Borio, Dolsten say FDA’s COVID-19 vaccine guidance hits mark

Guidance lays groundwork for robust trials, but harmonization of endpoints, assays needed

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FDA has laid the groundwork for robust, randomized, placebo-controlled trials of vaccines for COVID-19, but it will be up to groups such as NIH and Operation Warp Speed to encourage coordination among developers to harmonize endpoints and assays.

Vaccines to prevent the novel coronavirus will need to demonstrate disease prevention, not just meet surrogate immunogenicity endpoints, FDA made clear in guidance released Tuesday.

Pfizer Inc. (NYSE:PFE), whose COVID-19 vaccine is among the most advanced, welcomed the guidance.

Mikael Dolsten, Pfizer’s CSO and president of worldwide research, development and medical, called the guidance “agreeable.”

“The guidelines are very much in line with what we expect,” Dolsten said on a conference call Wednesday. “FDA is setting high standards and have decided not to cut corners.”

He added that he thinks the guidance “favors experienced vaccine companies.”

Former acting FDA Chief Scientist Luciana Borio also thinks the guidance hit the right note.

“The guidance is everything I really would’ve hoped FDA would do at this juncture,” Borio told BioCentury. “Now let’s hope FDA adheres to their own guidance.”

She is VP of non-profit investment firm In-Q-Tel and a former director for medical and biodefense preparedness policy for the National Security Council.

The guidance

According to the guidance, vaccines must reduce cases by 50% compared with placebo. Additionally, the guidance emphasizes that there are currently no surrogate endpoints that are reasonably likely to predict clinical benefit of a COVID-19 vaccine.

“They really made it clear that a vaccine needs to prevent infection or disease, and that there’s not enough understanding of the immune response to SARS-CoV-2 to be able to prove efficacy based on immunogenicity,” Borio said.

FDA’s document states trials will likely need to enroll “many thousands” of volunteers to meet the thresholds. It lists laboratory-confirmed COVID-19 disease or infection, including asymptomatic infection, as an acceptable primary endpoint, and recommends virologically confirmed SARS-CoV-2 infection with at least one symptom as a primary or secondary endpoint.

The guidance also recommended that late-stage studies include interim analyses to assess the risk of vaccine-associated enhancement of respiratory disease, and stated that participants should be monitored for at least six months after vaccination for any serious adverse event.

FDA may also require postmarketing studies to assess known or potential serious risks.

The commitment to safety monitoring was a welcome inclusion in the guidance, said Borio, as well as FDA’s framework for including pregnant women and children in clinical trials.

The guidance lists master protocol studies as an acceptable trial design.

The only master protocol underway for vaccines is being run by the World Health Organization. SOLIDARITY will compare multiple candidates in parallel with placebo (see “WHO Outlines First Master Protocol for COVID-19 Vaccines”).

“The guidance talks about the importance of relying on meaningful endpoints for establishing vaccine efficacy, but it is not prescriptive to make sure every company is doing clinical testing in the same way,” Borio said. “I think that’s when Operation Warp Speed and NIH, who are playing a significant role in helping execute these trials, come into play.”

The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) consortium is working in parallel with the Trump administration’s Operation Warp Speed to launch five master protocol therapeutics studies and develop harmonized protocols for vaccines. The protocols aim to make it possible to analyze correlates of protection across trials. ACTIV is also investigating immune response criteria that could potentially be used to support emergency use or accelerated approvals of vaccines (see “ACTIV Coming into Focus”).

“The infrastructure that was established to be able to move these vaccines into the clinic at warp speed is going to be very critical in assuring there are commonalities between assays to validate immune response, and between endpoints so that you’re comparing apples to apples,” Borio said.

She also suggested a common data safety monitoring board across trials.

Vaccine trials

The guidance came a day before Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX) reported Phase I/II data for BNT162b1, the first of four COVID-19 vaccines they are testing in parallel.

The partners reported BNT162b1 induced neutralizing antibody titers that surpassed FDA’s recommended titer of 160 for convalescent plasma (see “BioNTech, Pfizer Vaccine Yields Highest Titers to Date”).

On a conference call to discuss the data, Dolsten and Kathrin Jansen, CSO and SVP of vaccine R&D, provided details on the pharma’s upcoming Phase III trial.

Pfizer plans to start enrolling this month up to 30,000 volunteers in a randomized, placebo controlled Phase III trial. Enrollment is only expected to take four weeks, Jansen said.

Dolsten, who is an ACTIV executive committee member, said he doesn’t anticipate issues with enrollment or readouts due to the rising number of cases in the U.S., and expects to have sufficient safety, immunogenicity and vaccine efficacy data to file for approval in October.

Borio said a 2020 authorization isn’t out of the question.

“There is a possibility before the end of the year that we’ll have some doses and some data to support an EUA,” she said.

Other companies planning late stage trials this summer include Moderna Inc. (NASDAQ:MRNA) and Inovio Pharmaceuticals Inc. (NASDAQ:INO).

The Phase III study of Moderna’s mRNA-1273, which is slated to start in July, will enroll 30,000 volunteers and have a primary endpoint of prevention of symptomatic COVID-19 disease. Secondary endpoints include prevention of severe COVID-19 disease and prevention of SARS-CoV-2 (see “Moderna COVID-19 Vaccine Phase III in NIH-managed Trial Network”).

Inovio plans to launch a Phase II/III study this summer of INO-4800, a DNA vaccine encoding the SARS-CoV-2 spike protein. The company reported Phase I data on Tuesday showing that 94% of trial participants showed “overall immune responses” at week six following two doses; it did not report neutralizing antibody titers or quantitative measures of T cell responses (see “Inovio Vaccine Data Highlight Questions About Antibody Versus T Cell Responses”).

Two of the vaccine front-runners have so far focused their clinical work outside the U.S. The University of Oxford has already begun enrolling volunteers in the U.K. for a Phase II/III trial of AZD1222, which it’s developing with AstraZeneca plc (LSE:AZN; NYSE:AZN). And CanSino Biologics Inc. (HKEX:6185) received “military specially-needed drug approval” in China for its Ad5-nCoV vaccine last month, making it the first vaccine to be authorized for use, albeit in a limited population.

Assistant Editor Sandi Wong contributed to this report.

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