Celgene’s Setback and Historical Perspective on Refuse to File Letters

Regulatory NewsRegulatory News | 28 February 2018 |  By 

Celgene late Tuesday announced a setback for one of its most promising investigational medicines when it received a refuse to file (RTF) letter from the US Food and Drug Administration (FDA), setting off a flurry of questions for the company that may not be answered publicly.

According to Celgene’s press release on receiving the letter, the company said: “Upon its preliminary review, the FDA determined that the nonclinical and clinical pharmacology sections in the NDA [new drug application] were insufficient to permit a complete review. Celgene intends to seek immediate guidance, including requesting a Type A meeting with the FDA, to ascertain what additional information will be required to resubmit the NDA.”


In December 2017, FDA released new draft guidance on RTF letters, explaining that the agency exercises such an authority “for incomplete applications to optimize the use of both the applicant’s and the FDA’s resources. RTF actions allow the FDA to notify applicants of application deficiencies as soon as possible, rather than waiting until the end of a review cycle and notifying the applicant in a complete response letter.”

RTF letters are issued not because the data in the NDA is inadequate for an approval, but, as FDA explains, because of “omissions of clearly necessary information (e.g., information required under the statute or regulations) or omissions or inadequacies so severe as to render the application incomplete on its face and where the omissions or inadequacies are obvious, at least once identified, and not a matter of interpretation or judgment about the meaning of data submitted.”

And when Celgene says it has requested a Type A meeting, such meetings are reserved only for a stalled product development program to proceed or to address an important safety issue, and must be requested within 30 days of receiving the RTF letter, according to FDA guidance on such meetings.

Celgene vs. History

Jay Backstrom, chief medical officer and head of global regulatory affairs for Celgene, said in a statement: “We remain confident in ozanimod’s clinical profile demonstrated in the pivotal program in relapsing forms of multiple sclerosis.”

And if history is Celgene’s guide, Backstrom is right to remain confident as RTF letters can be a minor setback ahead of FDA approval.

A Focus review of other companies receiving RTF letters shows that more recently, companies have struggled to win quick approvals though many companies have received RTF letters and still gone on to win approval for their products.
Company Drug Type of Application RTF Announced Date Outcome
Allergan Vraylar (cariprazine) sNDA 22 September 2017 Meeting scheduled with FDA
Acorda Therapeutics Inbrija (levodopa inhalation powder) NDA 29 August 2017 FDA accepted NDA for filing on 20 February, PDUFA date set for 5 October 2018
SteadyMed Treyvant NDA 31 August 2017 Company has received final minutes from FDA on work necessary to resubmit NDA
Innocoll Xaracoll (bupivacaine HCl collagen-matrix implants) NDA 29 December 2016 Planned to resubmit NDA by end of 2017.
PTC Therapeutics Translarna (ataluren) NDA 23 February 2016 Company received a CRL on 25 October 2017.
Catalyst Pharmaceuticals Firdapse (amifampridine phosphate) NDA 17 February 2016 Company says 12 February that it plans to resubmit NDA in Q1 of 2018.
Gilead Sciences Truvada NDA 25 January 2011 Approved on 16 July 2012
Genentech (acquired by Roche) Kadcyla (ado-trastuzumab emtansine) BLA 27 August 2010 Approved 22 February 2013
ImClone Systems (acquired by Eli Lilly) Erbitux (cetuximab) BLA 28 December 2001 First won approval by FDA on 12 February 2004 and went on to gain other subsequent approvals.
Pfizer Pradaxa NDA 12 February 2010 Approved 19 October 2010


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