When Should COVID Vaccines Get Full Approval? US FDA Squeezed By ‘Too Fast’ And ‘Too Slow’ Camps
Executive Summary
Some experts argue full FDA approval will help boost vaccination rates that are waning, but others want the agency to mandate studies in special populations and gather other data before making a final decision.
US Food and Drug Administration officials once again find themselves in the middle of an application review speed versus thoroughness debate, this time over the final approval of the Pfizer Inc./BioNTech SE and Moderna, Inc. mRNA coronavirus vaccines.
The outcome of the reviews of both biologics license applications does not appear in doubt. Since the vaccines received emergency use authorizations in December 2020, millions in the US have been inoculated, new COVID-19 cases have dropped, and few serious side effects have been reported.
However, with US vaccination rates falling and the Biden Administration looking to convince those who are hesitant to take the shots, some are calling on the FDA to finish its review sooner rather than later. Full approval could allow employers, the military and other organizations to mandate vaccination.
At the same time, another group argues the agency should take its time to make sure all the relevant studies are completed and not consider issuing a full approval until 2022.
The too fast, too slow argument on approval speed is nothing new for the FDA, but escalating the debate could risk further alienating the unvaccinated population. Both camps at least in part are focusing their arguments on persuading more of that group to get the jab.
Jesse Goodman, director of the Georgetown University Center on Medical Product Access, Safety and Stewardship and former FDA chief scientist, said on 30 June during the DIA Global Annual Meeting that people will be confident in the vaccines “if they were approved and people feel that was not done under pressure and no shortcuts were taken.”
If Aduhelm Evidence Good Enough, Why Not COVID-19 Vaccine Data?
Eric Topol, a professor of molecular medicine at Scripps Research and the founder and director of the Scripps Research Translational Institute, wrote in a 1 July New York Times op-ed that the FDA already has offered feedback to the manufacturers based on some submissions.
“The emergency authorizations were granted more than six months ago,” Topol wrote. “That’s more than ample time for the agency to conduct plant inspections and review the applications.”
Topol also invoked the controversial accelerated approval of Biogen, Inc. and Eisai Co., Ltd.’s Aduhelm (aducanumab-avwa), saying it was “frankly unfathomable that mRNA vaccines have been proved safe and effective in hundreds of millions of people and yet still have a scarlet ‘E.’”
“While the FDA has vigorously defended its decision to approve aducanumab, it has yet to present any timeline for the mRNA vaccine approvals,” he wrote. “The agency should make full approval it’s No. 1 priority and its leadership should communicate its plans to the public.”
Zeke Emanuel, a special advisor for health policy and Office of Management and Budget director under President Obama and now vice provost for Global Initiatives at the University of Pennsylvania Health Transformation Institute, tweeted that he supported Topol’s position, saying that with more than 300 million doses administered in the US, “there is ample safety and efficacy evidence” and that moving from EUA to full approval will help increase uptake.
The Aduhelm application was assessed by a different center than the COVID-19 vaccines (the Center for Drug Evaluation and Research rather than the Center for Biologics Evaluation and Research) and comparisons of the circumstances associated with them may be difficult. Still, among the reasons Aduhelm’s approval was controversial was its questionable efficacy data, which is not the case with the vaccines. (Also see "FDA’s Mismanaged Aduhelm Review: What Went Wrong" - Pink Sheet, 6 Jul, 2021.)
Would BLA Approval Make A Difference?
Jerome Karabel, a sociology professor at the University of California–Berkley, also published an op-ed in USA Today on 6 July with the headline “Speed it up FDA,” arguing the agency should aim for full approval of the vaccine BLAs by early August before students return to college campuses and summer vacations end.
Karabel said only full approval “will persuade reluctant employers to require vaccines and only full approval will motivate millions of hesitaters to overcome their reservations.”
“The choice facing the FDA is clear: either continue its adherence to established bureaucratic procedures, or rise to the occasion by showing the flexibility needed to confer the full approval appropriate to the urgency of the situation,” he wrote.
Indeed, a segment of the hesitant population could be swayed by full approval. A Kaiser Family Foundation survey found 31% of unvaccinated adults would be more likely to get a shot if it was FDA approved. But the researchers indicated that full approval likely is a proxy for general safety concerns, adding that two-thirds of adults, including most who are not vaccinated, either believe the vaccines have been approved or are unsure whether they received full approval or an EUA.
Norman Baylor, president and CEO of Biologics Consulting and a former director of the CBER Office of Vaccines Research and Review, told the Pink Sheet that the pace of the reviews as they appear now is not unexpected or unreasonable. He added that the agency likely will not need six months to finish them, but will need “sufficient time to review all of the data.”
Baylor also was “not convinced that there will be a huge surge in uptake after the BLAs are approved.”
Pfizer and BioNTech began the rolling submission of their vaccine BLA on 7 May, which has now been completed, while Moderna announced it began filing its rolling submission on 1 June. (Also see "Keeping Track: US FDA Clears Pfizer’s Prevnar 20; Dermavant Submits Tapinarof; Adamis Returns With Zimhi" - Pink Sheet, 11 Jun, 2021.)
Citizen Petition Aims To Slow BLA Approval Until 2022
Still, a speedy approval could backfire by fueling arguments that the decision was too quick.
An international group of physicians, scientists and others took the idea to heart and filed a citizen petition with the FDA dated 1 June requesting the agency ensure eight safety and efficacy measures are met before “serious consideration is given to granting” BLA approval. In an opinion article in the BMJ, several petitioners said “if the FDA listens to us, they won’t give serious consideration to approving a COVID-19 vaccine until 2022.”
The group made clear that the petition “doesn’t argue that risks outweigh benefits or that benefits outweigh risks.” Their focus is on “methods and processes,” they said.
“We are concerned that the premature licensure of a COVID-19 vaccine can seriously undermine public confidence in regulatory authorities, particularly if long-term safety issues were to emerge following licensure,” they wrote in the petition.
The group requested the agency confirm in revised guidance that a minimum of two years of follow-up of clinical trial participants is required even if trials are unblinded or lack placebo controls and that safety data from individuals receiving more than two vaccine doses must be submitted.
The group also wants data required in special populations, such as infants, immunosuppressed individuals, and pregnant or nursing women, showing substantial evidence of clinical effectiveness that outweighs harms, as well as data on the safety of the pharmacokinetic profile of the spike protein and from biodistribution studies investigating the actual COVID-19 vaccines. The group also wrote that independent and impartial individuals should investigate pharmacovigilance data from US and other pharmacovigilance systems.
In addition, the petition asks for experts in gene therapy to be included on the FDA Vaccines and Related Biological Products Advisory Committee and that the FDA ensure analyses and decisions on the vaccine BLAs are informed by experts with no financial or research relationships with any vaccine manufacturers for at least 36 months.
The petition had drawn more than 1,500 comments as of 7 July. The FDA has not yet responded to it.
Marks Maintains Measured Stance
CBER Director Peter Marks said the vaccine BLAs are a priority because full approval can affect vaccine confidence, but that the application reviews will be thorough.
“Unless it’s done carefully. Unless we have not cut corners and we can say we’ve dotted every “I,” crossed every “T,” it’s not going to mean what it needs to,” Marks said during the DIA Global Annual Meeting session that also included Goodman. “It means that we’re going to have to make sure we do what we normally do. All the conformance lots need to be watched. All the proper inspections need to be done.”
Marks added that additional staff and effort will help “compress” the overall time needed, but he could not give a date when decisions will be made.
“We’re going to do whatever we can to move this forward as quickly as we can because we do think we need to do whatever we can to help get more people vaccinated,” he said.