Operation Warp Speed and the Standard for Review of the COVID-19 Vaccines

By Mark I. Schwartz

On August 7th, FDA Commissioner Dr. Stephen Hahn, CBER Center Director Dr. Peter Marks, and FDA Deputy Commissioner Dr. Anand Shah published an article in the Journal of the American Medical Association (JAMA) outlining what the review standards would be for the COVID-19 vaccines currently under development.

There are currently dozens of COVID-19 vaccine candidates in development, however, only five of those have been selected by FDA as the most likely to produce a vaccine for COVID-19 under Operation Warp Speed:

  • The two messenger RNA vaccines from Moderna and BioNTech/Fosun Pharma/Pfizer, both of which have recently begun phase 3 clinical trials;
  • Merck’s recombinant vesicular stomatitis virus vector vaccine;
  • Johnson & Johnson/Janssen Pharmaceuticals replication-defective human adenovirus 26 vector vaccine; and
  • AstraZeneca/University of Oxford’s replication defective simian adenovirus vector vaccine.

It is worth noting that all of these vaccine candidates are aimed at inducing antibodies directed against the receptor-binding domain of the surface spike protein of the virus.

The publication of this JAMA article by FDA officials is largely in response to concerns expressed that political pressure to get a vaccine approved will result in less robust vetting of the biological product by CBER than under normal circumstances.  To the contrary, the authors emphasize that the candidate vaccines “…will be reviewed according to the established legal and regulatory standards for medical products…[T]here is a line separating the government’s efforts to focus resources and funding to scale vaccine development from FDA’s review processes, which are rooted in federal statute and established FDA regulations…”

Apart from the concern over political pressure to license a COVID-19 vaccine that might not have been fully vetted, there are inherent risks in shortening the timeline of vaccine development from over a decade to less than a year.  Having spent many years at FDA, including several years as a deputy office director at CBER, it goes without saying that shortening timeframes by an order of magnitude is not easily achieved without creating unintended adverse consequences, particularly when a bureaucracy is involved.

In addition there is concern that the technologies being used for the vaccine candidates referenced above are largely novel in that only one of the five candidates uses a technology that has previously been employed for licensure of a vaccine intended for humans, namely, Merck’s recombinant vesicular stomatitis virus vector platform, which was most recently used for last year’s licensure of Ervebo, against Ebolavirus.  Indeed, there are no licensed messenger RNA vaccines, and because the RNA is so susceptible to degradation in vivo, its effectiveness depends in part on the novel lipid delivery system that would transport the RNA to the site of action.

To that end, the article states that the agency is committed to ensuring that all such vaccines are manufactured in accordance with FDA’s quality standards and that their safety and efficacy are verified before being authorized or licensed, adding that recommending a baseline for performance is necessary to provide confidence to the public that broad distribution of a potential vaccine could offer immunity to the majority of the population:

FDA has specifically recommended in its guidance to vaccine developers that the primary efficacy endpoint point estimate for a placebo-controlled efficacy trial should be at least 50%, and the statistical success criterion should be that the lower bound of the appropriately alpha-adjusted confidence interval (CI) around the primary efficacy endpoint point estimate is >30%.

Next, the authors state that to achieve population-wide immunity these vaccines would need to be widely disseminated in clinical trials, including with sufficient representation of racial and ethnic minorities, older adults, and individuals with medical comorbidities.

Finally, the article states that the vaccines could be reviewed under either the traditional Biologics License Application (BLA) framework or under the Emergency Use Authorization (EUA) program, and that issuance of an EUA for a COVID-19 vaccine could either occur once a sponsor’s studies have demonstrated safety and efficacy of the vaccine but before submission of the BLA or, alternatively, during the review of the BLA.

We are certainly hoping that FDA’s objectives are borne out when the application reviews take place in the coming months, and that the vaccines are legitimately determined to be safe, pure, and potent prior to widespread use.