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Regulators discuss accelerated approvals, Project Orbis at DIA

Posted 16 June 2020 | By Michael Mezher 

Regulators discuss accelerated approvals, Project Orbis at DIA

Regulators from the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and Health Canada gave their perspectives on different issues related to accelerated approval pathways in their respective jurisdictions at the DIA Global Annual Meeting.
All three regulators offer their own form of accelerated approval based on less comprehensive clinical data than a traditional marketing approval would require. In the US, that pathway is dubbed accelerated approval (AA), while the EU version is called conditional marketing authorization (CMA) and in Canada it is referred to as notice of compliance with conditions (NOC/c).
In each case, products approved via these pathways are required to comply with certain postmarketing requirements to maintain approval, such as conducting confirmatory studies to demonstrate benefit.
Julie Lepin, vice president, regulatory affairs, oncology at Amgen, who moderated the session, pointed out that in 2019, the number of new drugs approved based on surrogate endpoints was similar across the three regions, with eight approvals in the US, seven in the EU and six in Canada.
When asked about the ability of regulators to withdraw approval after granting accelerated approval, the three regulators explained their respective approach to withdrawing a product from the market.
Kelly Robinson, director of Health Canada’s Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics, said there are mechanisms for the agency to withdraw a product if efficacy is not demonstrated following a NOC/c.
“We would start a conversation with the sponsor and talk to them about their plans for the product and whether they would be voluntarily withdrawing their product from the market,” she said. If the company did not comply, Health Canada could re-evaluate “the benefit-risk based on the newly available information and could then ultimately withdraw the indication should that not be demonstrated.”
Falk Ehmann, who heads EMA’s Innovation Task Force, concurred, saying that “no product should be on the market … which doesn’t demonstrate a positive benefit-risk, and this applies for full approval as well for any kind of approval. The benefit has to positive.”
He added that EMA has other options before withdrawing a product from the market: “Maybe we have to prolong the conditional approval, or we have new conditions, maybe we have to modify the conditions.”
Falk also noted that in some cases, EMA might encourage an applicant seeking full authorization for a product to instead aim for conditional approval. “Why don’t we modify it and attach certain conditions … and as such you get a conditional approval now and get a full approval later on,” he said.
Patricia Keegan, associate director for medical policy at FDA’s Oncology Center for Excellence, said that FDA also has the ability to withdraw products granted accelerated approval from the market, but will typically have a conversation with the sponsor first, “To talk about the results of the studies that failed to show benefit … and whether or not a differently designed trial or a different set of evidence might be sufficient to verify benefit.”
“We will look at that totality of evidence to decide if it’s really necessary to remove the drug,” Keegan added.
On the use of accelerated pathways for drugs outside oncology, Keegan pointed out that one of the reasons oncology products have been successful in obtaining accelerated approval is because scientists have a “much clearer understanding of disease pathogenesis,” for cancers.
Keegan also noted that one of the reasons some products in and outside the oncology space have not gotten accelerated approval is because, “We’ve actually validated the surrogate [endpoints], so that they may result in traditional approval.”
Falk agreed, adding that there is more uncertainty around surrogate endpoints in other clinical areas.
Project Orbis
The regulators also discussed FDA’s recent collaborative review effort for oncology products that includes Australia’s Therapeutic Goods Administration (TGA), Health Canada, Singapore’s Health Sciences Authority (HSA) and Swissmedic.
When asked how products are identified for participation in Project Orbis, Keegan said, “We don’t have a formalized process, typically the review team will, in their discussions before the application comes in, ask about the timing of submission of an application to other agencies … and invite the sponsor to consider participation in Orbis, but there’s no reason that the sponsor couldn’t bring it up as well.”
Kegan said that the timing of submissions internationally is “a major issue,” as companies often target a handful of jurisdictions, such as the US and EU, for their initial submissions.
On Health Canada’s participation in Project Orbis, Robinson said, “it’s an opportunity … for new indications or new products to come to Canada sooner than they otherwise would,” adding that the initiative also gives reviewers from the different agencies more opportunities to interact.
Falk, when asked whether EMA would ever participate in Project Orbis, said he couldn’t comment, but emphasized that EMA has bilateral discussions with FDA related to ongoing submissions, “maybe on a daily basis.”


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