There is an urgent need to develop a safe and effective vaccine to prevent coronavirus disease 2019 (COVID-19). However, recent surveys suggest that more than half of Americans are hesitant about receiving a potential COVID-19 vaccine, owing to concerns about adverse effects or lack of effectiveness.1 There is also concern that the US Food and Drug Administration (FDA) might authorize a vaccine prematurely.2 To understand the usual approval process followed by the FDA, we systematically evaluated all novel vaccines approved by the FDA over the last decade, characterizing the premarket development and regulatory review times, the clinical evidence on which approval was based, and the size and follow-up duration of the prelicensure safety database.
We identified all original biologics licensing applications (BLAs) for vaccines approved by the FDA between January 2010 and June 2020, excluding supplemental approvals of existing vaccines. Using publicly available FDA documents,3 we identified 3 regulatory dates for each vaccine: investigational new drug submission (when human testing can begin), BLA submission, and FDA approval. We first identified all trials that provided safety and efficacy evidence for approval, characterizing them by study purpose and number of patients. Next, we identified all pivotal efficacy trials and determined the use of randomization, masking, comparator group, and primary end point using methods described previously.4 For pivotal efficacy trials using a clinical primary end point, we collected vaccine efficacy. Finally, we estimated the total number of patients in the prelicensure safety database and determined the longest duration of follow-up for serious adverse events among all trials included in the safety database. The study did not require Yale University institutional review board approval or patient informed consent because it was based on publicly available information and involved no patient records.
Between January 2010 and June 2020, the FDA approved 21 vaccines, most commonly for influenza (5 [23.8%]) and meningococcus (5 [23.8%]). Of these, 4 (19.0%) received Accelerated Approval. The median premarket clinical development period (investigational new drug submission to FDA approval) was 8.1 (interquartile range [IQR], 6.1-10.5) years, including a median FDA review period (BLA submission to FDA approval) of 12.0 (10.8-21.0) months (Table 1).
Each vaccine approval was supported by a median total of 7 (IQR, 5-13) clinical trials, including 2 (IQR, 1-3) pivotal efficacy trials and 1 (IQR, 1-1) trial considered essential to establishing lot-to-lot consistency. The median number of patients in the prelicensure safety database was 6710 (IQR, 4576-15 997), and the median follow-up for serious adverse events was 6 months (IQR, 6-12). The median aggregated number of patients enrolled among all pivotal efficacy trials supporting a given vaccine approval was 4961 (IQR, 3537-7775). All 21 vaccines were approved based on at least 1 randomized pivotal efficacy trial and 14 (66.7%) based on at least 2 pivotal efficacy trials. Among the 21 vaccines, 17 (81.0%) had at least 1 pivotal efficacy trial that used masking, 20 (95.2%) that used an active or placebo comparator group, and 8 (38.1%) approved based on a clinical primary end point; of these, the median vaccine efficacy was 91.9% (IQR, 79.6%-98.0%) (Table 2). Among the 5 vaccines for diseases for which no FDA-approved vaccine existed at time of approval, 4 (80%) used a clinical primary end point.
Since 2010, most novel vaccines approved by the FDA required about 8 years of clinical development and were based on evidence from a median of 7 clinical trials, including at least 2 pivotal efficacy trials that were randomized, masked, and used a comparator group. These pivotal efficacy trials enrolled a median of 5000 patients, who were followed up for serious adverse events for at least 6 months. Given the urgency of developing a COVID-19 vaccine, trials will need to be larger than those supporting prior vaccine approvals and include sufficient follow-up time for emergence of adverse effects.
Accepted for Publication: October 22, 2020.
Published Online: November 10, 2020. doi:10.1001/jamainternmed.2020.7472
Corresponding Author: Joseph S. Ross, MD, MHS, Department of Internal Medicine, Yale University School of Medicine, PO Box 208093, New Haven, CT 06520-8093 (joseph.ross@yale.edu).
Author Contributions: Dr Puthumana had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Puthumana, Schwartz, Ross.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Puthumana.
Critical revision of the manuscript for important intellectual content: Egilman, Zhang, Schwartz, Ross.
Statistical analysis: Puthumana.
Supervision: Ross.
Conflict of Interest Disclosures: Dr Zhang reported research support through the Collaboration for Research Integrity and Transparency at Yale University from the Laura and John Arnold Foundation and the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation program (U01FD005938). Dr Ross reported grants from the US Food and Drug Administration, Johnson & Johnson, Medical Devices Innovation Consortium, Agency for Healthcare Research and Quality, National Institutes of Health/National Heart, Lung, and Blood Institutes, US Centers for Medicare and Medicaid Services, Laura and John Arnold Foundation, and Medtronic outside the submitted work. No other disclosures were reported.