Research Priorities for Coronavirus Disease 2019 in Critical Illness

The Surviving Sepsis Campaign

Craig M. Coopersmith, MD, MCCM; Massimo Antonelli, MD; Seth R. Bauer, PharmD, FCCM; Clifford S. Deutschman, MS, MD, MCCM; Laura E. Evans, MD, MSc, FCCM; Ricard Ferrer, MD, PhD; Judith Hellman, MD; Sameer Jog, MD; Jozef Kesecioglu, MD, PhD; Niranjan Kissoon, MB BS, MCCM; Ignacio Martin-Loeches, MD, PhD; Mark E. Nunnally, MD, FCCM; Hallie C. Prescott, MD, MSc; Andrew Rhodes, MB BS, MD(Res); Daniel Talmor, MD, MPH; Pierre Tissieres, MD, DSc; Daniel De Backer, MD, PhD

Disclosures

Crit Care Med. 2021;49(4):598-622. 

In This Article

Discussion—Performing Research During a Pandemic

A final research priority was the question "How can quality research be performed and assessed during a pandemic?" This question directly relates to all 12 research priorities above and more globally, to all research being performed in the midst of the current pandemic. To address this question, we start with a quote from the first line of an editorial from Doug Altman[213] published over 25 years ago that has direct relevance to current times—"We need less research, better research, and research done for the right reasons." Research in COVID-19 has mushroomed in the most challenging of times, when practitioners are faced with a new, highly contagious disease, often in the setting of limited resources with clinical demands outstripping staffing.

Yet, during this pandemic, it is important to conduct rigorous, timely, relevant, ethical research to improve care and outcomes.[214] Indeed, the need for research focused on the optimal outcome for the individual patient should be balanced by the need for maximal societal benefit.[214] With the large number of critically ill patients, significant mortality rates, and few therapeutic options of proven benefits, it is tempting to relax rigorous research standards and offers therapies of dubious benefits.[215] Yet, studies conducted during COVID-19 should be held to the same high ethical, methodologic, and implementation standards as during nonpandemic periods.[216,217] Funding priorities should be driven by the broader needs of the community based on the need for resilient health systems which are able to support research.[218] Research priorities cannot be a "one size fits all" but rather take into account local factors as to what optimal utility of the proposed study might be. For instance, in high-income countries, research on the modes of ventilation may be prioritized, whereas in low- and middle-income countries, research on optimal delivery of supplemental oxygen may confer greater benefit.[219,220] We hereby outline many of the important issues to consider in research conduct during COVID-19:

  1. "Optimizing randomized controlled trials in COVID-19 research"—In a rapidly evolving disease, clinical studies should include short-term efficacy evaluation along with long-term efficacy indicators. The randomized controlled trial is firmly entrenched as a key method for evaluation of therapies, whereas observational and nonrandomized trials are generally considered scientifically inferior.[221] Randomized trials should be conducted with the same rigor as they are in non-COVID patients. It is important to minimize bias and to collect sufficient data (not just a minimal dataset) in order to ensure absence of imbalance between the treatment arms. For the randomization process, it is important to stratify patients according to key elements associated with outcome determined in a pre hoc manner. In this regard, it is particularly important to stratify patients across different centers, as large differences in outcome may be observed even in centers of the same region.[9,09] Cohort studies and pragmatic trials may be alternatives, and newer methodologies such as adaptive design and platform trials offer exciting methods to study patients, even in the time of pandemic.[2,42]

  2. "Research should be embedded and integrated in critical care when possible"—Embedding research in clinical care such that it becomes standard work, reduces the stress involved in research endeavors when clinicians are already overburdened.[222] Implementation science is needed to ensure that the latest discoveries are quickly translated into clinical practice.

  3. "Ethical consideration in the conduct of research"—Even in this unprecedented global pandemic, the rights of subjects including voluntary participation, right to be informed, right to privacy and security, and the right to timely treatment should be ensured.[223,224] Data safety monitoring committees need to be nimble and quickly adapt to protect subjects such as the re-evaluation of risk and benefit ratios as studies progress.[225] In addition, ethics committees should pay attention such that care in the use of experimental drugs, inclusion and exclusion criteria, and informing participants of the risks of the trial are strictly adhered to.[226]

  4. "Issues of equity, benefits and burdens"—COVID-19 has exposed inequities and disparities in health outcomes for minority groups in multiple countries. These disparities may be exacerbated if clinical trials are not designed with equity considerations in mind. Different racial and ethnic backgrounds may respond differently to medical interventions and are underrepresented in clinical trials.[227] In addition, careful consideration should be given to the continuation of nonpandemic research using objective transparent criteria and revisited as the pandemic abates.[228] Research should be performed in high- and low-and-middle-income countries. Finally, equity also implies that governments and pharmaceutical industry will make effective therapeutics available for all countries at reasonable prices.

  5. "Ensuring accurate communication of research findings"—Failure to adequately communicate research findings in the time of a pandemic has important consequences.[229] This is especially important in light of heightened interest in the face of social media campaigns, increased lay press reporting and potential panic, and/or unrest in the general public in the setting of a pandemic.[230] Infodemiology is now acknowledged by public health organizations and the World Health Organization as an important emergent field of critical practice during the pandemic. This helps to amplify messages that are beneficial to the public and is based on sound scientific principles while attempting to limit inappropriate content that favors political or commercial interests.[231] Notably, communication of research findings has been fundamentally altered during the pandemic, with increasing information coming via press release and preprint services prior to manuscripts undergoing peer review. Although there is an inherent benefit in having results enter the public domain as rapidly as possible, this is balanced by a desire for data to be externally vetted and as comprehensive as possible. Ultimately, the core interest of data dissemination after peer review remains; however, there are circumstances in which care will be altered by a trial result (either showing efficacy or lack of efficacy of a treatment) in which there is utility in rapidly releasing study results prior to peer review.

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