A Phase 3 Trial Analysis Proposal for Mitigating the Impact of the COVID-19 Pandemic

Two pivotal, randomized, double-blind studies in a chronic dermatology disease were ongoing when the COVID-19 pandemic broke out. The trials had identical design, with four parallel treatment arms: two doses of active drug, an active comparator and placebo. When recruitment was temporarily halted due to the pandemic, both trials had already achieved over 80% of the targeted sample size. The unprecedented and unpredictable dynamic of the pandemic caused concerns about potential risks to data integrity and interpretability, which needed to be addressed. In this article, we describe some of these challenges and mitigation strategies. In particular, the complex confirmatory situation involving multiple active doses, endpoints and comparators led to a careful modification of the testing scheme to maintain the power of key endpoints and comparisons while still controlling the relevant Type I error rates. Specifically, the strategy was adjusted to perform some lower-level statistical tests in the hierarchy on the pool of both studies, taking advantage of the replicate study design. Primary endpoint comparisons against placebo and active control remained separately by study. In this article, we share our ideas and experiences in devising this risk mitigation proposal for the statistical methodology of these pivotal trials during the COVID-19 pandemic.