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FDA officials are moving to clarify standards and requirements for vetting and approving viable preventives.
With more than 100 vaccine research programs looking to address the pandemic, FDA officials are moving to clarify standards and requirements for vetting and approving viable preventives. The agency recently issued a lengthy guidance outlining recommendations for documenting vaccine quality, safety, and efficacy in order for a product to move forward.
A main point of discussion is the provision that a vaccine should be at least be 50% more effective than placebo in preventing the disease, a standard that some criticized as much too low to tackle COVID-19 effectively. However, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), which oversees vaccine production and approval, considers the 50% benchmark as hitting the “perfect spot,” he said in a webinar sponsored by the Alliance for a Stronger FDA on July 8, 2020. Efficacy lower than the 50% level yields a vaccine that may have very little effect, he explained, but if manufacturers had to achieve an 80% effect, there might not be a vaccine for months. “So,” he said, “50% seems the right place.”
Marks expects that clinical trials for the first COVID vaccines will need to pursue a fairly traditional approval process, with Phase III studies enrolling 10,000–50,000 patients in each arm. Clinical trials for COVID vaccines need to be done efficiently and quickly, but still must be randomized, blinded. and placebo controlled. And adaptive trials need to describe the study plan up front. Studies should aim to enroll a broad spectrum of the population, as it will be important to see the effect of a vaccine on both older individuals and pediatric populations, as well as those with immune compromised systems and specific health conditions.
FDA also seeks consistent, high-quality manufacture of vaccine candidates to ensure product safety. Safety concerns often link back to manufacturing quality issues, Marks explained, noting that CBER scientists will assess product sterility and potency through lot release requirements and look for consistency in manufacturing processes and controls for scale-up. Early safety studies need to enroll at least several thousand patients, because even a rare adverse event could affect thousands with a vaccine administered to many millions. And post-market surveillance will be important to track vaccine effectiveness in the real world, with manufacturers following up for a year or longer through well-planned pharmacovigilance programs. “We don’t want to skimp here,” stated Marks.
A main objective for the agency is to instill widespread confidence in any FDA-approved vaccine, a critical factor at a time of considerable vaccine “hesitancy” in the United States. Marks admits to being very scared by polls showing that up to one-third of Americans are hesitant about taking the vaccine. “People need to have confidence that what’s out there will be of high quality and safe and effective, and that we’ll be monitoring for any problem.” And he emphasizes that full transparency on the part of manufacturers is very important to support clear messages about likely vaccine side effects and acceptable risks.
The vaccine development approach mapped out by FDA is unlikely to produce an approved preventive this fall, Marks acknowledged. It will take weeks or months to enroll the thousands needed in clinical trials. And most of the current candidates will require two doses, which adds to testing timeframes. FDA will support efforts by manufacturers to look for ways to speed production. But “at the end of the day,” Marks stated, “we have to be able to tell the public that these are high quality products, and that corners were not cut.”