Most first-wave COVID-19 clinical trials have ‘major design shortcomings’

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Most of the registered clinical trials of potential treatments for COVID-19 underway as of late March were designed in ways that will greatly limit their value in understanding potential treatments, according to a study from researchers at Johns Hopkins Bloomberg School of Public Health.

The researchers analysed the 201 clinical trials for drugs or plasma that, as of 26 March, had been registered in the US under ClinicalTrials.gov and in the international clinical trials registry maintained by the World Health Organisation (WHO). Of the trials analysed in this early snapshot, 100 (49.8%) were registered in China and 78 (37.8%) in the US. The majority of trials in the US clinical trials registry were registered from international researchers. Among the 201 trials analysed, 126 were recruiting participants from China, 31 from Europe, 14 from the US.

The researchers found that many of the trials lacked key features needed to optimize their scientific value such as the use of control groups and patient and clinician blinding. The analysis found that one-third of trials lacked clinical endpoints to clearly define success or failure. Nearly one-half were designed to enrol fewer than 100 patients, limiting their usefulness to assess modestly-sized treatment benefits. Two-thirds were “open label,” meaning that patients and doctors were aware who did and didn’t receive the treatment – in principle, allowing their unconscious expectations to influence the results.

“Because of these weaknesses, many of these studies are likely to yield only preliminary evidence,” says study first author Dr Hemalkumar Mehta, an assistant professor in the department of epidemiology at the Bloomberg School. “Given the urgency of identifying definitive evidence on potential COVID-19 treatments, this is an instance where we wish we did not have to say ‘further research is needed’ because of basic trial design shortcomings and small trials.”

The rapid initiation of so many clinical trials reflects the lack of any effective treatment for acute COVID-19 disease, whose global toll exceeds 400,857 deaths worldwide as of 8 June, 2020, according to the World Health Organisation’s situation report. Of the 201 trials the researchers analysed in their paper, the vast majority involved treatments already used for other diseases – treatments that could potentially be repurposed for COVID-19 relatively quickly because they have existing safety profiles and have already been evaluated by the US Food and Drug Administration or other regulators around the globe.

US doctors generally have wide discretion to prescribe FDA-approved drugs for other, “off-label” conditions. The authors note that off-label use can carry risks, and it is essential that therapies, including those used off-label, are studied for safety and effectiveness for COVID-19.

In all, the 201 trials involved 92 distinct drugs as well as antibody-containing blood plasma.

Mehta and colleagues found that most of these trials demonstrated design weaknesses. For example, about a third had no defined clinical endpoint, such as hospital discharge or survival, by which success could be measured. About a quarter lacked the standard random assignment of patients to a candidate treatment or control/comparator drug. Of the 152 trials that did randomize patients to a treatment or comparator, only 55 involved the usual practice of ‘blinding’ – a bias-reducing strategy in which patients as well as doctors and others who direct care and assess outcomes are kept from knowing who received the treatment or placebo.

“We understand the urgency of clinical research on COVID-19, but this is a time when we need rigorous science to inform policy and clinical decision-making,” says study senior author Dr G Caleb Alexander, professor in the department of epidemiology at the Bloomberg School. “Any treatment that is ultimately deemed safe and effective via robust trials could potentially be used by millions of people.”

The researchers noted that the number of US – or WHO-registered clinical trials of potential COVID-19 treatments tripled from the beginning of March to 26 March when they did their snapshot survey, and since 26 March has risen to more than 2,000 registered trials as of 8 June, 2020, as new trials are registered on a daily basis.

“As the safety and effectiveness of new treatments are evaluated, it’s vital that we use the best science to do so,” Mehta says. “It’s especially important at this juncture with many lives in the balance.”

Abstract
Objectives: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19.
Design, setting and participants: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO’s International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers.
Main outcome(s): Trial intervention, sponsorship, critical design elements and specified outcomes.
Results: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020.
Conclusions: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.

Authors
Hemalkumar B Mehta, Stephan Ehrhardt, Thomas J Moore, Jodi Segal, G Caleb Alexander

 

Johns Hopkins University Bloomberg School of Public Health material

 

BMJ Open abstract

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