The need for a standardized approach in COVID-19 clinical
research
However, in order to make feasible secondary analysis of individual
studies, these should follow guidelines for standard protocols and
minimal requirements for outcome measures such as the Standard Protocol
Items Recommendations for Interventional Trials (SPIRIT)X and the Core Outcome Measures in Effectiveness
Trials (COMET) initiativeXI.
In fact, the major criticism emerging from a review of the ongoing
trials is the heterogeneity of protocols. Following the decision of both
FDA and EMA, respectively, to allow the use of chloroquine or
hydroxichloroquine and remdesivir in COVID-1923,XII,
several small trials have started using these drugs on a compassionate
basis. The EMA has expressed concern for these small studies and the
compassionate use programmes across Europe, as they are unlikely to
produce the required level of evidence of efficacy and safety of
investigational drugs. On the contrary, the EMA strongly recommends that
a more coordinated approach and efforts are put in place to prioritize
large multi-country randomized trials and multi-arm clinical trials
investigating different agents simultaneouslyXIII.
Unarguably, high quality clinical trials cannot be easily performed in
the setting of an outbreak, when investigators are often asked to make
patients’ care a priority. Nonetheless, even if adapted to this
challenging context, high quality research is still
needed24. Accordingly, a more standardized approach to
clinical research on COVID-19 should be warranted, including a rigorous
but realistic study design, a well characterized study population
stratified on the basis of age and severity of the disease, a rationale
behind the use of the investigational drug and the choice of comparator,
and optimal minimal primary outcome(s).
With regard to the study design, while masking might be difficult in
studies of COVID-19, randomization should be mandatory. Multi-centres
trials are highly advisable provided that standard operational
procedures are set out. Adaptive designs might be considered and the
setting should be specified. Rules for informed consent must adapted to
the chosen population. Centralized Ethics Committees or IRBs might
favour a more rapid start of the trial. Investigators should be
encouraged to publish the study protocol to be drafted according to the
SPIRIT and COS-STAP statement25.
Age, gender, ethnicity, previous diseases and undergoing treatments have
been reported to influence the incidence of
COVID3,26-28. Demographic and history data should be
obtained, possibly through a standard questionnaire, along with other
patients’ characteristics such as social status and environmental
exposure.
While waiting for a consensus on criteria for the diagnosis of COVID-19
and a classification of the disease, patients should be stratified on
the basis of the study setting, severity, and the predominant
pathophysiological abnormality in different phases of the disease
(viral, pulmonary, inflammatory; Fig.1)29.
Several research groups are working on a variety of preventive and
therapeutic interventions. However, despite the accelerated development
pathways adopted by many regulatory bodiesXIV, the
marketing authorization pathway for new drugs is a long process, with a
high attrition rate. Therefore, there has been considerable interest in
repurposing existing drugs – such as antiviral and immunosuppressant
agents - for use in COVID-1922. Studies with these
drugs should keep in consideration the putative mechanisms of action of
the investigational drug in relation to the different phases of
COVID-19. Antiviral agents, for example, should be used during the early
viral phase of the disease while immunosuppressant may be promising
candidate drugs in the severe inflammatory phase (while they might
dampen the immune response if used early on14).
Combination or sequential treatment might also be considered.
Standard of care seems to be a more realistic comparator than placebo,
in view of the emergency nature of the epidemic.
Collaborative trials and multi-arm studies comparing different drugs
should also be considered. A commendable example of this kind of
approach is represented by the Solidarity clinical trial launched by the
WHOXV. The Solidarity trial is a randomized
multi-countries open label trial which compares the efficacy of four
treatment options (Remdesivir, Lopinavir/Ritonavir, Interferon beta-1a
and Chloroquine or Hydroxychloroquine) against standard of care in
hospitalized adult patients with COVID-19. Underlying conditions are
recorded and severity of illness at entry is determined by a reduced set
of end-points that can be recorded even in overwhelmed hospitals.
Clinically relevant outcomes undergo an interim analysis by an
independent Global Data and Safety monitoring Committee. The simplicity
of the trial is balanced by the thousands of patients that are expected
to be recruited in more than 70 countries. Preliminary results of this
trial are expected by June 2020.
In more rigorous study designs, primary end-points should be chosen in
relation to the phase of the disease and the drug under investigation.
While SARS CoV-2 RNA clearance and the effects on the progression of the
disease may represent significant outcome measures for antivirals in the
mild forms of the disease, hard end-points such survival/death are
advisable in the most severe forms. However, a core outcome standard set
is urgently needed to define a minimal set of outcome measures relevant
to patients, investigators and regulators30.