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Pink Sheet – What Goes Up … US FDA Expects 2016 NME Approval Total To Come Down

Pink Sheet – What Goes Up … US FDA Expects 2016 NME Approval Total To Come Down

Executive Summary

After a record-setting 2015 for new drug approvals, there were not enough applications with user fee goals in 2016 to reach that level again.


FDA’s approval metrics could not remain at record levels forever, and it now appears the regression toward the mean has begun.


Office of New Drugs Director John Jenkins said approvals in 2016 are down from last year, in part because the agency has received fewer NDAs.


Jenkins also said that first-cycle approval rates for standard new molecular entity (NME) applications have slipped.


“We’ve seen a fallback to a more usual level of first-cycle approval rates for standard NMEs,” he said Nov. 4 during the BioPharma Congress, sponsored by Prevision Policy and the Friends of Cancer Research. “When you combine fewer NMEs to take action on with the fall-off in the first-cycle approval rate, you get smaller numbers.”


So far this year, the agency has approved 19 NMEs, which is well short of the pace that was seen last year. The Center for Drug Evaluation and Research approved 45 novel agents in 2015, which was a 19-year high. (Also see “User Fee Extensions Are Key To CDER’s First Cycle Review Success” – Pink Sheet, 18 Jan, 2016.)


FDA saw the number of NDAs and BLAs it received increase during the last several years. (Also see “Surge In Applications Triggers User Fee Inflation” – Pink Sheet, 10 Aug, 2015.)


Jenkins reiterated that the drop-off was not because FDA’s approval standards changed, but rather that there are simply fewer applications overall for FDA to consider. He said in 2015, the agency reached all-time highs in the number of NMEs under review at any given time. This year, that figure has dipped.


“Earlier this year, it dipped down below that trend line so that we had fewer applications under review,” he said.


Indeed, the Pink Sheet had projected at midyear that the 2016 approval total would be lower than 2015. FDA equaled its total for the first half of 2015 this year, but based on the number of applications with user fee goals in the second half of the year, there were not enough for FDA to repeat its record performance.


After CDER posted 14 approvals in the first six months of 2016, there remained only 20 novel agents under review with goals between July and December. (Also see “FDA New Drug Approval Count May Fall Back To Earth In 2016” – Pink Sheet, 18 Jul, 2016.)


But while this year may not approach a record, Jenkins said toward the end of the year the number of NMEs under review returned to the trend line again. He said that, along with the number of expedited reviews, could bode well for next year.

Quality, Not Efficacy, Primary Source Of Complete Responses

Facility and quality issues appeared to be the primary reason for the lower first-cycle approval rate.


The most prominent deficiencies reported in complete response letters have been good manufacturing practice (GMP) issues.


Jenkins said only a few complete response letters were issued because of a failure to show efficacy. Many of the major deficiencies related to GMP problems, in part because they are “often very hard to address when it’s identified during a review cycle,” even the longer one that the agency now operates under.


FDA put NMEs on a longer review timeline as part of the 2012 prescription drug user fee reauthorization. It allowed for mid-cycle communications and late-cycle meetings where sponsors and FDA could discuss problems with an application and potentially fix them.


The ‘Program’ was intended to push the first-cycle approval rate higher, although some in FDA questioned how much more it could improve. (Also see “First-Cycle Approval Rate Already High; Can PDUFA V Actually Boost It?” – Pink Sheet, 6 May, 2013.)


The Program has been so successful that biosimilar applications will begin using the model when the reauthorized biosimilar user fee program launches in October 2017. (Also see “Biosimilars Reviews Could Be Extended Two Months In BsUFA II” – Pink Sheet, 22 Apr, 2016.)

Breakthrough Not The Cause

Jenkins would not pin the decrease in first-cycle approval rate on breakthrough therapies, one of the most popular programs in PDUFA V.


Breakthrough allows sponsors of drugs judged by FDA to be potential transformative therapies to receive increased involvement from agency staff in the hopes of getting the product to market faster – a program that has excited both industry and FDA, and has also placed considerable strain on the agency’s resources.


But Jenkins said the increased workload and decreased time to resolve issues is not the reason for FDA issuing more complete responses. The applications that failed to get first-cycle approval did not exhibit “deficiencies that if we had more manpower, you could have resolved those.”


“They look more like substantial deficiencies that are either going to require new studies or remediation of major cGMP deficiencies at manufacturing facilities and may require a new inspection that shows they’ve been remediated,” he said. “I don’t see deficiencies in the letters that suggest that it’s just a lack of effort on our part; it’s more the applications didn’t meet the standards.”


FDA has received 469 breakthrough designation requests since the program launched in 2012 and granted 160. Both figures are much higher than expected. (Also see “‘Breakthrough Therapy’ Designations” – Pink Sheet, 22 Feb, 2016.) To help FDA resolve the workload problem associated with breakthrough, industry and the agency agreed to allocate user fee dollars to hire more review staff. (Also see “FDA’s Breakthrough Workload Will Be Eased By Hiring Reviewers With PDUFA VI Funds” – Pink Sheet, 20 Jul, 2016.)–US-FDA-Expects-…