FDA action expected within 24 hours or less

For the second time this month, the FDA’s Vaccines and Related Biological Products Advisory Committee overwhelmingly voted to recommend that the FDA issue an Emergency Use Authorization (EUA) for a vaccine to combat SARS CoV-2 infection and thus end the Covid-19 pandemic.

By a vote of 20 with one abstention, the VRBPAC members said “yes” to this question: “Based on the totality of scientific evidence available, do the benefits of the ModernaCOVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?”

There was a brief hiccup as the FDA initially displayed last week’s question concerning the Pfizer/BioNtech vaccine instead of the question concerning Moderna’s vaccine, before one committee member pointed out the error.

Data from some 30,000 trial participants suggested the vaccine was 94.5% effective: there were 30 cases in the placebo arm and one case in the active vaccine arm.

This week’s meeting held less drama than last week’s meeting on the Pfizer/BioNetech vaccine, perhaps because both vaccines use novel messenger RNA platforms, so there was a risk that the process would take on a laissez-faire motif, but the panel members were careful to avoid giving a “rubber stamp” impression to their work.

Blind or Unblind?

Much of the discussion among committee members, as well as those who spoke during the public comment period, focused on the vexing question of what to do with the trial participants who received the placebo.

The answer to that question will not only impact the roughly 15,000 individuals who were injected with placebo in this trial but could also affect the ability of researchers to conduct future placebo controlled trials, said Steven Goodman, MD, MHS, PhD, who is Assoc. Dean, Clinical and Translational Research and Professor of Epidemiology & Population Health and Medicine at Stanford.

Goodman, who also testified about this issue during last week’s VRBPAC meeting on the Pfizer-BioNtech vaccine, said that if Moderna receives the expected EUA, a “large crossover is anticipated because 25% healthcare workers and others who were in the placebo arm will have early eligibility for a vaccine.”

Moderna wants to offer “unblinding” to those participants who request it. Doing that would most likely mean that many, if not all, of the control subjects would opt to receive the vaccine. The plan for doing that would be to offer “proactive reconsent as part of the offer to receive the mRNA-1273 vaccination.” They want those control subjects to “remain in the trial, enabling ModernaTX to continue to collect the relevant safety and effectiveness data over the entire two years of follow-up while increasing the likelihood of retaining participants on trial.”

Thus, adverse events “among those vaccinated within the trial will be captured, regardless of the treatment group to which the participants were originally allocated, over the entire follow-up period of 24 months.”

But Goodman warned that “unblinding participants destroys the randomization and thereby a valid comparison group.”

Melissa J. Moore, PhD, Moderna’s chief scientific officer, explained in the case data presented to the FDA as part of the EUA application, “the serious cases in the placebo group included one death and that weighed very heavily on us as we realized the efficacy of the vaccine.” She noted that “another 450 cases are now working their way through adjudication and there will be more deaths. That is a grave concern.”

Pfizer-BioNtech is addressing this issue by offering vaccine to unblind participants as they become eligible for vaccination based on the priority groups recommended by the CDC’s Advisory Committee on Vaccine Practices (ACIP).

New England Journal of Medicine Editor-in-Chief Eric Rubin, MD, PhD, who is a VRBPAC committee member, said “the study probably should have been designed as a blinded-crossover study from the beginning.” He said the FDA should urge future sponsors to use a blinded-crossover methodology.

A consumer member of the committee, attorney Sheldon Toubman, JD, noted that Moderna developed the vaccine with a hefty investment of taxpayer dollars; thus, he suggested that taking a vote to direct Moderna how to proceed with the unblinding issue would be within the committee’s purview.

Arnold Monto, MD, of the University of Michigan School of Public Health, who served as chair of the meeting, repeatedly tried to ask the committee members to limit comments to a choice between blinded crossover, unblinded crossover, and open-label unblinded crossover, with little success, so he turned to the FDA staff for guidance.

Marion Gruber, PhD, director of the FDA’s office of Vaccines Research and Review Center for Biologics Evaluation and Research, said that the FDA really did not want a vote on the issue, but rather wanted to get “a sense of the committee.” And, after consulting with her colleagues, she asked the committee not to vote on the unblinding question, but rather confine themselves to offering a “sense” of the committee.

Other Issues

Sidney Wolfe, MD, who said he was speaking for Public Citizen, the healthcare watchdog group where he served as medical director for many years, said any EUA should include a requirement that vaccinated individuals be informed that they must continue to exercise recommended Covid-19 mitigation strategies including mask-wearing, physical distancing, and hand washing. That requirement, Wolfe said, will be key, since the vaccine by itself will initially eliminate the Covid-19 risk.

Less than 24 hours after immunizations with the Pfizer/BioNtech vaccine were started in England, there were two reports of severe reactions, which triggered an anaphylaxis warning. In both cases, the patients were healthcare workers with a history of severe allergic reactions and both recovered after treatment with epinephrine. Those reports, along with two reports from Alaska of severe allergic reactions among persons who received the Pfizer/BioNtech vaccine, prompted the FDA to move to require monitoring for anaphylaxis.

Rachel Zang, MD, an FDA medical officer in the Agency’s Division of Vaccines and Related Products, who testified about safety in the Moderna vaccine, said that thus far there have only been reports of hypersensitivity reactions—injection site rash, urticaria, hives, and the like—and no verified cases of anaphylaxis.

Peggy Peck, Editor-in-Chief, BreakingMED™

Cat ID: 190

Topic ID: 79,190,730,933,190,31,926,192,561,927,725,928,925,934