FDA Issues Wave Of "Breakthrough Therapy" Denials
This article was originally published in RPM Report
Executive Summary
FDA denied 10 requests for breakthrough therapy within a four-week period. The reasons behind the wave of rejections are unclear, but may be inherent to the rollout of the program.
As the first anniversary of “breakthrough” therapy approaches, the Food & Drug Administration delivered a string of rejections to drug sponsors seeking the popular designation.
Within four-week period (July 26-August 23), FDA’s Center for Drug Evaluation & Research denied 10 breakthrough requests and granted no new requests. As of August 23, of the 82 requests for breakthrough status, CDER denied 32 and granted 25. The Center for Biologics Evaluation & Research, meanwhile, denied one request in August, keeping its record perfect: As of Aug. 31 it had rejected eight of ten requests, with two still pending.
CDER’s denial streak ended in early September, when the agency granted a 26th breakthrough designation (and rejected two more requests).
The sudden increase in breakthrough denials means that CDER is now, on average, granting less than one-third of requests from drug sponsors for the designation. That is a marked decline from earlier in the program, when the center was granting requests in about half of all cases.
There are likely multiple reasons for the recent wave of denials.
FDA officials have described a “know it when you see it” mentality in assessing potential breakthroughs. The agency has 60 days to consider a request, and the early designations may have come quickly because officials had an easier time recognizing those drugs as true breakthroughs. The recent denials may be for products with a less obvious profile, and FDA simply took more time to reach a final decision.
Also, the early breakthrough requests tended to be for later-stage products, which may have been easier for FDA to designate as breakthrough – especially if officials were familiar with the application and, perhaps in some cases, encouraged sponsors to apply. But as that “catch-up” phase subsides, FDA will start seeing requests for products earlier in development, where the data may not be as clear-cut.
Finally, larger pharmaceutical companies have been out in front on requesting breakthrough status, and given their experience at FDA, may be more successful at the agency in receiving a designation.
Overall, FDA is still granting far more breakthrough requests than expected when the designation was first conceived: the agency initially expected to designate just a handful of breakthroughs each year – not the 26 that have been granted since the program started nearly one year ago.
And there are other signs that the program is moving along: the first breakthrough NDA is now officially under review at FDA.
On August 29, Pharmacyclics Inc. announced that FDA had accepted for filing ibrutinib for two B-cell malignancy indications: previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia /small lymphocytic lymphoma. Pharmacyclics is developing ibrutinib in partnership with Johnson & Johnson.
The indications also received priority review, which would put the user fee deadline toward the end of January. However, given the intense “all hands on deck” mentality for breakthrough products like ibrutinib, a review decision could come much earlier.