On Sunday, Endo Pharmaceuticals (NYSE:ENDP) announced that the FDA had issued a "not approvable" letter in response to the company's attempt to expand the label for migraine treatment Frova.  

Endo markets Frova in the U.S. on behalf of developer Vernalis. The drug is already approved to treat acute migraine headaches. Since its approval in 2002 and marketing by Endo in 2004, sales have been relatively weak.

In the first half of 2007, Frova sales grew 25% year over year to $25 million, hampered in part by plenty of generic competition in the triptan class of drugs that Frova belongs to.

In an attempt to differentiate Frova from other triptans, Endo and Vernalis experimented with using the drug to preventing menstrual migraines. In both of two phase 3 efficacy and safety studies, they were successful on the primary endpoints.

Based on these studies, Endo filed a supplemental New Drug Application (sNDA) to expand Frova's use into this indication in July of last year. In March, the FDA pushed back the Frova PDUFA date by three months. Then in August, the agency pushed it back again, to get a more thorough look at the data Endo and Vernalis presented in their sNDA.

The not-approvable letter the FDA issued this weekend was due to concerns about the meaningfulness of the primary endpoint -- migraine-free menstrual periods -- that was used in the phase 3 trials, and also safety concerns about Frova's long-term use.

It's relatively rare for pharmas to receive not-approvable letters on their drugs, because they usually have some idea of whether they've satisfied the FDA requirements for drug approval, via numerous meetings with the agency before and during the clinical trial process.

Whether it was a miscommunication about the relevance of the primary endpoints in the phase 3 trials, FDA shifting of the approval goalposts, or drugmaker stubbornness in not listening to concerns about its trial design, only Endo and the FDA are privy to what happened.

Partly in anticipation of getting the menstrual migraine prophylaxis indication for Frova, Endo expanded its sales force earlier in the year. Now that this label expansion is off the table and it won't be able to market Frova against GlaxoSmithKline's (NYSE:GSK) Imitrex, Endo may cut some of the additional reps that it hired. No financial guidance was given following the not approvable announcement, but expect to hear something about cost cutting by the time Endo releases its third-quarter financial results.

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