Moderna Inc.'s two-dose COVID-19 vaccine should be permitted for emergency use, a panel of expert advisers told the U.S. Food and Drug Administration.
The FDA's Vaccines and Related Biological Products Advisory Committee voted 20 to 0, with one abstention, that based on the available scientific evidence, the benefits of Moderna's COVID-19 vaccine outweigh its risks for use in people age 18 or older.
The FDA is not bound by the outside experts' advice but generally follows it. The agency is expected to soon act on granting an emergency use authorization, or EUA, to the vaccine, which Moderna developed with the U.S. National Institutes of Health.
If authorized, Moderna's vaccine would be the second shot permitted for emergency use in the U.S.
Pfizer Inc. and BioNTech SE were granted an EUA on Dec. 11 for their COVID-19 vaccine — a decision that came one day after the FDA's advisory committee gave its thumbs-up to the product.
Both the Moderna and the Pfizer-BioNTech vaccines are based on a messenger RNA platform. Messenger RNA, or mRNA, plays a fundamental role in human biology, transferring the instructions stored in DNA to make the proteins required in every living cell.
Tal Zaks, chief medical officer at Moderna, emphasized at the Dec. 17 advisory committee meeting that mRNA vaccines do not change a person's DNA.
The FDA's review of Moderna's data found that the vaccine, known as mRNA-1273, was "highly effective" in preventing symptomatic COVID-19 at least 14 days after the second shot.
The data also demonstrated a favorable safety profile, with no specific concerns that would preclude the agency from issuing an EUA, Rachel Zhang, a medical officer in FDA's Center for Biologics Evaluation and Research, told the committee.
The FDA will continue to update the prescribing information and fact sheets if it gets new information that it determines is necessary to inform providers and vaccine recipients, Doran Fink, deputy director of the agency's Division of Vaccines and Related Products Applications, told the panelists.
Anaphylaxis
Members of the committee questioned Moderna and regulators about whether there was any potential for anaphylaxis with mRNA-1273 after two cases of allergic reaction were reported in the U.K. and two more in the U.S. with the Pfizer-BioNTech product — all in healthcare workers who got the shots days after they were available.
Pfizer and the U.S. Centers for Disease Control and Prevention confirmed on Dec. 16 that there had been an allergic reaction in a healthcare worker in Alaska. But the FDA's Fink revealed at the Dec. 17 advisory committee meeting that a second case in the same state had also been reported with the Pfizer-BioNTech vaccine.
David Martin, vice president of pharmacovigilance at Moderna, said there were two anaphylactic reactions in the company's phase 3 trial — one in a placebo participant attributed to an X-ray imaging radiocontrast agent and the other in a volunteer who got the vaccine, though the anaphylaxis occurred 63 days after the second dose and the person had a history asthma and shellfish allergy.
Neither reaction met the Brighton Collaboration Anaphylaxis Case Definition criteria, Martin said.
Jacqueline Miller, senior vice president and therapeutic area head of infectious diseases development at Moderna, said after the initial Pfizer cases were reported, her company had undertaken a "very rapid review" of its safety database to evaluate whether there had been any reports of anaphylaxis with any of its other experimental mRNA products and only found one case.
In that case, the person, who received a different experimental vaccine — not the COVID-19 shot — had a soy allergy and had the reaction outside the trial period, Miller said.
Moderna is continuing to monitor for any other cases of anaphylaxis among its experimental vaccines, Miller said.
Unblinding
Panelist Michael Kurilla, director of clinical innovation at the NIH's National Center for Advancing Translation Sciences, said he abstained from the Moderna vote because he felt the EUA indication was a "blanket statement" and "too broad."
"I'm not convinced that for all of those age groups the benefits do actually outweigh the risk, and I would prefer to see it more targeted towards people at high risk of serious and life-threatening COVID disease," he said.
During the pandemic, Kurilla said the FDA should permit the COVID-19 vaccines to be used under the agency's expanded access program — also known as compassionate use — which allows people with immediately life-threatening conditions or serious diseases to obtain access to experimental products outside of clinical testing when no comparable alternative is available.
"It would have given us a lot more opportunities to continue to collect the data," Kurilla said.
Moderna has proposed letting placebo participants in its phase 3 trial be unblinded and immediately receive mRNA-1273, which the company said would allow it to continue to collect data over the two-year follow-up period under an open-label crossover design.
The company is concerned that without that option, study participants would leave the trial, especially healthcare workers, to seek an available COVID-19 vaccine.
Moderna's proposal is different from Pfizer's plan to unblind placebo participants and allow them to get its vaccine when they are eligible under national immunization recommendations and provide the shot to everyone in the placebo group after six months.
Unblinding study participants when something is shown to be effective and is available "is a precedent you may not want to set," Steven Goodman, associate dean of clinical and translational research at Stanford University School of Medicine, warned at the FDA meeting.
Goodman suggested an alternative of using a blinded crossover study, where the placebo participants would be brought back and given the vaccine and the people who got the vaccine would be given a placebo — without any of the participants told what they originally got.
But Lindsey Baden, associate professor at Harvard Medical School and a lead investigator for Moderna, called that idea "impractical" in the ongoing pandemic and said it would result in study participants leaving the trial, therefore impairing biopharmaceutical manufacturers' ability to "learn anything further."
