A Primer on Clinical Trials for COVID-19
By Carl H. Coleman
Efforts to develop treatments and, ultimately, a vaccine for COVID-19 center on the successful design and implementation of clinical trials. To help you make sense of developments in this area, we have put together a few questions and answers about how clinical trials work.
What are clinical trials?
Clinical research is typically divided into two broad categories: interventional studies and observational studies. In an interventional study, investigators assign participants to receive specific interventions – such as a drug, a medical procedure, or a behavioral modification – according to the research plan or protocol. By assigning some participants to receive one intervention and other participants to receive something different, researchers can assess the impact of the chosen intervention on various health-related outcomes. Often, interventional studies are used to compare a new, experimental intervention to either the existing standard of care or, if no treatment for the condition being studied exists, a placebo. Sometimes, clinical trials are designed to compare two existing interventions to each other.
Observational studies may also involve individuals receiving medical interventions, but in contrast to interventional trials, the investigators do not determine which intervention the individuals will receive. Instead, the participants in observational studies receive whatever interventions they would normally receive as part of their standard medical care, with researchers observing what happens and recording the results.
The term “clinical trial” technically refers only to interventional studies, but sometimes you may see the term applied to the entire category of clinical research, including observational studies.
Are clinical trials required for all COVID-19 treatments and vaccines?
All new drugs and biologics (a category that includes vaccines) must go through clinical trials before they can be marketed. In most cases, before approving a new product, the Food and Drug Administration (FDA) requires the manufacturer to submit results from two well-designed clinical trials, but in some cases, convincing evidence from a single trial may be accepted.
Once a drug or vaccine has been approved, physicians are not limited to prescribing it for the specific uses for which the product received FDA approval. In fact, about one in five prescriptions in the United States are for purposes different from those described in the FDA-approved labeling – a practice known as “off label” prescribing. This means that, as a legal matter, physicians are free to prescribe any approved product for the prevention or treatment of COVID-19, without waiting for new clinical trials to be performed. In fact, some physicians are already doing that, especially with the drugs Hydroxychloroquine and Chloroquine, which are used to treat malaria, lupus, and rheumatoid arthritis. Because the supply of these drugs is limited, some state pharmacy associations have imposed measures to limit the filling of off-label prescriptions for these drugs to certain categories of patients.
From a public health perspective, widespread off-label prescribing of existing drugs for COVID-19 would be very problematic. When patients take drugs without the rigorous monitoring and controls used in clinical trials, there is no way to know whether any improvements or declines in the patients’ condition are due to the drug or to other factors that distinguish patients receiving the drug from the population at large. Therefore, even though physicians are not legally required to wait for clinical trials before prescribing existing drugs for COVID-19, it is essential that such trials be conducted. Fortunately, as noted below, clinical trials of existing drugs for the treatment of treatment of COVID-19 are already underway.
What clinical trials for COVID-19 are already in progress?
Over 900 clinical trials related to COVID-19 have been registered with the World Health Organization’s (WHO) International Clinical Trials Registry Platform. Not all of these are for treatments or vaccines; some, for example, focus on issues such as identifying risk factors for transmission, or assessing the mental health impact of the disease in different populations. Among the many ongoing studies related to treatments and vaccines, the following are particularly notable:
- The WHO-initiated “SOLIDARITY Trial,” which will enroll thousands of people infected with COVID-19 in multiple countries to compare the effects of four existing antiviral compounds (Remdesivir, Lopinavir/Ritonavir, Lopinavir/Ritonavir with Interferon beta-1a, and Chloroquine or Hydroxychloroquine) against the existing standard of care.
- Studies funded by the National Institutes of Health (NIH) to evaluate the use of Hydroxychloroquine and Remdesivir for the treatment of adults hospitalized with COVID-19
- An NIH-funded study of an investigational vaccine for COVID-19
- A national study in the United Kingdom, the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which is evaluating the effects of Lopinavir-Ritonavir, low-dose Dexamethasone, Hydroxychloroquine, and Azithromycin in COVID-19 patients
- A study at Johns Hopkins University to test the use of plasma from persons who have recovered from COVID-19 as a treatment for critically ill COVID-19 patients
You can find updated information about all registered COVID-19 clinical trials at the COVID-19 TrialsTracker. You can also search for COVID-19 trials near you at clinicaltrials.gov, which allows you to filter your results by recruitment status, eligibility criteria, study type, and other categories.
When can we expect the first treatments and vaccines for COVID-19 treatments to be available?
Clinical trials of existing medications for the treatment of COVID-19 are expected to produce results relatively quickly, with preliminary evidence potentially available as early as April or May. As noted above, physicians already have the legal authority to prescribe these drugs for COVID-19, so if early evidence is favorable, it is likely that they will be incorporated into clinical practice quickly.
By contrast, clinical trials of new drugs and vaccines normally take many years. However, government and industry are working to speed up the timeline for developing new COVID-19 treatments and vaccines. Dr. Anthony Fauci, the federal government’s top infectious disease expert, has suggested that a vaccine might be available in as soon as 12 to 18 months, but other experts have suggested that this timeline may be overly optimistic.
Is it possible to get access to an investigational COVID-19 treatment without participating in a clinical trial?
Two mechanisms permit (but do not require) pharmaceutical companies to make unapproved drugs available to patients who are unable to participate in clinical trials. First, under the FDA’s “expanded access” or “compassionate use” program, the agency may authorize access to investigational drugs for patients with “serious or immediately life-threatening disease or conditions” if no comparable or satisfactory alternative therapy exists, the potential benefit to the patient justifies the risk, and providing the drug will not interfere with the initiation, conduct or completion of clinical investigations. Second, the Right to Try Act of 2017 permits manufacturers to grant requests to access to investigational dugs for patients with life-threatening illnesses who have exhausted approved treatment options and are unable to participate in clinical trials. Unlike the expanded access program, the Right to Try Act does not require any FDA oversight, and it does not require prompt reporting to the FDA of serious adverse events. A few companies have authorized compassionate use of investigational COVID-19 drugs, but so far, no company has allowed access to these drugs pursuant to the Right to Try Act.
Gilead, the company that manufactures Remdesivir, has provided the drug to “several hundred patients” through a compassionate use program, but it recently stopped granting such access due to “overwhelming demand,” making exceptions only for pregnant women and children with “severe manifestations” of COVID-19. According to an April 10 paper in the New England Journal of Medicine, 36 of 53 patients treated with Remdesivir through Gilead’s compassionate use program showed some clinical improvement. However, as the authors of the paper noted, the significance of these results is limited because of “the small size of the cohort, the relatively short duration of follow-up, potential missing data owing to the nature of the program, the lack of information on 8 of the patients initially treated, and the lack of a randomized control group.” Citing these limitations, some experts have characterized the results as “almost uninterpretable.”
What are some of the things I should I think about before deciding to participate in a COVID-19 clinical trial?
The best reason to participate in a COVID-19 clinical trial is that you want to contribute to public health by participating in the development of safe and effective treatments or vaccines. In fact, making such a contribution is the only benefit you can be assured of when you enroll in a clinical trial. While you might be fortunate and receive an investigational intervention that helps you, that’s not something you can count on. According to the Biotechnology Industry Organization, a trade group, only about one in five new infectious disease drugs entering clinical trials ultimately satisfies the standards of safety and efficacy necessary for FDA approval. In addition, remember that, when you enroll in a clinical trial, you may not even receive the investigational drug; you might be enrolled in a control group that receives standard treatment and/or a placebo.
That being said, while there are inherent risks in clinical trials, federal regulations require these risks to be minimized as much as possible. In addition, if you participate in a clinical trial you can expect to have access to highly qualified health care teams and state-of-the-art supportive care. You also have the right to end your participation in the study at any time.
To learn more about participating in a clinical trial, visit the NIH Clinical Trials and You website.
Carl H. Coleman is a Professor of Law at Seton Hall University School of Law and specializes in the legal, ethical, and public policy implications of medical treatment, research, and public health. He also currently serves as Academic Director of the Law School's Division of Online Learning. Professor Coleman's biography and publications are available online.