential treatments for COVID-19 are under investigation: existing antiretrovirals, anti-malaria drugs, monoclonal antibodies, and Chinese traditional medicines among them. Additionally, companies are rapidly developing new drugs. “It is critical that any new treatment for COVID-19 be rigorously evaluated in one or more randomized, controlled trials,” Weijer stresses.

Uncontrolled trials that yield no conclusions “are themselves inherently unethical,” according to Gerald T. Keusch, MD, professor of medicine and international health at Boston University School of Medicine. Keusch co-chaired a committee for the National Academy of Medicine on the clinical research response during the West Africa Ebola epidemic in 2014-2015.1

Poorly designed studies subject patients to the risks of adverse events without learning if the intervention works. That is ethically problematic. “There is an ethical obligation to employ rigorous trial design that can provide answers about efficacy and safety,” Keusch says.

Investigators are testing drugs in Phase III randomized, controlled trials with hundreds of patients on the basis of “very minimal evidence” indicating these are likely to work, Weijer notes. There are several key ethical issues to consider:

• It is unclear whether investigators are adequately protecting the welfare interests of patients in COVID-19 clinical trials.

• Failure to conduct prior research in animal models and Phase II trials with smaller groups of patients generally is thought to violate equipoise. This requires that at the start of a trial there be a state of honest disagreement as to the preferred treatment.

“But if there is no evidence in animals or humans that a drug has an effect against COVID-19, how can we say equipoise exists?” Weijer asks.

• Proceeding directly to Phase III trials may not be a responsible use of resources. “The worry is that we may be exposing patients with COVID-19 to ineffective or possibly harmful treatments that could have been weeded out with smaller preliminary trials,” Weijer observes.

• The sheer number of treatments under evaluation is affecting ongoing and planned clinical trials for other diseases. An increasing number of clinical trials globally are putting recruitment on hold. This slows the pace of other medical research.

“Should some of these trials be postponed or canceled, this would undermine the social value that was key in the ethical justification for enrolling human volunteers,” Weijer warns.

• The use of unproven interventions for COVID-19 outside of ongoing clinical trials is ethically worrisome. “It seems as though every modern epidemic starts with unwarranted enthusiasm about untested treatment, only to be corrected by time, experience, and evidence,” Weijer notes.

Thus, clear public health messaging is critical. “Plainly irresponsible messages about some unproven treatments, including malaria drugs, have already cost lives,” Weijer laments.

Off-label uses of drugs for COVID-19 treatment, “based on hype and weak data, is one of my biggest ethical concerns right now,” says Holly Fernandez Lynch, JD, MBe, assistant professor of medical ethics and health policy at University of Pennsylvania Perelman School of Medicine. Such practices may backfire, says Fernandez Lynch, because they likely will inhibit rigorous investigation.

That is the case not only for off-label use of approved drugs, but also for drugs that are not yet approved for any use. “We’re taking a big gamble that these off-label uses are going to be safe and effective, and that they’re going to be better than some of the other options under investigation,” Fernandez Lynch cautions.

Another concern is that patients will favor certain investigational options over others, based solely on the amount of media attention they receive. “Patients will likely have a preference for what they can actually get their hands on,” Fernandez Lynch predicts.

This favors off-label prescribing over unapproved drugs, but not for strong scientific reasons. This speaks to a need to make clinical investigations more accessible. “That can be a challenge in emergency circumstances,” Fernandez Lynch admits. “But it is even more critical because of them.”

Poorly designed trials could lead patients and providers to form treatment preferences that are not supported by actual evidence of efficacy. “This can lead to the widespread use of ineffective or harmful interventions, and delay recruitment into studies that would tell us what actually works,” says Alex John London, PhD, director of the Center for Ethics and Policy at Carnegie Mellon University in Pittsburgh.

In reality, the vast majority of medical interventions fail in clinical testing; about half of those fail in Phase II testing. These are cases in which researchers have had time to pick the best candidates for an indication and to conduct carefully planned studies before introducing the intervention into humans. “Just because a treatment is urgently needed doesn’t mean that it is going to be easier to discover,” London notes.

Well-designed clinical trials play an important role in epidemic response, according to a National Academy of Medicine report.1 “When there are no established effective treatments for a disease, new interventions should be tested as early as possible in well-designed, randomized clinical trials,” says London, one of the committee members who wrote the report.

The goal is to quickly generate reliable medical evidence so physicians know whether an intervention is likely to help or harm a patient. This also helps policymakers know that scarce resources are not squandered on interventions that are ineffective or even harmful.

Clinicians have the discretion to prescribe drugs already approved to treat one condition on an off-label basis. “But in an outbreak of this size, that practice risks creating the perception that a drug works for a new indication when that has yet to be established,” London cautions.

It also can make it more difficult for patients to access those drugs for the indications where they have been proven to be effective. Additionally, if trial administrators cannot recruit enough participants, the information they produce can be misleading. Likewise, if trials are not coordinated with similar endpoints and measures, it is going to be difficult to compare their results.

“This makes research less efficient, and that raises questions of justice,” London says.2 Protocols that establish a single approach for testing multiple interventions across different clinical centers is a way of conducting trials quickly. “This ensures that the many different stakeholders who rely on that information can make better decisions,” London says.


  1. National Academies of Sciences, Engineering, and Medicine. Integrating Clinical Research Into Epidemic Response: The Ebola Experience. Published 2017.
  2. London AJ, Kimmelman J. Clinical trial portfolios: A critical oversight in human research ethics, drug regulation and policy. Hastings Cent Rep 2019;49:31-41.