The Food and Drug Administration generally approves vaccines when their benefits outweigh their risks for their intended use. In this paper, we review current and potential approaches to this critical role of the FDA. The FDA has established pathways to accelerate vaccine availability prior to approval, such as emergency use authorization, and to channel resources to high-priority products and allow more flexibility in the evidence required for approval, including accelerated approval based on surrogate markers of effectiveness. Among the 35 new vaccines approved in the US from 2006-2020, about two-thirds of their pivotal trials used the surrogate outcome of immune system response, and just one-third evaluated actual disease incidence. Post-approval safety surveillance of new vaccines-particularly vaccines receiving expedited approval-is crucial. Currently this is accomplished through such mechanisms as the Centers for Disease Control and Prevention/FDA Vaccine Adverse Event Reporting System, the CDC Vaccine Safety Datalink, and the CDC Clinical Immunization Safety Assessment Project. Adverse events detected in this way may lead to changes in a vaccine's recommended use or its withdrawal from the market. Regulatory oversight of new vaccines will have to balance speed with rigor and decisiveness to effectively address the coronavirus disease 2019 (COVID-19) pandemic.

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IMPORTANCEIn recent years, drug approvals have been based on fewer, smaller, and less rigorous pivotal trials. Less robust preapproval testing raises questions about the efficacy and clinical value of these drugs. OBJECTIVE To assess the regulatory context, pivotal design characteristics, and postmarket requirements (PMRs) and postmarket commitments (PMCs) of novel 2020 drug approvals to characterize the state of evidence at the time of approval. DESIGN, SETTING, AND PARTICIPANTS This cohort study identified novel drugs approved by the US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research in 2020. The Drugs@FDA database was used to extract key characteristics of each drug's pivotal trials. Drug approval packages provided regulatory information. The prevalence of key trial design features was compared between oncology and nononcology drugs. EXPOSURES Drug names, date of approval, indication on labeling, and clinical and regulatory details. MAIN OUTCOMES AND MEASURES Number of pivotal trials, pivotal trial design (randomization, masking, groups), trial comparator, trial hypothesis, trial end points, results, number and type of expedited pathway designations, and number and type of PMRs and PMCs. RESULTSThe 49 novel therapeutics approved in 2020 were supported by 75 pivotal trials. More than half of drugs (28 [57.1%]) were supported by a single pivotal trial. Trial sizes ranged from 19 to 2230 participants. More than three-fourths of trials (57 [76.0%]) had a randomization component, and nearly two-thirds (46 [61.3%]) were double-masked. Most used a superiority approach. Roughly half (39 [52.0%]) compared the novel therapeutic with a placebo or vehicle control; 13 (17.3%), an active control; 2 (2.7%), both a placebo and active control; and 21 (28.0%), a historical, external, or other control. Nearly half of pivotal trials (34 [45.3%]) used a surrogate measure as a primary end point. Pivotal trials supporting oncology approvals were much more likely to have historical controls than nononcology approvals (13 of 18 [72.2%] vs 8 of 57 [14.0%]; P < .001) and to use at least 1 surrogate measure as a primary end point (17 [94.4%] vs 17 [29.8%]; P < .001). Forty drugs had at least 1 PMR or PMC, accounting for 178 PMRs and PMCs across the cohort. CONCLUSIONS AND RELEVANCEThese findings suggest that the increased flexibility in the characteristics of acceptable preapproval evidence can be partially explained by the increase in trials of drugs for rare and other serious conditions that require flexible testing strategies as well as the associated regulatory changes that have accumulated over time. The FDA and consumers may (continued) Key Points Question What were the key design characteristics of the pivotal trials supporting novel drugs approved by the US Food and Drug Administration (FDA) in 2020? Findings This cohort study of 49 drugs approved by the FDA in 2020 found that they were supported by 75 pivotal trials, of which nearly two-thirds were double-masked, more than threefourths had a randomiz...