With the race to create a safe and effective vaccine to prevent COVID-19, concerns have been raised about the process with which the FDA approves new vaccines for use in the United States.

That’s why researchers recently evaluated all new vaccines approved by FDA over the last decade. The research letter in JAMA Internal Medicine focused on 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.

The authors from the Yale University School of Medicine point to recent surveys showing that more than one-half of Americans are hesitant about receiving a potential COVID-19 vaccine because of concerns about adverse effects or lack of effectiveness. “There is also concern that the US Food and Drug Administration (FDA) might authorize a vaccine prematurely,” they add.

For the study, investigators 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. Then, using publicly available FDA documents, the study team identified three regulatory dates for each vaccine: investigational new drug submission (when human testing can begin), BLA submission, and FDA approval. 

In addition, researchers identified all trials that provided safety and efficacy evidence for approval, characterizing them by study purpose and number of patients. After that, they identified all pivotal efficacy trials and determined the use of randomization, masking, comparator group, and primary endpoint using methods described previously.

Focusing on pivotal efficacy trials using a clinical primary endpoint, the team collected vaccine efficacy, 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 report advises that the FDA approved 21 vaccines between January 2010 and June 2020. Most were for influenza (five [23.8%]) and meningococcus (five [23.8%]). Of these, four (19.0%) received Accelerated Approval. 

The authors point out that “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.”

The review further documents that each vaccine approval was supported by a median total of seven (IQR, 5-13) clinical trials, including two (IQR, 1-3) pivotal efficacy trials and one (IQR, 1-1) trial considered essential to establishing lot-to-lot consistency. The trials had a median number of participants in the prelicensure safety database of 6,710 (IQR, 4576-15?997), with a median follow-up for serious adverse events of 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),” the researchers further recount. “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%).”

They add that, among the five vaccines for diseases for which no FDA-approved vaccine existed at time of approval, four (80%) used a clinical primary endpoint.

“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,” the authors conclude. “These pivotal efficacy trials enrolled a median of 5,000 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.”
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