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July 31, 2020

Weighing the Benefits and Risks of Proliferating Observational Treatment Assessments: Observational Cacophony, Randomized Harmony

Author Affiliations
  • 1Verily Life Sciences (Alphabet), South San Francisco, California
  • 2Duke Clinical Research Institute, Durham, North Carolina
  • 3Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
  • 4Nuffield Department of Population Health, University of Oxford, Headington, Oxford, United Kingdom
JAMA. Published online July 31, 2020. doi:10.1001/jama.2020.13319

Amid the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, substantial effort is being directed toward mining databases and publishing case series and reports that may provide insights into the epidemiology and clinical management of coronavirus disease 2019 (COVID-19). However, there is growing concern about whether attempts to infer causation about the benefits and risks of potential therapeutics from nonrandomized studies are providing insights that improve clinical knowledge and accelerate the search for needed answers, or whether these reports just add noise, confusion, and false confidence. Most of these studies include a caveat indicating that “randomized clinical trials are needed.” But disclaimers aside, does this approach help make the case for well-designed randomized clinical trials (RCTs) and accelerate their delivery?1 Or do observational studies reduce the likelihood of a properly designed trial being performed, thereby delaying the discovery of reliable truth?

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    2 Comments for this article
    Observational Studies and Clinical Trials
    Sylvia Smoller, PhD | Albert Einstein College of Medicine
    I agree with Dr. Califf that clinical trials are the gold standard, but they are not always possible. Let's not forget that the tobacco-lung cancer and the tobacco-CVD evidence of harm came from observational studies and had enormous impact on public health. There are good observational studies and bad observational studies, just as there are well-powered or under-powered clinical trials. Good observational studies can be extremely useful.
    Randomized Clinical Trials. Necessary but with Limitations
    Jeanne Dobrzynski, BA; John B. Kostis, MD, DPhil | Cardiovascular Institute, Rutgers Robert Wood Johnson Medical School
    We recently itemized “Limitations of Randomized Clinical Trials” in the American Journal of Cardiology (1).  Clinical trials are necessary to establish efficacy of interventions, but by themselves do not describe the effectiveness when the intervention comes to general practice. In particular as it pertains to COVID-19, there may be bias in choosing the hypothesis to be examined, especially when randomized clinical trials are sponsored by the industry. Examining 370 randomized drug trials, Als-Nielsen (2) reported that trials funded by for-profit organizations were more likely to report positive results although equipoise dictates that in 50% of the cases an intervention would be beneficial and in 50% not beneficial. In addition, favorable presentation of clinical trials by emphasizing relative risk reduction rather than absolute risk reduction or number needed to treat may be misleading. In our opinion, clinical decisions on individual patients should be made by considering clinical trials as well as from observational studies.


    1. Kostis JB, Dobrzynski JM. Limitations of randomized clinical trials. Am J Cardiol. 2020 May 16:S0002-9149(20)30486-0. doi: 10.1016/j.amjcard.2020.05.011. Online
    2. Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials. A reflection of treatment effects or adverse events? JAMA. 2003;290:921-928.

    John B. Kostis, MD, DPhil
    Jeanne M. Dobrzynski, BA
    Cardiovascular Institute
    Rutgers Robert Wood Johnson Medical School