Kerry Dooley Young
December 17, 2020
Federal advisers on Thursday overwhelmingly recommended an emergency clearance for Moderna Inc's COVID-19 vaccine, while noting concerns about potential allergic reactions and the challenges of continued testing of this medicine.
The US Food and Drug Administration (FDA) put Moderna's application before its Vaccines and Related Biological Products Advisory Committee. The panel voted 20-0 on this question: "Based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?" There was one abstention.
The FDA is not bound to act on the recommendations of its advisers, but the agency usually takes the panel's advice. The FDA cleared the similar Pfizer-BioNTech vaccine on December 11 through an emergency use authorization (EUA), following a positive vote for the product at a December 10 advisory committee meeting. In this case, the FDA staff appeared to be pushing for a broad endorsement of the Moderna vaccine, for which the agency appears likely to soon also grant an EUA.
Marion Gruber, PhD, director of the Office of Vaccines Research and Review at FDA's Center for Biologics Evaluation and Research, earlier rebuffed attempts by some of the panelists to alter the voting question. Some panelists wanted to make tweaks, including a rephrasing to underscore the limited nature of an EUA, compared with a more complete approval through the biologics license application (BLA) process.
FDA panelist Michael Kurilla, MD, PhD, of the National Institutes of Health was the only panelist to abstain from voting. He said he was uncomfortable with the phrasing of the question.
"In the midst of a pandemic and with limited vaccine supply available, a blanket statement for individuals 18 years and older is just too broad," he said. "I'm not convinced that for all of those age groups the benefits do actually outweigh the risks."
In general, though, there was strong support for Moderna's vaccine. FDA panelist James Hildreth Sr, MD, PhD, of Meharry Medical College in Nashville, Tennessee, spoke of the "remarkable achievement" seen in having two vaccines ready for clearance by December for a virus that only emerged as a threat this year.
Study data indicate the primary efficacy endpoint demonstrated vaccine efficacy (VE) of 94.1% (95% CI, 89.3% - 96.8%) for the Moderna vaccine, with 11 COVID-19 cases in the vaccine group and 185 COVID-19 cases in the placebo group, the FDA staff noted during the meeting.
The advisers and FDA staff also homed in on several key issues with COVID-19 vaccines, including the challenge of having people in the placebo groups of studies seek to get cleared vaccines. Also of concern to the panel were early reports of allergic reactions seen with the Pfizer product.
Doran L. Fink, MD, PhD, an FDA official who has been closely involved with the COVID-19 vaccines, told the panel Thursday that two healthcare workers in Alaska had allergic reactions minutes after receiving the Pfizer vaccine, one of which was a case of anaphylactic reaction that resulted in hospitalization. In the United Kingdom, there were two cases reported of notable allergic reactions, leading regulators there to issue a warning that people who have a history of significant allergic reactions should not currently receive the Pfizer-BioNTech vaccine.
The people involved in these incidents have recovered or are recovering, Fink said. But the FDA expects there will be additional reports of allergic reactions to COVID-19 vaccines.
"These cases underscore the need to remain vigilant during the early phase of the vaccination campaign," he said. "To this end, FDA is working with Pfizer to further revise fact sheets and prescribing information for their vaccine to draw attention to CDC guidelines for post-vaccination monitoring and management of immediate allergic reactions."
Moderna has said that the most common adverse reactions seen to date with its vaccine include injection site pain (88.2%), erythema (8.6%), swelling (12.2%), and ipsilateral lymphadenopathy (14.2%). The company has proposed a regimen of having its vaccine administered in two doses, 28 days apart. The Pfizer vaccine is meant to be given in two doses, 21 days apart.
Contentious Questions About the Placebo Group
Perhaps the most contentious issue in the consideration of both vaccines has been when study participants from the placebo arms of trials should get the active drug.
Members of the FDA panel noted that it would be difficult to truly understand the likelihood of adverse events if people who were in a placebo group quickly get doses of COVID-19 vaccines as they become available.
Some people from the placebo groups will seek the active drug from the trials in which they participated. They might also seek to get a different COVID-19 vaccine; experimental COVID-19 vaccines from Johnson & Johnson, AstraZeneca, and Novavax are in the advanced stages of testing.
The FDA's Gruber said the agency will be considering these issues as it works with vaccine developers on their BLA applications. She noted that having a follow-up from a placebo-controlled group is the "gold standard of every clinical study," but this may no longer be "feasible" at a certain point.
Members of the FDA panel noted the challenge in seeking quick approval of vaccines to curb the COVID-19 pandemic while also maintaining tough scientific standards. Panelist Paul Offit, MD, with the Division of Infectious Diseases at Children's Hospital of Philadelphia, said the data gathered to date clearly supported emergency clearance of the Moderna vaccine.
"The question is never 'When do you know everything?' said Offit, "It's 'When do you know enough?'"
Moderna's bid for an EUA for its vaccine, known as mRNA-1273, is based on data from trials in which about 30,400 people participated. The FDA application for the Pfizer-BioNTech vaccine rested on data from research involving about 44,000 people. These numbers exceed those seen for routine pediatric vaccine trials, Offit said.
What's different with the COVID-19 vaccines is the lack of knowledge about how these medicines will fare in the long term, with the FDA considering studies with a median of only 2 months of follow-up due to the urgent need to curb the pandemic.
"So we don't know whether or not it's going to be effective 6 months from now or a year from now, but there are systems in place to know that,” Offit said about the Moderna vaccine. "We don't know whether or not it's going to have a rare serious side effect, which is true of any medical product, but there are systems in place to know that."
FDA panelist A. Oveta Fuller, PhD, a virologist at the University of Michigan, also noted the need for longer-term follow-up on COVID-19 vaccines.
"What will happen if this vaccine isn't a lifelong vaccine?" Fuller asked. "We expect that it is not. So how will we know if somebody needs a boost or how will we know if they are protected against new strains?"
The Issue of Age
Fuller had been among the FDA panelists who voted no in the advisory committee's 17-4 vote on the Pfizer-BioNTech vaccine at its December 10 advisory committee meeting. On Thursday, she cited a feeling of greater transparency about the discussion of the Moderna application among the reasons for her positive vote. She also cited a need for urgent action.
"We're in an unparalleled crisis. I did not think an EUA was the way to go," Fuller said. "But since the train has left the station, I appreciate that Moderna has given us a very transparent and thorough study that even from the beginning seemed to be very well organized," including enrolling people who have chronic conditions.
The other committee members who voted no on the Pfizer-BioNTech vaccine at the December 10 meeting subsequently told Medscape Medical News that their concerns centered around a question of whether to include younger people, ages 16 to 17, in the FDA's emergency clearance (Pfizer's vaccine was authorized for those 16 and up). Abstaining on the December 10 vote was H. Cody Meissner, MD, an expert in pediatric infectious disease from Tufts University in Boston.
Meissner told Medscape Medical News in a follow-up interview that he abstained only because of his concerns about the use in people ages 16-17. "I didn't feel that I could vote for that. I didn't want to vote against the vaccine because it's so important that the vaccine becomes available for the United States," Meissner said.
In an emailed statement, another committee member who voted no, David Kim, MD, said he too was concerned about the inclusion of 16-17 year-olds. "Unfortunately, I and other members who had also voted 'no' did not have an opportunity to explain our positions before the meeting was adjourned," Kim said in an emailed statement. "I would have voted 'yes' most enthusiastically had the language been ... 18 years of age and older."
FDA panelist Archana Chatterjee, MD, PhD, from Rosalind Franklin University of Medicine and Science, another no voter, said she fully supports emergency use of the Pfizer-BioNTech vaccine for people age 18 and older.
"This is a serious public health issue that requires data and science at the forefront," Chatterjee said in an emailed statement. "However, we currently have 16- and 17-year-olds who, as minors, are not able to make their own decisions on whether or not to take part in a vaccination program, and we have limited safety and efficacy data on how the vaccine affects the pediatric population."
She noted that few teenagers will qualify for the earliest rounds of vaccinations. The limited supplies of COVID-19 shots are being reserved for healthcare workers and frail elderly people.
"Since most of them will not be eligible to receive the vaccine in the near future, and because they are not in a high-risk group, I believe we have time to gather and analyze additional data in this and younger age groups," Chatterjee said.
Moderna last week said the US government has exercised its option to purchase an additional 100 million doses of its COVID-19 vaccine candidate, bringing its confirmed order commitment to 200 million doses. Of the first 100 million doses purchased by the government, about 20 million doses were expected to be delivered by the end of December and the balance will be delivered in the first quarter of 2021. The new order of 100 million doses will be delivered in the second quarter of 2021.
All of these deliveries are subject to the FDA issuing the EUA, Moderna said.
mRNA Vaccines in the Lead
An FDA emergency clearance for Moderna's product would be another vote of confidence in a new approach to making vaccines. Both the Pfizer-BioNTech and Moderna vaccines provide the immune system with a kind of blueprint in the form of genetic material, mRNA. The mRNA sets the stage for the synthesis of the signature spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells.
In a December 15 commentary for Medscape, Michael E. Pichichero, MD, wrote that the "revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced."
"This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it's straightforward to synthesize mRNA in the lab — and it can be done incredibly fast," he wrote.
The FDA allowed one waiver for panelist James K. Hildreth in connection with his personal relationship to a trial participant and his university's participation in vaccine testing.