All Times EDT
Keywords: COVID-19, Phase 1/2/3, dose-finding, multiple endpoints, interim analyses, temporal changes, Placebo rates, non-constancy assumption, non-inferiority
In March 2020, the WHO declared COVID-19---a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)---a pandemic. Over 2 years since then through mid-May 2022, the global number of COVID cases stands at over 521 million with a total of 6.26 million deaths. To combat the pandemic, the world responded with multiple strategies including national lockdowns, stay-at-home policies, mask mandates, travel restrictions, and pharmaceutical breakthroughs of vaccines and therapeutics. Discovery and development of vaccines and therapeutics initially seemed impossible at worst and daunting at best, but Biopharmaceutical R&D rose to the occasion. In this presentation, we discuss the clinical development program of a therapeutic in a novel class called monoclonal antibodies that target SARS-CoV-2, eg, REGEN-COV (casirivmab+imdevimab) which was developed in record time and received marketing authorization for emergency use. Many statistical challenges will be discussed here including: a) issues associated with the design, conduct and operationalization of clinical trials that went through first-in-human, Phases 1/2/3 extremely rapidly; b) issues associated with dose-finding, identification of target populations, search of multiple indications for treatment or prophylaxis, use of multiple endpoints (biomarkers and clinical outcomes) in the development of COVID-19 therapeutic trials; and c) issues associated with interim analyses and control of multiplicity. Of importance, we will also discuss the temporal shift of Placebo rates in patient populations, caused by the evolution of SARS-CoV-2 variants and hence failure of non-constancy assumption that could potentially challenge non-inferiority designs of future therapeutics.