Setting Expectations for Clinical Research During the COVID-19 Pandemic | Infectious Diseases | JAMA Internal Medicine | JAMA Network
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Editor's Note
July 27, 2020

Setting Expectations for Clinical Research During the COVID-19 Pandemic

Author Affiliations
  • 1Department of Medicine, University of California, San Francisco
  • 2Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts
  • 3Associate Editor, JAMA Internal Medicine
  • 4Department of Medicine, Duke Clinical Research Institute, Durham, North Carolina
JAMA Intern Med. 2020;180(10):1400-1401. doi:10.1001/jamainternmed.2020.2882

“Knowing and understanding an epidemic is the first step to defeating it.” Since Tedros Ghebreyesus, PhD, Director-General of the World Health Organization, tweeted this on March 2, 2020,1 coronavirus disease 2019 (COVID-19) has become a pandemic that has claimed hundreds of thousands of lives. The medical and research community has mobilized with unprecedented rapidity to address knowledge gaps for this novel disease.

In this issue of JAMA Internal Medicine, Pundi et al2 provide an early barometer for the clinical research response to COVID-19. Using ClinicalTrials.gov, they found 1551 studies registered on COVID-19 as of May 19, 2020. Although this work is impressive in quantity, the authors concluded that fewer than one-third of these studies were designed to provide evidence strong enough to be potentially practice changing. Mortality, arguably the most important outcome, was rarely a component of the primary outcome for randomized clinical trials.

These data are an important reminder that we should manage our expectations of initial studies.3 Small cohort studies in the initial phase of a new pandemic serve to delineate the patient population in the context of current treatments for the planning of future research. However, multiple, small, flawed trials will not give us the answers we need to treat this disease. Although the product of lower research standards may be marginally more useful than knowing nothing, we must seriously consider the potential harms of disseminating invalid findings mined from convenience samples or poorly controlled or underpowered studies. Equally important to managing expectations is for the clinical research community to set expectations. We should not sacrifice well-designed trials in the haste to generate new knowledge. Given the high stakes, all of us—clinicians, researchers, research funders, research regulators, and research publishers—are responsible for ensuring that the scientific value derived from conducting the trial justifies the risk our patients bear when they participate and their expectations of contributing to societal good.

In diseases such as COVID-19 that have a rapidly changing disease landscape and evolving standards of care, adaptive trial designs4 can allow research to respond nimbly but still maintain a valid control arm by using interim results and new standards of care to launch new study arms while allowing early stopping for efficacy, safety, or futility. The World Health Organization recommends using a consistent primary outcome between COVID-19 therapeutic trials and proposes an ordinal scale for clinical improvement to be responsive to the patient population and disease course. This is similar to a traditional composite end point, except it ranks component events, with mortality ranked as the most clinically important outcome.5

There are many ways to promote collaboration and efficiency. Can our patients coenroll in multiple studies? Can we use the same control group for multiple trials? How do we fast-track rate-limiting steps in research such that clinically overloaded or research-naive sites can easily participate? As we adjust to post–COVID-19 life, it is important that we take steps forward, not backward, in research.

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Article Information

Published Online: July 27, 2020. doi:10.1001/jamainternmed.2020.2882

Corresponding Author: Tracy Y. Wang, MD, MHS, MSc, Department of Medicine, Duke Clinical Research Institute, 200 Morris St, Durham, NC 27701 (tracy.wang@duke.edu).

Conflict of Interest Disclosures: Dr Wang reported receiving grants from Abbott Laboratories, Boston Scientific Corporation, Chiesi USA, Merck & Co, Portola Pharmaceuticals, and Regeneron Pharmaceuticals, Inc, and grants and personal fees from AstraZeneca, CryoLife, Inc, and Bristol-Myers Squibb outside the submitted work. No other disclosures were reported.

Disclaimer: Drs McWilliams and Wang are associate editors of JAMA Internal Medicine, but they were not involved in any of the decisions regarding review of the manuscript or its acceptance.

References
1.
@DrTedros. Knowing & understanding an epidemic is the first step to defeating it. We are in unchartered territory with #COVID19. We have never before seen a respiratory pathogen that is capable of community transmission, but which can also be contained with the right measures. March 2, 2020. Accessed May 9, 2020. https://twitter.com/drtedros/status/1234532869197922304?lang=en
2.
Pundi  K, Perino  AC, Harrington  RA, Krumholz  HM, Turakhia  MP.  Characteristics and strength of evidence of COVID-19 studies registered in ClinialTrials.gov.   JAMA Intern Med. Published online July 27, 2020 doi:10.1001/jamainternmed.2020.2882Google Scholar
3.
Bauchner  H, Fontanarosa  PB.  Randomized clinical trials and COVID-19: managing expectations.   JAMA. 2020. Published online May 4, 2020. doi:10.1001/jama.2020.8115 PubMedGoogle Scholar
4.
National Institutes of Health Clinical Center. A multicenter, adaptive, randomized blinded controlled trial of the safety and efficacy of investigational therapeutics for the treatment of COVID-19 in hospitalized adults. Accessed May 26, 2020. https://clinicalstudies.info.nih.gov/ProtocolDetails.aspx?A_2020-I-0073.html
5.
World Health Organization. COVID-19 therapeutic trial synopsis. R& D blueprint. Published February 18, 2020. Accessed May 13, 2020. https://www.who.int/publications/i/item/covid-19-therapeutic-trial-synopsis
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    3 Comments for this article
    EXPAND ALL
    Mortality and anticoagulants
    Camilo Colaco, PhD | ImmunoBiology Ltd
    Does the fact that mortality was rarely the primary outcome for CoVID randomized clinical trials and the numerous trials on the same drugs reflect the commercial drivers of clinical trials or the requirement of publications for career progression and research funding? With regard to the dangers of media uptake of the results of poor clinical studies it is notable that the single intervention with the largest impact on mortality, the early use of anticoagulants in CoVID19 remains unpublicized. Is cytokine release syndrome leading to ARDS a more high profile scientific publication than the routine treatment of coagulopathy?
    CONFLICT OF INTEREST: None Reported
    Expectations from COVID-19 Clinical Research
    Michael McAleer, PhD(Econometrics),Queen's | Asia University, Taiwan
    The prescient editorial on managed expectations from COVID-19 clinical research shows that, although there has been an impressively large volume of clinical research in the search for a vaccine for COVID-19, the question remains how and when the research will lead to safe, effective, timely, available, and accessible treatments for general international distribution.

    It is understandable that, in the face of the raging pandemic, there is a maelstrom of active clinical research.  

    Pool testing for COVID-19 through combining a large number of local individual randomized clinical trials from different sites might lead to fast and effective treatment outcomes
    (for example, see Cherif, Grobe, Wang et al. (2020), and Petkova, Antman and Troxel (2020)).

    Nevertheless, setting the expectations bar too high, especially from possibly rushed and flawed small scale initial clinical trials, which can lead to misleading outcomes, is likely to lead to far more than disappointment in the face of the pandemic.  

    Quality medical science must be the final arbiter.

    References

    Cherif, A., N. Grobe, X.L. Wang et al. (2020), Simulation of Pool Testing to Identify Patients With Coronavirus Disease 2019 Under Conditions of Limited Test Availability, Journal of the American Medical Association (JAMA) Network Open, Global Health, published online 23 June 2020, 3(6): e2013075. doi:10.1001/jamanetworkopen.2020.13075.
    https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767513.  

    Petkova, E., E.M. Antman and A.B. Troxel (2020), Pooling Data From Individual Clinical Trials in the COVID-19 Era, Journal of the American Medical Association (JAMA), published online July 22, 2020. doi:10.1001/jama.2020.13042. https://jamanetwork.com/journals/jama/fullarticle/2768851?guestAccessKey=ee231aef-691b-4d60-8aed-21845dab8fb9&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jama&utm_content=olf&utm_term=072220.
    CONFLICT OF INTEREST: None Reported
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    Science has to be strictly defined,as it is also the case for clinical trials in COVID-19 patients
    Giuliano Ramadori, Professor of Medicine | University Clinic Göttingen,Internal Medicine Germany
    Salazar and colleagues have taken the responsibility to mention some of the conditions for clinical trials to be defined as "clinical research."

    I have already expressed my opinion in this journal regarding the unethical use of different drugs just because we deal with a "life threatening disease". It is also unethical to allow every hospital to participate in a study without having an appoved structure and coworkers trained for this particular task.

    Patients and their relatives in a dramatic clinical condition should be able to give an "informed" consent after
    having read the proposal of the clinical
    research The authority, which approved the trial, should have the possibility and the obligation to control the proper execution of the trial by controlling the conditions of enrollment of the patients and the collection of the results.

    Under the actual plethora of different conditions under which the pandemic leads patients to ICU-treament and to death, the execution of clinical research looking for effective antiviral drugs is almost impossible.
    CONFLICT OF INTEREST: None Reported
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