Failed clinical trials on COVID-19 acute respiratory distress syndrome in hospitalized patients: common oversights and streamlining the development of clinically effective therapeutics

ABSTRACT

Introduction

The coronavirus disease 2019 (COVID-19) pandemic has put a strain on global healthcare systems. Despite admirable efforts to develop rapidly new pharmacotherapies, supportive treatments remain the standard of care. Multiple clinical trials have failed due to design issues, biased patient enrollment, small sample sizes, inadequate control groups, and lack of long-term outcomes monitoring.

Areas covered

This narrative review depicts the current situation around failed and success COVID-19 clinical trials and recommendations in hospitalized patients with COVID-19, oversights and streamlining of clinically effective therapeutics. PubMed, EBSCO, Cochrane Library, and WHO and NIH guidelines were searched for relevant literature up to 5 August 2022.

Expert opinion

The WHO, NIH, and IDSA have issued recommendations to better clarify which drugs should be used during the different phases of the disease. Given the biases and high heterogeneity of published studies, interpretation of the current literature is difficult. Future clinical trials should be designed to standardize clinical approaches, with appropriate organization, patient selection, addition of control groups, and careful identification of disease phase to reduce heterogeneity and bias and should rely on the integration of scientific societies to promote a consensus on interpretation of the data and recommendations for optimal COVID-19 therapies.

KEYWORDS:

• SARS-CoV-2
• remdesivir
• dexamethasone
• guidelines
• randomized trials

Article highlights

• The number of clinical trials has increased exponentially during the pandemic; however, some of them have failed due to underpowered samples, unclear study designs, frequent withdrawal, organizational issues, and repeated or duplicated results, thus posing a risk of biased results.

• Development of high-quality clinical trials to rapidly generate recommendations on possible therapeutics in hospitalized patients who developed mild-to-severe COVID-19 and COVID-19 acute respiratory distress syndrome (C-ARDS) has produced positive effects across the research community. Nevertheless, identification of factors involved in the success and failure of these clinical trials is essential.

• The pathophysiologic and molecular mechanisms of COVID-19 are beginning to be better understood, allowing novel therapies to emerge. Understanding COVID-19 phenotypes may help in developing targeted clinical trial designs among cohorts of patients who developed mild-to-severe COVID-19 and C-ARDS to test specific treatments.

• Despite this challenging scenario regarding the development of new recommendations due to failed trials, a few effective therapies have become available, and numerous clinical trials are currently ongoing to explore potential new pharmacotherapies for mild-to-severe COVID-19 and C-ARDS patients.

• Suggestions to improve clinical trial design in the near future may include: repurposing of established drugs to accelerate treatment development; adapting vaccines and drugs originally developed for other viruses; use and implementation of pre-existing biotechnologies; large-scale accessibility to clinical trials; publication of study design protocols to allow suggestions and criticism; data sharing; new statistical approaches; more accurate selection of patients and interventions; always using a control group; choosing multiple-arm over single- or double-arm designs; and testing different dose regimens.

Abbreviations

ACE2, angiotensin converting enzyme 2; ERS, European Respiratory Society; G-CSF, granulocyte-colony stimulating factor (G-CSF), GM-CSF, granulocyte-macrophage colony stimulating factor; IDSA, Infectious Disease Society of America; IL-6R, interleukin-6 receptor; IP-10, interferon-γ-inducible protein 10; MIP1-α, macrophage inflammatory protein 1-α; MCP-1, monocyte chemoattractant protein 1; MERS, Middle East respiratory syndrome; NIH, National Institutes of Health; RCT, randomized controlled trial; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF-α, tumor necrosis factor-α; WHO, World Health Organization.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2022.2120801

Additional information

Funding

This work was supported by the Brazilian Council for Scientific and Technological Development (COVID-19-CNPq; 401700/2020-8 and 403485/2020-7); Rio de Janeiro State Research Foundation (COVID-19-FAPERJ; E-26/210.181/2020); and Funding Authority for Studies and Projects (01200008.00), Brazil.