Source : 'The Pink Sheet'
Rolling submissions of chemistry, manufacturing and controls information are playing a key role in accelerating regulatory reviews of COVID-19 vaccines and therapeutics to speeds never envisioned in the many acceleration initiatives of recent years.
A recent international regulatory panel discussion that pointed to several factors such as platform technologies and regulatory policies for pandemics that can play a role in safely rushing coronavirus vaccines to market returned frequently to the challenges and opportunities of rolling reviews.
CASSS, a non-profit group that organizes scientific biopharmaceutical development conferences, began planning the 13-15 October forum, “CMC Strategies and Phase-appropriate GMP Approaches for Expedited Program Development,” at a time when treatments involving highly efficacious new medicinal modalities were acing clinical trials so quickly that quality reviews were delaying approval. The question was what more could be done to accelerate these CMC reviews; the answers involved an array of rearranged and sped-up review processes. But the question of expedited review drew even more attention this year with the SARS-CoV-2 virus that caused the COVID-19 pandemic.
Sponsors of SARS-CoV-2 vaccine candidates have asked the the US Food and Drug Administration to use every tool the agency has developed to expedite their reviews.
But the agency has found another gear during the coronavirus pandemic, said Robin Levis of the Office of Vaccines Research and Review in the FDA’s Center for Biologics Evaluation and Research. “We’ve really been forced to expedite the expedited,” Levis, who is deputy director of the Division of Viral Products, told the conference, held virtually.
“Coronavirus vaccine sponsors request breakthrough [therapy designation] and they request fast track and all of the modalities we have to expedite reviews,” she said. “But at this point, the reality is we’re actually working faster and in a more expedited fashion than any of those modalities dictate.”
The question of just how regulatory authorities and sponsors found that higher gear is one that participants returned to in one fashion or another throughout the free-flowing discussions that are the hallmark of CASSS events. The follow-on question of how methods for accelerating reviews of COVID-19 therapeutics and vaccines could be applied post-pandemic to reviews and post-approval changes of other products bubbled up in a later industry panel discussion.
Levis shared some insight into the internal discussions behind the agency’s recent guidance on enhanced use authorization for COVID-19 vaccines.
“We’re really trying to wrap our head around … how we’re going to be able to use the EUA for vaccines,” she said, explaining that the problem is with the “may be beneficial” standard for authorizing emergency use. “That bar is not really appropriate for a vaccine that’s going to be given to essentially the entire population, most of whom are healthy.”
She called attention to two recent COVID-19 vaccine guidance documents, one for development and licensure and the other for emergency use authorization, that have resulted from “a lot of policy discussions about what it means to have an EUA for the SARS-CoV-2 vaccines.”
A key difference is that for emergency use, the agency is setting aside the question of long-term stability. ()
Canada does not have a process for authorizing emergency use like the US, but it has something else that is enabling it to expedite coronavirus vaccine approvals, said Jason Fernandes, a biologist evaluator working in Health Canada’s COVID-19 vaccines quality division.
Using an approach similar to the one it took in response to the 2009 H1N1 influenza pandemic, the Canadian government issued a pair of interim orders, one to allow greater flexibility to speed up COVID-19 clinical trials and the other to enable interim authorization of COVID-19 vaccines.
Fernandes focused his remarks on the authorization interim order, approved 16 September by the minister of health, Patricia Hajdu.
This interim order allows sponsors to apply for authorization earlier in the development process by submitting known quality, safety and effectiveness information along with a plan for providing the missing information. “The key here is it allows for rolling submissions,” Fernandes said, something that Health Canada does not allow for traditional new drug submissions.
The EU decides on market applications in 210 days for normal products, in 150 days for accelerated-review products like PRIME priority medicines – and even faster for rolling reviews of “ultra-accelerated” COVID-19 medicinal products, “where you’re able to submit data in portions during the assessment,” said Mats Welin, senior expert with Sweden’s Medical Products Agency.
The key with rolling reviews is taking a thoughtful approach to the sequencing of data. Good choices regarding which information to frontload into the review, which information to backload and which information to save for post-approval adjustments can make for a quicker, less stressful review process.
Welin put it in terms of how problematic it can be to backload the entire CMC review for an urgent approval: “You can imagine that if a lot of the information comes at a very late stage, the pressure on the quality assessor will be enormous, particularly if this looks good clinically and we would like to approve this and we have loads of documentation to assess.”
For this reason, he beseeched the industry audience to “try to frontload as much as possible, submit as much as possible documentation as soon as ever possible to help us … to make this procedure quicker.”
Upvoted questions submitted to the conference online platform showed that participants wanted greater clarity about the rolling review process, including requirements for initiating rolling reviews.
Welin said that, as EU authorities saw during the 2009 H1N1 influenza pandemic, the key is to do as much as possible as soon as possible. “It’s much easier said than done, I realize that.”
Welin encouraged companies to discuss their plans up front regarding what they can do and when. He noted that it helps for the rolling submissions to be “sufficiently conclusive and broad … that we don’t have to go back to everything that was handled two or three rounds earlier.”
Veronika Jekerle, who heads the European Medicines Agency’s pharmaceutical quality office, cautioned about trade-offs with early data submissions for rolling reviews in terms of possible supplements required during the review cycle and in terms of gaps that could impact assessment of other modules, slowing down the entire review.
The FDA’s Robin Levis said “a quite extensive dialogue” with sponsors must precede data submissions for rolling biologics license applications. She said the agency expects “a pretty complete list of what is going to be submitted when with respect to the rolling BLA, and what is going to be the critical piece of data at which the rolling stops and the official review time clock starts.”
In these discussions, the agency is looking for assurance that the up-front review work isn’t wasted. “There isn't any pre-specified amount of data that’s required to start your rolling BLA,” Levis explained, “other than clinical data that supports that this is a product that is actually going to go to licensure and a fairly robust product development status where you are going to be able to submit to the rolling BLA reviewable data that’s going to push your product towards licensure."
Susan Kirshner, a review chief in the Office of Biotechnology Products in the FDA’s Office of Pharmaceutical Quality, explained that with rolling BLAs, sponsors “get to submit modules separately rather than all at once like with a standard submission. However, the review clock does not start until all the modules are in and are substantively complete.”
So a sponsor could submit the CMC module several months ahead of the clinical module and the FDA could begin reviewing it well before the review clock starts, she said.
Levis noted that if pre-agreed, submissions can continue to roll in after the review clock has started. For example, the agency took this approach in its recent Ebola vaccine review. However, for such an approach to work, she said, “it really has to be a fine-tuned set of conversations with very well-defined pivot points on what data is going to be available when.” And it must be decided prior to BLA submission.
Kirshner noted though that it would be very high risk in an expedited rolling review to plan on delivering process performance qualification batch results after the review clock already has started ticking.
Mikhail Ovanesov, a reviewer in CBER’s Office of Tissues and Advanced Therapies, stressed the importance of completeness, something the FDA discusses with sponsors when deciding on the rolling BLA approach.
When the sponsor submits a section of the BLA early, “FDA will start review of the section under the assumption that no further changes to the section will arrive later on,” he said.
Certain exceptions can be pre-arranged, he noted. For example, a method could be submitted with the understanding that it will not be validated until later.
However, he said, the review clock will not begin until the BLA submission is complete, which means there must not be any significant gaps that haven’t been discussed with agency.
By Bowman Cox