FDA Center for Drug Evaluation and Research Director Janet Woodcock was consulted about a manufacturing issue in the final days of FDA’s review of Novartis AG’s Zykadia (ceritinib) as the agency struggled to meet its expedited action goal for the “breakthrough” therapy-designated lung cancer drug.

FDA’s Office of Compliance “had cGMP concerns” with a manufacturer involved in the production of the ceritinib active pharmaceutical ingredient that “were discussed with senior management in [the review division] and the CDER center director on April 9, 2014,” Zykadia review team leader Gideon Blumenthal reported. “A final decision on the impact of these concerns on the timing of NDA action is pending at this time,” his April 11 memo states.

The inclusion of the CDER director in discussion of what appears to have been a late-breaking issue indicates that the review team went straight to the proverbial top in an attempt to resolve quickly an issue that could have delayed the expedited approval of ceritinib. The potential for manufacturing to be a roadblock to FDA’s efforts to speed review of breakthrough drugs has been a persistent concern for stakeholders Also see "“Breakthrough Therapy” Development Speed May Be Tempered By Manufacturing Hurdles" - Pink Sheet, 26 November, 2012..

The minutes of a series of teleconferences starting on April 2, although heavily redacted, suggest that a new issue with manufacturing had just arisen overseas. An import alert is referenced, and minutes of the FDA wrap-up meeting April 8 refer to “a potential compliance issue with a foreign site.”

Another clue is provided by an April 11 email mentioning that on April 4 Novartis had provided FDA with inspection information identifying a “major” concern with “cross contamination of [redacted] manufactured in the same facility.”

The new manufacturing concerns appear about two weeks before FDA’s internal action goal date of April 17, 2014 for the Zykadia NDA. The priority review application carried an official Aug. 24 PDUFA goal date, but the oncology division often sets more ambitious targets for promising agents for unmet medical needs.

Zykadia was approved on April 29, indicating that FDA and Novartis came to terms with the issue in less than a month. A final review team meeting the day of approval suggests how quickly the agency was moving to digest and address the manufacturing findings. “FDA received a copy of the form FDA 483 issued to the site this morning,” according to the April 29 minutes. “Office of Compliance representatives had a conversation with the inspection team to understand and assess the significance” of the findings, and “deemed the facility acceptable in terms of manufacture of the API.”

Manufacturing compliance issues, including an impending import alert regarding an API manufacturer, also complicated FDA’s review of Gilead’s hepatitis C drug Sovaldi (sofosbuvir) Also see "Sovaldi NDA Review Marred By Manufacturing Compliance Issues" - Pink Sheet, 22 April, 2014..

FDA has emphasized the challenges that expedited approval programs like the breakthrough designation will pose for manufacturing Also see "Breakthroughs for Patients, CMC Regulatory Flexibility" - Pink Sheet, 30 January, 2014.. But the swift resolution of compliance issues with both Sovaldi and Zykadia suggest that FDA is successfully extending the regulatory flexibility it has shown about clinical data for potential medical advances to the manufacturing arena.

[Editor’s note: This article is one of a package of stories in Pharmaceutical Approvals Monthly’s latest drug review profile, a series that looks behind the scenes at issues affecting approval of key drugs. Other stories in the recent Zykadia coverage include ([A#06140601011]) and ([A#06140601013]).]

Zykadia Expedited Timeline Challenged By Late-Breaking GMP Concern

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