Source : 'The Pink Sheet'
The US Food and Drug Administration wants COVID-19 vaccine developers to have plans for ensuring their clinical trials will continue after an emergency use authorization is granted and that product safety is actively followed in individuals vaccinated under an EUA.
A vaccine EUA request should include strategies that will be implemented to ensure ongoing trials are able to assess long-term safety and efficacy in sufficient numbers of subjects after authorization to ultimately support licensure. This includes evaluating for vaccine-associated enhanced respiratory disease, as well as decreased effectiveness as immunity wanes over time, the agency says in its finally-released guidance on COVID-19 vaccine EUAs.
In addition, these strategies should address how ongoing trials will handle loss of follow-up information for subjects who withdraw from study to receive the vaccine under an EUA.
"FDA does not consider availability of a COVID-19 vaccine under EUA, in and of itself, as grounds for stopping blinded follow-up in an ongoing clinical trial," the agency said.
The agency doesn't say exactly what sponsors should do, perhaps in part because it is still considering what the best procedures should be. ("After First COVID19 Vaccine Approval How Will Other Trials Maintain Placebo Control" "Pink Sheet" )
Sponsors also should include in their EUA request a plan for active follow-up for safety – including deaths, hospitalizations and other clinically significant adverse events – among individuals given the vaccine under EUA to inform ongoing benefit-risk determinations to support the continued authorization.
These are among the recommendations the FDA has been providing to individual sponsors in response to questions regarding EUAs for COVID-19 vaccines. (See box for more stories on the political and practical elements of the EUA guidance.)
The guidance is substantively similar to the summary of advice document although more comprehensive, with additional details about regulatory information that should be submitted with an EUA request and the actions sponsors need to take to prepare for expedited advisory committee meetings of those requests. It details the types of information the FDA expects to be included in any vaccine EUA request with regard to safety, effectiveness, and chemistry, manufacturing and controls information.
The advice strikes a balance between the lower evidentiary burdens and speedier path to market under an EUA with the agency’s desire to ensure that any authorized vaccine is sufficiently safe and effective such that it ultimately would be expected to receive full licensure
“It is FDA’s expectation that, following submission of an EUA request and issuance of an EUA, a sponsor would continue to collect placebo-controlled data in any ongoing trials for as long as feasible and would also work towards submission of a Biologics License Application (BLA) as soon as possible,” the guidance states.
An EUA request could be supported by an interim analysis of a clinical endpoint from a Phase III study, although the results would have to meet the 50% minimum efficacy threshold laid out in the FDA’s June guidance on COVID-19 vaccine development. ("COVID19 Vaccine Should Demonstrate At Least 50 Effectiveness US FDA Says" "Pink Sheet" ) However, additional safety and effectiveness data also would be needed to support an EUA.
“The timing of interim analyses planned for a Phase III study would thus ideally be aligned with the ability of the analyses to meet these criteria,” the guidance states.
The agency “strongly encourages” a vaccine sponsor to provide notice within 24 hours after any interim analysis has been completed to discuss proposed timelines for EUA submission.
An EUA request should include all safety data accumulated from Phase I and II studies conducted with the vaccine, with a focus on serious adverse events, adverse events of special interest and cases of severe COVID-19 disease among study subjects.
“We recognize that the Phase I and II safety data likely will be of a longer duration than the available safety data from the Phase III trial at the time of submission of an EUA request,” the guidance states. “The Phase I and II data are intended to complement the available data from safety follow-up from ongoing Phase III studies.
As expected, the agency wants to see Phase III study results that include a median follow-up duration of at least two months after completion of the full vaccination regimen. ("US FDA Expects COVID19 Vaccines To Meet EUA Plus Standards Marks Says" "Pink Sheet" ) However, CBER’s Marks has said there is some flexibility around this recommendation. (See sidebar)
This length of follow up will help provide adequate information to assess a vaccine’s benefit-risk profile, including adverse events, cases of severe COVID-19 disease among study subjects, “and cases of COVID-19 occurring during the timeframe when adaptive (rather than innate) and memory immune responses to the vaccine would be responsible for a protective effect,” the guidance states.
This two-month safety window is based on the FDA’s adverse event experience with other types of vaccines. ("US FDAs Two-Month Safety Window For COVID Vaccines Based On Adverse Events In Other Products" "Pink Sheet" )
The EUA request should include Phase III data on local and systemic solicited adverse reactions collected for the protocol-defined duration of follow-up in an adequate number of subjects to characterize reactogenicity in each age cohort participating in the trial.
The agency also expects to see all safety data collected up to the point at which the database is locked to prepare the EUA request submission. This would include a high proportion of enrolled subjects – “numbering well over 3,000 vaccine recipients” – followed for serious adverse events and adverse events of special interest for at least one month after completion of the full vaccination regimen.
The guidance notes that prelicensure safety databases for preventive vaccines for infectious disease typically consist of at least 3,000 study participants vaccinated with the dosing regimen intended for licensure.
“FDA anticipates that adequately powered efficacy trials for COVID-19 vaccines will be of sufficient size to provide an acceptable safety database for each of younger adult and elderly populations, provided that no significant safety concerns arise during clinical development that would warrant further evaluation,” the guidance states.
In addition, the agency requests data on “sufficient cases of severe COVID-19 disease” among study subjects to support a low risk for vaccine-induced enhanced respiratory disease.
A total of five or more severe COVID-19 cases in the placebo group would generally be sufficient to assess whether the severe disease case split between the vaccine and placebo groups supports a favorable benefit-risk profile or conversely raises a concern about enhanced respiratory disease, the agency said.
In addition, the FDA wants to see subgroup analyses of safety and efficacy endpoints stratified by prior infection status at study entry as determined by prevaccination serology or medical history. This will be important data “because screening for prior infection is unlikely to occur prior to administration of COVID-19 vaccines under EUA.”
By Sue Sutter