The US FDA shows its teeth

With the advent of PDUFA V nearly four years ago the US regulator heralded a new era of unprecedented collaboration and transparency, and drug approvals rose. Biopharma applicants and investors alike would have been excused for thinking that happy days were here again, and the stage was set for the biotech bull market.

But after the agency's issuing of two refuse-to-file letters in the past seven days, for Catalyst Pharmaceuticals’ Firdapse and PTC Therapeutics’ Translarna, the message now seems to be that enough is enough (see tables below).

It could be that drug applicants had simply become too complacent in putting together data packages in an approval-friendly climate. But refuse-to-file (RTF) letters had become such a rarity after 2011 that for two to have been issued in the space of a week seems a remarkable coincidence.

The actual details of the FDA slapdowns are confidential, so we have to take Catalyst and PTC’s word for it that both were the result of incomplete dossiers. Still, it is noteworthy that these are two of only five major disclosed RTF letters to have been issued since PDUFA V took effect in October 2012.

Until that point RTF letters had been relatively common, and an analysis by Leerink suggested that their issuance rose between 1998 and 2011, with deficiencies in clinical data, chemistry manufacturing and controls, and the electronic file the most common reasons.

Those hoping that the past week’s developments are just a blip could argue that it is solely incompetence on the part of Catalyst and PTC that is to blame. But these letters have previously been issued to Pfizer, Novartis and Roche, companies who theoretically should know better.

Earlier RTF letters included those for Merck KGaA’s cladribine, Pharmacyclics’ Xcytrin and – most notoriously of all – Imclone Systems’ Erbitux in 2001, leading ultimately to the conviction and jailing of the group’s chief executive, Sam Waksal, for securities fraud.

The FDA lists several reasons for issuing a RTF letter, with materially incomplete or inadequately organised applications top of the list. Intriguingly, relying on a single trial if prior communication had “determined the need for more than one” is also given.

Profound absence

Cowen yesterday said that there was probably a profound absence of some type of required pivotal data in PTC’s Translarna package, pointing to the FDA’s emphasis on dystrophin production in its recent damning briefing documents for Sarepta’s eteplirsen; dystrophin is the only pivotal data type that PTC’s study did not produce.

PTC shares crashed 62% yesterday, and investors in other Duchenne stocks took the hint, sending Sarepta and BioMarin down 7% and 4% respectively.

The implication, of course, is that the US regulator is no pushover after all, even when it comes to debilitating, poorly treated diseases. While the PTC slapdown, eteplirsen briefing papers and Kyndrisa rejection level the Duchenne playing field, rivals can only bemoan their coincidence with the market downturn.

To contact the writers of this story email Jacob Plieth or Edwin Elmhirst in London at [email protected] or follow @JacobPlieth or @EPVantage on Twitter