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FDA Refuse to File: Merck Zetia & Pfizer Lipitor

Merck disclosed that FDA refused to file its 505(b)(2) NDA for the combination of Pfizer’s Lipitor (atorvastatin) with Zetia (ezetimibe).  According to Merck’s disclosure, the FDA reason for he refusal is:

The FDA has identified additional manufacturing and stability data that are needed and the Company is assessing the FDA’s response in order to determine a new timetable for filing.”

What is a refuse to file?  The FDA reviews all NDA applications and determines if ” the application is sufficiently complete to permit a substantive review.”( CRF 314.101).  Merck said that FDA didn’t find certain manufacturing and stability data sufficient for review.

I don’t know what manufacturing information is lacking here.  On the stability side though we’ve been seeing a sea change the past two years.  The NDA requirement for stability data is 6 months at accelerated temperature and high humidity (so-called AST) and 12 months at room temperature.  The data has to be presented for 3 representative batches and in the commercial packages.  The FDA often bended this rule, particularly for 505(b)(1)’s, allowing stability data to be accumulated during the review.  But starting about 18 months ago, we asked in a pre-IND submission to FDA if we could file using 6 months AST and 6 months RT.  I reported the results of this correspondence at the 2008 Drug Repositioning Summit:


Note that FDA said it would not be a filing issue.  However, we believe that it becoming one.  FDA resources being scarce, it may be tightening down – making the stability data  a requirement.

Merck doesn’t usually do 505(b)(2) submissions, so maybe they just used the 505(b)(1) “rules’ and got caught.  In any case, it would appear that they can just follow the directions FDA gave them and resubmit.  There is no prejudice for a re-submission.