Discussion
Clinical trials are study designs central to the regulatory and commercialization process of therapeutic interventions such as pharmaceutical agents and devices. Regulatory decisions informed by clinical trials data often represents a certificate of clinical and safety value to new medicines or new indications of existing medicines.21 Given the potential severity of the COVID-19 infection, the need to find a mitigating or curative treatment is beyond urgent. Several candidate compounds addressing different disease processes (e.g., antibiotics, anti-viral, immune-suppressants, anticoagulants, oxygen delivery, etc.) have been proposed and are now undergoing clinical trials. Both HQ and chloroquine have been popular potential therapies described in the scientific literature and social media, and evidence for their efficacy/effectiveness and safety are desperately needed. Nevertheless, one recent evaluation of the three published HQ trials found important methodological weaknesses and sub-optimal reporting of key information.22
In this study, we found that RCTs proposed to evaluate the clinical efficacy/effectiveness and safety of HQ or chloroquine in the treatment of patients diagnosed with COVID-19 are designed to collect data that vary substantially in terms of the outcome domain used to determine the evidence base upon which these drugs will be judged. Moreover, data on safety outcomes are overlooked or only superficially included among the outcomes planned to be measured in these trials. Finally, essential information related to dosing schedules, treatment duration and timeframe of outcome assessment were frequently missing in the description of the RCTs. Overall, this analysis yielded three major areas of concern.
Selection of efficacy /effectiveness outcomes
The outcomes measured in clinical trials are critical in providing meaningful data and in allowing comparison among the results of other RCTs and different interventions.23 Though most of the evaluated RCTs specified at least one clinical outcome as a primary endpoint, the outcome domains varied widely. For example, while half of the registered trials described plans to assess all-cause mortality/mortality and clinical status/recovery to evaluate the efficacy/effectiveness of the drugs, the remaining trials defined over 15 different outcome domains. Ideally, the results of RCTs are subsequently combined in systematic reviews and meta-analysis, which are vital to informing all healthcare providers and health decision-makers. This may be particularly true during the COVID-19 pandemic, as many of the existing trials are small and a definitive, mega-trial trial may not emerge from the list identified. In the presence of highly heterogeneous outcomes, the development of systematic reviews and meta-analysis is likely less informative if not precluded.
During the writing of this study, a set of core outcomes of relevance to be measured in studies including adult hospitalized patients diagnosed with COVID-19 was released (http://www.comet-initiative.org/Studies/Details/1538). The core outcome set comprised mortality and respiratory support, outcome domains included in some, but not all, RCTs planned to evaluate the effect of HQ or chloroquine in patients diagnosed with COVID-19. More concerning, several of the clinical trials registered in the WHO-ICTRP database included only surrogate outcomes to estimate the efficacy/effectiveness of the drugs. There exist several examples where positive results in trials measuring surrogate outcomes were not replicated in efficacy/effectiveness trials where clinical outcomes were measured.14, 24
To increase research usefulness and relevance to patients and the health system, any investigation on drugs that might potentially treat patients diagnosed with COVID-19 needs to include a minimal standardized set of clinical outcomes of efficacy/effectiveness. This set of outcomes will likely be informed by the evolving research on the clinical characteristics of this new disease. Ultimately, the strain on capacity on the health system will only abate when we identify treatments that improve patients’ clinical outcomes, such as the reduction of intubation rates and subsequent deterioration. The development of a safe, effective, and widely available vaccine will be the long-term solution to the COVID-19 pandemic.