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While much has been achieved, much remains to be accomplished in learning how best to achieve, in the midst of a pandemic, evidence-based advances regarding interventions to treat and prevent diseases.
Clinical trials that are properly designed, conducted and analyzed are of integral importance in the pursuit of timely and reliable insights during a pandemic. Key design and conduct considerations include the importance of randomized clinical trials with proper controls, using either superiority designs or non-inferiority designs with rigorous non-inferiority margins, and having regular oversight by independent Data Monitoring Committees to safeguard interests of trial participants. Ideally effects on endpoints of greatest interest to the public should be reliably assessed such as, for therapeutics, the risk for progression to severe disease or risk of mortality.
During public health emergencies, there is even greater need for efficiencies achieved by international collaboration, such as through participation in platform trials for either therapeutics or vaccines, or through global participation in large simple trials, or the use of factorial designs when interventions have complementary and potentially synergistic effects.
Experiences and learnings during the pandemic will be discussed, with particular focus on the development of COVID-19 vaccines. Impressively, multiple vaccines already have been established to be safe and to have worthwhile efficacy. Even though several have received emergency use authorization, more will be needed to address the international pandemic in a timely manner. New vaccines might be more effective against emerging viral variants, or be single dose, or avoid cold chain constraints, or have improved manufacturing scalability. Trials of new vaccines can yield reliable and interpretable results in an efficient manner by randomizing, by evaluating effects not only on immunological but also on clinical endpoints, and by using placebo controls when ethically appropriate, such as in communities where vaccine supply is very limited. Creative designs are being developed to enable evaluation of durability of effects, effects on severe disease, and on measures of safety. Use of large simple trials not only has had great utility for registrational trials of Covid-19 therapeutics and vaccines, but also may be valuable for studying remaining safety and efficacy questions for authorized vaccines. For example, in settings where vaccine demand exceeds supply, there could be randomization during vaccine deployment, between accelerated vs standard timing of access, or between timing of second doses, or between different vaccines, in each instance assessing the influence of viral variants of concern.
Whether trials are being conducted to address Covid-19 or other diseases, recent guidance from the US Food and Drug Administration urges sponsors of clinical trials to be “assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing the risks to trial integrity during the COVID-19 pandemic”. Designing, conducting and analyzing clinical trials of interventions for the treatment and prevention of diseases, in a manner to obtain reliable as well as timely insights during a pandemic, is an ethical as well as scientific imperative.