By Deborah Borfitz

February 16, 2021 | At the recent COVID-19 and Cancer virtual meeting of the American Association for Cancer Research, the role of the U.S. Food and Drug Administration (FDA) in expediting the development and deployment of a vaccine was the topic of a keynote address by Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). His talk focused heavily on a pair of guidance documents issued by the agency last year, including one in October specific to requests for Emergency Use Authorization (EUA) for COVID-19 vaccines.

FDA’s role spans the lifecycle of vaccine development, Marks says. This includes strain selection, reference standard production and lot release, evaluation of safety and efficacy, post-marketing surveillance, advancing vaccine technology, and helping ensure public confidence in authorized vaccine products.

The two guidance documents were intended to accelerate vaccine development by spelling out the agency’s expectations of COVID-19 vaccines, and to encourage developers to engage the FDA early in the process, integrate two or all three trial phases, manufacture large quantities of product at risk, and use an optimal path to facilitate product availability, he says. The second of the two expounded on the required efficacy, safety, and manufacturing information in the initial document.

Last June, the first guidance was issued to encourage enrollment of participants across phases reflective of the country’s diversity, says Marks. Sponsors were also “strongly encouraged” to include older and medically compromised individuals, pregnant woman, and children, even if that could not happen during the initial round of trials.

The guidance set an efficacy goal of at least 50% over placebo, the typical floor for influenza vaccines, and a minimum of two months’ follow up on participants following their final vaccination series, he says. “We know adverse events typically happen in the first 42 days.

“We want to ensure a minimum duration of protection, but do not have the luxury of one to years of follow up, so post-licensure safety evaluation is important,” Marks continues. Early planning is suggested, and the FDA has itself conducted such studies in collaboration with the Centers for Disease Control and Prevention (CDC) and other federal and non-federal partners, he adds.

The safety studies were all done in a transparent manner so the public could see the agency was not hiding adverse events or withholding anything about vaccine efficacy, he stresses. To that end, any EUA request was brought to a Vaccines and Related Biological Products Advisory Committee and related document briefs were posted on the web for anyone to access, as were a webcast of that meeting and decisional documents used for justifying the EUA.

A Higher Standard

Ultimately, the product approval process will involve meeting the higher standards of a Biologics License Application (BLA), which requires “substantial evaluation of efficacy” from well-controlled, randomized clinical trials, Marks says. The pandemic necessitates the interim step of an EUA, an authority established in the aftermath of the 9/11 terrorist attack.

Wanting to “operate closer to the ceiling than the floor,” guidance on EUA for vaccines to prevent COVID-19 made clear that vaccine candidates cleared for use would need to have “clear and compelling evidence of efficacy in a large phase 3 trial,” Mark says. “We look at quality, safety, efficacy and [the data are] evaluated by a public advisory committee, and we have enhanced post-deployment surveillance.”

Administrative steps have been “streamlined” so the review process could be condensed, says Marks, but the FDA wants EUAs to become BLAs.

Safety monitoring being done by the FDA and its partners is both active and passive, Marks adds. Passive methods include the joint FDA-CDC Vaccine Adverse Event Reporting System and the CDC’s smartphone-based V-safe tool that uses text messaging and web surveys to provide personalized health check-ins after people receive a COVID-19 vaccine.

Active monitoring is being done through the Vaccine Safety Datalink (a collaborative project between CDC’s Immunization Safety Office and nine healthcare organizations) and CBER’s Biologics Effectiveness and Safety (BEST) System, part of the FDA’s Sentinel Initiative that is using claims data and electronic health records in conjunction with natural language processing and artificial intelligence to establish automated adverse events reporting. Using BEST, CBER plans to monitor more than 20 adverse events seen with the deployment of previous vaccines, he says.

Vaccine Candidates

As of January 2021, two messenger RNA vaccines (developed by Moderna and Pfizer/BioNTech) have been authorized via the EUA pathway, says Marks. Other vaccines under development include a pair of non-replicating viral vector vaccines, one by AstraZeneca whose efficacy is “not as good” in people over age 55 and seems to depend on a longer dose interval. News will be forthcoming soon about another viral vector vaccine being developed by Janssen that is “somewhat similar” to the company’s Ebola vaccine licensed for use in Europe.

Additionally, two protein subunit vaccines are being pursued by Novavax—phase 3 study results have just been announced—and Sanofi, although the company is “a little further behind,” Marks says.

The lipid composition of the COVID-19 vaccines developed by Moderna and Pfizer/BioNTech are “quite similar,” he continues, and is a derivative of polyethylene glycol 2000 used in a lot of over-the-counter products such as laxatives, bowel preps, and some cosmetics. “The rest of the [ingredients] are mostly buffers.”

The Moderna vaccine comes in 10-dose vials, is stored at minus 25 to minus 50 degrees Celsius, and had 30,418 participants in its phase 3 trial, he says. The Pfizer/BioNTech vaccine, in contrast, has six doses (originally five) per vial, needs to be kept at minus 60 to minus 80 degrees Celsius, and had 43,551 phase 3 clinical trial volunteers.

“It is notable that there was a small drop-off in efficacy in older individuals [with the mRNA approach],” says Marks, which is “unusual” for a vaccine. “Adverse events were also more common after the second injection and in people less than 55 years of age.”

Fatigue and flu-like symptoms have been the predominant complaints, Marks says, although severe allergic reactions have happened in roughly 1 in every 1,000 individuals. This has heightened safety surveillance and highlighted the need to administer the COVID-19 vaccine in a place where such reactions can be treated quickly.