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US FDA expert panel raises concerns COVID-19 vaccines target mild disease

At the end of a nearly nine-hour meeting where expert advisers weighed in on the development and regulatory processes for COVID-19 vaccines, Marion Gruber, director of the U.S. Food and Drug Administration's Office of Vaccines Research and Review, said her takeaway was the agency was "right on the money" with the standards it has set.

The FDA's 18-member Vaccines and Related Biological Products Advisory Committee did not vet any specific vaccines at the much-anticipated Oct. 22 meeting.

But members of the committee raised a number of concerns and were skeptical on several matters about the FDA's requirements for COVID-19 vaccines.

In particular, some of the panelists said they would like to see stricter standards than what the FDA laid out in its guidelines for licensing or granting emergency use authorization, or EUA, for COVID-19 vaccines.

"I have a problem with the standardization of efficacy," said panelist Luigi Notarangelo, chief of the clinical immunology and microbiology laboratory at the U.S. National Institute of Allergy and Infectious Diseases.

While Notarangelo said he appreciated the work the FDA did in outlining broad standards for multiple companies working with a number of different platforms, the efficacy measures are "skewed to mild disease."

"That is a concern," he said.

The FDA should have put more emphasis on COVID-19 infection and severe disease, Notarangelo said. "Mild disease may not mean very much."

The efficacy measures in the FDA's guidelines are also more subjective than objective, Notarangelo said.

"We're relying on reporting from the [study] subjects without any objective validation of what they're reporting," he said.

Panelist James Hildreth, president and CEO of Meharry Medical College in Nashville, noted that minority populations have had the highest rates of severe COVID-19 and deaths.

"And if we put a vaccine out that doesn't address that issue, it's just going to perpetuate the perception that that population or that segment of our population doesn't matter much in dealing with this challenge," Hildreth said.

The U.S. could end up with a vaccine that does well against mild COVID-19 "but actually does very little to address what we really care about, which is serious disease and death," added Sheldon Toubman, staff attorney at New Haven Legal Assistance Association, the consumer representative on the committee.

Under the FDA's guidelines, COVID-19 vaccines should be able to prevent the disease or decrease its severity in at least 50% of people who are vaccinated. But most companies are using severe disease as a secondary rather than a primary endpoint, Toubman noted.

Doran Fink, deputy director of FDA's Division of Vaccines and Related Products Applications, said the agency tries "to strike a balance between getting information on the most clinically significant outcomes of COVID-19 and how a vaccine might be able to prevent those outcomes versus being able to make an impact on the pandemic in a reasonable amount of time as possible based on good data."

Vaccine manufacturers are free to choose what they consider to be the most relevant primary endpoints and the FDA evaluates whether the data show the products are effective, Fink said.

The FDA determined it could not mandate a specific primary endpoint for COVID-19 vaccines, including one that focused on severe disease, he said.

Nonetheless, the FDA anticipates that companies will likely have data to inform whether their vaccines are effective against more severe disease, Fink said.

However, Hildreth took issue with that response, noting that American taxpayers are footing much of the bill for the development of the COVID-19 vaccines that will be sold in the U.S.

"So maybe you have more authority to mandate than you might think," he said.

Safety data

A number of the panelists, as well as several of the 25 members of the public who weighed in during the Oct. 22 meeting, also raised concerns that the FDA's requirement for a median of two months of phase 3 trial safety data to gain the EUA was too little and was based on an arbitrary timeline.

That brief amount of time after study volunteers are vaccinated "does not engender confidence," Sidney Wolfe of the consumer advocacy group Public Citizen said during the open public hearing portion of the meeting.

But FDA officials argued two months allowed sufficient time for adverse reactions to be observed and evaluated.

Any longer than that may result in a vaccine that could "make an impact" being withheld from the public, FDA's Fink said.

The FDA's requirement for the two months of safety data in its EUA guidelines had been a source of contention with the White House. President Donald Trump called the FDA's move "political" and said it was aimed at impeding his desire to have a vaccine approved by the Nov. 3 election.

Unblinding

One issue the FDA is grappling with is the impact that granting an EUA may have on ongoing placebo-controlled trials and whether a company that receives the emergency authorization should unblind their phase 3 study so that all volunteers who are getting the placebo can receive the vaccine.

Pfizer Inc. told the FDA in public comments the company believes it has an ethical responsibility to inform all study participants about the availability of an EUA if one is granted and the eligibility requirements to receive the product.

Pfizer said if its experimental vaccine is granted an EUA, the company wants to amend its study to allow cross-over of eligible placebo participants to the active vaccine arm if they wish to do so.

But Fink said the FDA does not consider the issuance of an EUA for a COVID-19 vaccine, in and of itself, grounds to unblind an ongoing trial and offer the vaccine to the placebo recipients.

"Once a decision is made to unblind an ongoing placebo-controlled trial, that decision cannot be walked back and that controlled follow-up [data] is lost forever," Fink said.

But he acknowledged the FDA does not have any remedies from preventing volunteers from dropping out of trials and seeking the marketed vaccine.

However, a number of the committee members noted that supplies of the first COVID-19 vaccines are expected to be limited and the first doses are anticipated to be allocated to priority groups, like healthcare workers, first responders and older Americans living in congregate settings, like nursing homes.

Being a placebo recipient in a trial does not guarantee anybody a spot to be first in line to get a vaccine once it is granted an EUA or a license, said Philip Krause, deputy director of the FDA's Office of Vaccines Research and Review.