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Regulation

FDA panel for mRNA-1273 highlights challenges ahead for COVID vaccine trial recruitment, retention

Dec 18, 2020 | 3:24 AM GMT

The discussion at Thursday’s FDA advisory committee meeting on a COVID-19 vaccine from Moderna and NIH highlighted the increasing difficulties of conducting trials as more vaccines become authorized and widely available. 

Out of the committee’s 21 voting members, 20 voted that the benefits of mRNA-1273 from Moderna Inc. (NASDAQ:MRNA) outweigh its risks for use in individuals 18 years of age and older.

If last week’s meeting on BNT162b2 from Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX) is any indication, Moderna’s vaccine should be expected to sail through emergency use authorization (EUA) by Friday.

Michael Kurilla, director of the division of clinical innovation at NIH’s National Center for Advancing Translational Sciences, abstained. “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. I’m not convinced that for all of those age groups that the benefits do actually outweigh the risks,” said Kurilla.

He said he would prefer an expanded access program rather than an emergency use authorization (EUA) to preserve data collection since 25% of trial participants in Moderna’s Phase III COVE study are healthcare workers, and therefore may leave the study to receive an authorized vaccine.

Lindsey Baden, associate professor of medicine at Harvard Medical School and co-investigator of Moderna’s pivotal study, substantiated the concern.

“We are currently, since the EUA authorized last week, having substantial dropout from study participation, given the increasing availability of vaccines,” he said. 

Unblinding bind

In a conversation with BioCentury last month, Moderna CMO Tal Zaks made clear that it is a question of when, not if, Moderna will unblind the COVE trial and offer the vaccine to participants who received placebo, which would interfere with long-term data collection.

Stanford University’s Steven Goodman, who attended the meeting as an independent guest speaker, suggested a blinded crossover trial with a “deferred vaccination” arm, as described in a medRxiv article published on Monday. Under this study design, participants would cross over blindly from the placebo arm to the vaccine arm and vice versa, and the crossover could occur whenever an individual becomes eligible for an available vaccine outside the trial.  Goodman is professor of epidemiology and population health and medicine at Stanford University

Although the panelists generally supported the crossover trial design, most acknowledged that the logistics are not feasible for Moderna’s trial at this point. They supported an open-label trial going forward.

Some panelists said Moderna should modify its plan to match Pfizer and BioNTech’s, in which participants will remain blinded until they become eligible for an available vaccine. 

Whether or not Moderna and other sponsors unblind their Phase III trials, authorization and approval of the first cohort of COVID-19 vaccines could make it difficult or impossible to conduct placebo-controlled trials of a second wave of vaccines. 

Identifying correlates of protection could make large-scale, placebo-controlled trials unnecessary, but those data are still emerging. 

Jacqueline Miller, SVP, therapeutic area head, infectious diseases at Moderna, said that binding and neutralizing antibodies, but not T cell immunity, will be evaluated in the ongoing Phase III study.

Follow-up trials

The panelists suggested multiple possibilities for follow-up studies, such as testing two doses versus one — mRNA-1273 showed signs of efficacy after a single dose — or testing different vaccine concentrations, as the safety data so far show fewer adverse reactions in older populations.

Panelist Mark Sawyer had a further idea.

“One of the things we eventually need to learn is what happens if you get one dose of the Pfizer vaccine and then a second dose of the Moderna, or vice versa,” said panelist Mark Sawyer, professor of clinical pediatrics at the University of California San Diego.

Separately, EMA has moved up its CHMP meeting to assess mRNA-1273 from Jan. 12 to Jan. 6 after Moderna submitted its data package ahead of schedule. 

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