COVID-19 has impelled the scientific community to research and develop new therapies to counter a serious viral pandemic. Since 2020, many old drugs repurposed as treatment for COVID-19 have been studied in clinical trials to assess efficacy and safety. As per PubMed, 6013 clinical trials on COVID-19 treatments have been published, of which only 22.9 per cent (1377) were randomised controlled trials. However, from these only a few high-quality clinical trials have provided evidence of efficacy of treatments – oxygen, dexamethasone, tocilizumab, remdesivir – for COVID-19. Many other clinical trials of drugs have been publicised by the media. But the quality and validity of most such trials are in question. Conducting clinical trials which meet globally expected scientific and ethical standard is always challenging but more so during a pandemic. The need to rapidly announce results in media seem to have affected the design and conduct of clinical trials of COVID-19 treatments.
For clinical trials of COVID-19 treatments to be valid and useful, the sponsor company or the clinical research investigator should consider the following in planning (USFDA May 20):
Population – moderate to severely ill patients with RT-PCR positive test
Standard of care – current accepted of treatments – oxygen, steroids, remdesivir, tocilizumab, intensive care management, heparin, antibiotics etc as background therapy
Design – Randomised comparison of standard of care + repurposed drug vs standard of care, blinding of the investigator team assessing the efficacy endpoint, placebo control if feasible
Efficacy endpoints – clinically meaningful based on clear definitions and specific clinical criteria e.g., mortality, need for oxygen or ventilator or hospitalisation or intensive care management, sustained clinical recovery
Duration – Efficacy assessment after adequate duration of at least 28 days
Sample size – large enough to provide a reliable answer to the safety and efficacy questions
When we review clinical trials of drugs for COVID-19 conducted in India, we see many deviations from these scientific requirements. Recently, 2-Deoxy-D-Glucose was launched for the treatment of COVID-19. The press release mentioned that the drug helped in faster recovery of patients hospitalised with COVID-19, reduced their dependence on supplemental oxygen, and showed a favourable trend in median time to achieving normalisation of specific vital signs parameters compared to standard of care. However, in absence of a peer-reviewed publication in a reputed journal, it is difficult to judge the validity of these trials and the risk-benefit of this drug in seriously ill patients. Some obvious questions remain regarding the design, and conduct of 2-Deoxy-D-Glucose trial:
1) Definitions of endpoints – clinical criteria
2) Process of Randomisation and allocation concealment in an open trial subject to selection bias from the investigators
3) Avoidance of clinician-observer bias in the evaluation of clinical endpoint
4) Statistical method of estimation of sample size
5) Statistical methods to compare the efficacy and safety endpoints in two arms.
For 2-Deoxy-D-Glucose, one major concern would be safety in COVID-19 patients who can suffer from myocarditis and develop diabetes mellitus. A Phase I trial in patients with advanced solid tumours (Cancer Chemotherapy and Pharmacology volume Dec 2012) had reported serious adverse events – hyperglycemia, gastrointestinal bleeding, and grade 3 QTc prolongation.
In 2020, a meta-analysis of 23 clinical trials of COVID-19 (BMJ Jul 20) reported that the majority – 21 trials had a high risk of bias:
1) during the randomisation process
2) because of departures from the intended intervention
3) due to missing outcome data
4) in the measurement of the outcome and<...
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