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Keywords: Covid-19, statistical considerations, clinical trial, SARS-CoV2, omicron
The COVID-19 pandemic presents challenges to public health and continuous rethinking of how to best conduct clinical investigations of therapeutics. A national emergency in response to COVID-19 was issued on March 13, 2020. The Agency published a guidance “COVID-19: Developing Drugs and Biological Products for Treatment or Prevention” in May 2020. This guidance was updated several times due to ever-changing landscape for this infection. During the early stages of the pandemic, several drugs were investigated for the treatment of Covid-19 including repurposed antivirals, repurposed immunomodulatory drugs, and monoclonal antibodies (mAbs). Anti-viral therapeutics including Veklury, Paxlovid, Molnupiravir, and several mAbs were granted emergency use authorization (EUA) based on available clinical data in patients with various disease conditions. We have encountered several circulating variants of SARS-CoV2 including Delta (B.1.617.2), Omicron (BA.1, BA.1.1 and BA.2.) and other lineages with significant changes in viral transmissibility, disease severity and clinical manifestations. It has impacted the potential for interpretable designs and its feasibility. Randomized, double-blind, well-controlled clinical trials have always been considered as ‘the gold standard’ for providing reliable evidence of efficacy and safety for various Covid-19 therapeutics. Add-on placebo-controlled superiority trial designs using available background standard-of-care therapies were considered to be ethically acceptable in providing the most reliable and interpretable evidence at various stages of the pandemic. Several statistical issues and challenges will be discussed pertaining to trial designs, endpoint considerations, multiplicity issues, handling of missing values, intercurrent events, and possible adaptive design strategies.