Pfizer’s RSV Vaccine: US FDA Panel Wants Robust Safety Program With Public Accountability
Executive Summary
Advisory committee offers strong support for approval of Pfizer’s RSV vaccine to protect infants while simultaneously offering the agency a handful of suggestions that were directed towards the review and post-market surveillance of all vaccinations.
Pfizer Inc.’s maternal respiratory syncytial virus vaccine program got positive efficacy and safety votes from the US Food and Drug Administration’s vaccine advisors 18 May with the strong caveat from many members that rigorous post-marketing surveillance be required as part of an expected approval.
The Vaccines and Related Biological Products Advisory committee voted unanimously that Pfizer’s data package for Abrysvo (RSVpreF) is adequate to support the effectiveness of the vaccine in preventing RSV lower respiratory tract disease and severe RSV lower respiratory trace disease in infants from birth through 6 months of age through active immunization of pregnant individuals during the second or third trimester of pregnancy.
The committee also voted 10-4 that the sponsor’s data was adequate to support the safety of the vaccine.
Mandatory, Fast Surveillance
The efficacy of the vaccine was never really in question during the VRBPAC’s deliberation. Safety, particularly the possibility the vaccine may increase the risk of preterm births, took up most of the VRBPAC’s attention. (Also see "Pfizer’s Maternal RSV Vaccine Quest May Hinge On FDA Advisors’ Views of Preterm Birth Data" - Pink Sheet, 16 May, 2023.)
At the end of the day, the majority of the committee voted in favor of the safety profile, with many of those on the affirmative side saying they were comfortable with approval under the assumption the agency would call for and enforce strong post-marketing requirements.
“A lot of the [unknowns] are going rely on the post-marketing requirements and to use the FDA parlance, the requirements, not the commitments here. I think we want to make sure that these are actually carried out because the information is too important for us to make sure that we’re actually informing pregnant persons on how to actually move forward with treatment in this case,” said Adam Berger, the director of the division of clinical and healthcare research policy in the office of science policy, office of the director at the Nationals Institutes of Health.
The timelines to conduct this surveillance should be short, committee members added.
“On balance, I felt comfortable voting yes on this, but that doesn't absolve everyone involved from doing aggressive proactive, post-marketing surveillance and post-marketing surveillance that uses methods that provide early answers rather than sort of waiting for a few years for those answers,” said Saad Omer, the director of the Yale Institute for Global Health.
“Those methods have been developed, systems have been developed through FDA and other federal investments. CDC has come up with methods within [Vaccine Safety Datalink] to evaluate things quickly. I would say it's an ethical imperative to deploy those methods in service of this endpoint.”
“There are other vaccines in the future for pregnant women. So I think this is our chance to really step it up and do the right thing and develop systems that we can get a quick answer,” added Daniel Feikein, a scientific advisor and respiratory disease consultant.
VRBPAC Wants More Oversight Of Pharmacovigilance
Steven Pergam, an infectious disease expert at the Fred Hutchinson Cancer Center, who like Berger, Omer and Feikein, voted yes on safety, said it would be a good idea in this case, as well as in the case of some of the other vaccines the committee has reviewed recently, for the FDA or the Centers for Disease Control and Prevention to publicly present the post-marketing data to the committee when its ready for review.
“I think it is important that some of this data does come back to us so we can actually evaluate it. Because this is becoming increasingly something that we're having to make decisions about for more and more of the vaccines that we've been seeing. … I think it would be very highly valuable in helping us to understand and then really be confident that the decisions we're making are being followed,” Pergam said.
Amanda Cohn, director of the division of birth defects and infant disorders at the CDC, also made a push for FDA to require sponsors to come prepared at the advisory committee with more complete pharmacovigilance plans the advisors could review.
“It feels like this committee is frequently asked to review the data at hand without having any transparency about what the pharmacovigilance products of the companies produce. They just do a lot of analysis and we never see the results of those. I don't recall having those results brought back to this committee, nor do I recall having the companies really share their methodology,” said Cohn.
This type of transparency is particularly important due to the unique nature of vaccinating pregnant women and needing to track safety in both the vaccinated individuals and their babies, Cohn added.
“Pregnant women, and infant outcomes and pregnancy outcomes, I think are much more complicated” than monitoring other safety signals, Cohn said. “And I frankly think ... that we should have more transparency on these pharmacovigilance plans, and that they should have strong plans prior to this meeting. There's been a long time for these plants to be developed.”
Missed Chance In Phase III Design
The No voters on safety said the lingering safety concerns should not be left to the post-marketing space.
“I'm uncomfortable with the notion of kicking the can down the road, as others have said, towards post-marketing surveillance studies. I think it's a bit different to rely on surveillance studies to confirm what appears to be a safe product. Whereas here, I think the signals are such that the post-marketing surveillance data would be asked to refute what’s sort of a potential hypothesis here. And I think that's a higher bar,” said Holly Janes, a biostatistician in the vaccine and infectious disease division of the Fred Hutchinson Cancer Center.
The committee chair also questioned why Pfizer did not design its Phase III trial to better study the risk of preterm birth given the signal was seen it a Phase II trial as well.
“There is a pattern here that occurred. The Phase IIb should have triggered action in terms of adjusting the Phase III design in order to answer whether the signal observed in the Phase II was real or not. So that was a big missed opportunity and I feel its unfair that we kick the can down the road to the larger public,” said Hana El Sahly of Baylor College of Medicine.
Paul Offit, of the Children’s Hospital of Philadelphia, who also voted No on safety, said leaving this issue to the post-market space could hurt public acceptance of other immunizations given to pregnant people to protect them and their babies.
“The pregnancy platform is an important platform. You don’t want to mess with it and I worry that if preterm births are in any way a consequence of this vaccine that would be tragic in many ways.”