DIA/FDA Forum: CBER's pandemic journey continues

Regulatory NewsRegulatory News | 14 April 2021 |  By 

Crushing workloads and statistical conundrums characterized the work of FDA’s staff as they raced to formulate guidelines and then evaluate vaccine candidates amid the pressure of the pandemic, attendees at a biostatistics conference heard on Wednesday.
More complex analysis awaits as real-world vaccine data roll in and FDA’s Center for Biologics Evaluation and Research (CBER) and sponsors both work toward full biologic license applications (BLAs) for the vaccines that currently have or will receive emergency use authorizations (EUAs), said Tsai-Lien Lin, PhD, speaking at the joint DIA-FDA Biostatistics Industry and Regulator Forum.
Lin, a lead mathematical statistician for CBER’s Vaccine Evaluation Branch, mapped out the agency’s journey, highlighting the sheer volume of information exchange that had to happen for EUAs to be issued, and that is ongoing as more data roll in.
For example, Lin said, Pfizer’s first conversation with FDA about vaccines for COVID-19 began a little more than a year ago. In that interval, CBER has received more than 400 submissions from Pfizer – more than one per day, she said, adding, “All those have to be responded to very quickly.”
Many considerations factored into the regulatory framework for vaccines, including the variety of vaccine platforms for the candidates, route of administration, and dosing regimens.
The ordinary vaccine development process takes years, or even decades, to move from preclinical and Phase 1 trials to licensure, noted Lin. The first COVID-19 Phase 1 vaccine trials began in March 2020, with FDA’s issuing early guidance on development and licensure considerations in June 2020 and a full EUA guidance document in late October 2020. From that point in time, it was just about 6 weeks until FDA issued an EUA for the Pfizer-BioNTech COVID-19 vaccine on 11 December 2020.
Despite the high bar, there were still some knowledge gaps that CBER staff had to work with, said Lin. Scientific understanding of the disease course of COVID-19, characteristics of SARS-CoV-2 – the virus that causes the disease, and even the novel mRNA vaccine platform were all evolving.
The need for “extremely quick turnaround” was indisputable, said Lin, but global regulators also wanted to move through the process in a fashion that allowed harmonization. All of this was set against a backdrop of great uncertainty about the trajectory of the pandemic – and then, the variants appeared.
Even so, FDA’s early focus on key quality and manufacturing considerations, together with guidance on endpoints for clinical trials, allowed sponsors to move with alacrity through the development process.
As FDA prepared to issue the guidance on requirements for issuance of an EUA for COVID-19 vaccines, sponsors were seeing that the surge in cases associated with the second, and then the third, surge of the pandemic meant that trials for the front-runner candidates were quickly accumulating the number of cases that had been pre-specified for interim analysis of efficacy, said Lin.
The early focus on endpoints of protection against clinical, rather than asymptomatic, disease, was necessary given the limited assays that were available in the early stages of these trials. Now, some ongoing trials are better able to capture all SARS-CoV-2 infections, yielding important data about vaccines’ effectiveness against disease transmission.
Further, said Lin, work is being done to identify a robust surrogate endpoint, such as immune response, that may be used in future accelerated approval or extension of indications for vaccines. The agency is also considering whether a “burden of disease” endpoint could be used in some cases. This composite endpoint would capture both the presence of disease and disease severity. On the plus side, this endpoint would be “more informative,” and yield greater statistical power, she said. On the other hand, it cannot be expressed as an exact percentage reduction in risk, and its clinical meaning would not be immediately clear.
Statistical issues faced by CBER staff included the higher bar for these vaccine EUAs, which required “the same standard for efficacy and safety as for a vaccine BLA,” up to the time of the data cutoff for the EUA application, said Lin. Still, some information was necessarily missing from the EUA submissions, including long-term efficacy and safety data, some chemistry, manufacturing and controls (CMC) data and most clinical assay validations, except for diagnostic assays.
“Challenging statistical issues are emerging as the pandemic evolves rapidly,” said Lin. “While the acute crisis may be over in the near future, there are still challenges ahead.”



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Tags: BLA, CBER, coronavirus, EUA, FDA, US

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