The presentation Forest Laboratories Inc. made at last week's Pulmonary-Allergy Drugs Advisory Committee about Daxas roflumilast to treat COPD would have been perfect - if it had been made a decade ago. For better or worse, FDA has moved on, so instead of the endorsement Forest hoped for, a regulatory strategy and procedural tactics out of synch with the realities of 2010 produced a 10-5 recommendation against approval.
Forest's experience hammers home some of the changes a decade's focus on drug safety have wrought.
Simply showing an incremental, statistically significant improvement over placebo for a broad, undifferentiated population with multiple treatment options is no longer a safe regulatory strategy.
Submitting an NDA for chronic use of a compound with known adverse effects without a proposed risk evaluation and mitigation strategy (REMS) invites skepticism from advisory committee members.
And the need to cram additional time-consuming safety reviews into drug evalutions has squeezed flexibility out of the process, making the agency reluctant to consider changes to an indication submitted six months after filing of an NDA.
As a result, the Daxas NDA, which has an undisclosed mid-May PDUFA date, is virtually certain to receive a complete response letter.
The questions going forward are what needs to be done to salvage the NDA - whether FDA will be satisfied with essentially repackaging the application with a revised indication and a REMS, or if it will require lengthy clinical trials - and whether Forest will be willing to invest sufficient additional resources to meet the agency's demands.
The specialty pharma company, which faces patent cliffs for its Namenda memantine for Alzheimer's disease and Lexapro escitalopram for depression and anxiety, paid Nycomed $100 million last summer for U.S. rights to Daxas (see BioCentury, Nov. 23, 2009).
The asset was attractive because Daxas is intended to address a serious and large-scale unmet medical need. If approved, it would be the first new type of therapy in 30 years, and perhaps the only disease-modifying drug, for the estimated 7.6 million Americans who suffer from COPD associated with chronic bronchitis.
That potential emerged unscathed from the advisory committee meeting, as patients have few good treatment options.
But a number of problems, including some that could be expensive and time-consuming to overcome, also came to light.
The Daxas clinical development program, which started with an IND filing in 1999, left Forest ill-equipped to deal with FDA's current de facto comparative effectiveness and safety requirements.
Although more than 15,000 COPD patients have received Daxas in four 52-week and two 24-week Phase III