Yes+Yes=No? Forest's Daxas and the Pull of Comparative Studies

That wacky Pulmonary-Allergy Drugs Advisory Committee is at it again!

Last month, we noted the remarkable outcome of the review of Intermune’s pirfenidone, where the vote in favor of approval was stronger than the vote that the drug was effective enough to approve—in part because one committee member pulled the nifty trick of voting against efficacy and against safety, but in favor of approval.

The rationale: the drug may not meet the letter of FDA’s definition of substantial evidence, but in a condition as horrible as idiopathic pulmonary fibrosis, evidence of activity is enough to allow approval.

Now, Forest Labs brings it COPD drug Daxas to the same committee and wins a narrow vote that the drug is effective (9-6), a narrow vote that it is safe (9-6)—but a fairly firm vote against a favorable risk-benefit profile (10-5). As we put it in the headline of “The Pink Sheet” DAILY here, the committee said it is safe and effective but not both.

That sounds like a real head-scratcher, though the truth is that the vote is more rational than it looks. In fact, nine committee members voted “no” to either safety or efficacy or both, so it is not surprising that a majority voted against approval. (Trust us: the math works—if you would like a complimentary copy of our analysis of the votes, email us here.)

Of course, there is that one outlier: Richard Honsinger of Los Alamos Medical Center Clinic, who voted yes on safety, yes on efficacy, but no on approvability. His rationale? That while the drug may meet a minimal standard of safe and effective, it should only be approved if it is shown to be better (either more effective or more safe) than alternative therapies prior to approval.

That would obviously be tough for Forest if FDA agrees.

However, we suspect there will ultimately be a different outcome. As we noted in The RPM Report here, Forest made some important changes to the NDA after submission—and FDA basically said it was too late to talk about those before the committee. But we suspect the path forward for Daxas will involve putting brackets around the patient population and applying a robust post-marketing program—which may very well include comparative trials.

Still, let’s hear it for the Pulmonary-Allergy Drugs committee for once again tapping into the important themes of the regulatory process these days.

With pirfenidone, it was a perfect marker for one theme: the way the new regulatory process can make it easier for products to treat unmet medical needs (especially in relatively small patient populations) to reach the market.

With Daxas, the vote is a perfect marker for what happens to products where you cannot find such a population: there will be a strong desire for a de facto superiority standard for approval.

We look forward to the next meeting of this committee—no matter what is on the agenda.

image from flickr user RubyJi used under a creative commons license