Evidence-time dilemma in a pandemic with high mortality: Can outcome-driven decision making on vaccines prevent deaths?

When the first vaccines were authorized for coronavirus disease 2019 (COVID19) in December 2020, its death toll exceeded 2,500,000 deaths globally. Basic science showed an unprecedented pace in its response to the virus with the synthesis of mRNA1273 (Spikevax), the active substance of a COVID19 vaccine, on January 13, 3 weeks prior to the first confirmed death in the United States. Can regulatory science accelerate access to vaccinations, prevent deaths, and overcome the evidence– time dilemma in future pandemics? The death toll of the COVID19 pandemic has only been exceeded by the Spanish Flu in 1918. Early in the first wave of the pandemic, a highly disproportionate distribution of COVID19 infections and deaths was observed between the age groups with a disproportionately high case fatality rate in the elderly subpopulation (<1% in <64yearold, 8.0% in 70– 79yearold, and 14.8% in >80yearold subjects).1 Already at the start of the pandemic, it was obvious that effective vaccines will be the ultimate tool to control the COVID19 pandemic and bring societies back to normality. So, science excelled with the severe acute respiratory syndromecoronavirus 2 (SARSCoV2) virus genome being sequenced on January 11, the active substance, mRNA1273, synthesized on January 13, 2020.2 By December 2020, with an unprecedented speed of less than a year, the mRNA1273 and the BNT162 (Comirnaty) vaccine were developed and granted an Emergency Use Authorization (EUA) in the United States.2,3 In April 2020, the International Coalition of Medicines Regulatory Authorities (ICMRA) discussed aspects for COVID19 therapeutic developments, including clinical trials, realworld evidence (RWE), and compassionate use. They expressed the need for robust evidence to establish safety and efficacy for the proposed medicines, leading to timely regulatory decisions and thus guiding clinicians in defining the best treatment options for COVID19 to serve the patients’ needs in the fastest fashion possible.4 In support of the EUA, the pivotal clinical evidence was generated in large randomized controlled trials (RCTs) in an idealworld setting, in the broad adult population, with prevention as the primary end point (starting in July 2020).2 Due to the limited availability of the first two authorized COVID19 vaccines, the United States and almost all other countries prioritized the elderly in the vaccination process. This decision was based on modeling approaches revealing that mortality is minimized in scenarios where the subpopulation with the highest risk of COVID19related deaths is vaccinated first, already established for influenza vaccinations. Unfortunately, in a pandemic with such high mortality, there is an evidence– time dilemma; during the clinical evidence generation, the death toll continues to rise in the real world. Knowing that the second wave is often bigger than the first and was expected to start in autumn 2020 and last until spring 2021 further emphasizes the limited time. Indeed, emergencies and crises often act as