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.