FDA’s high approval rate for New Drug Applications (NDAs) is much in the news, with headlines like the one on a Matthew Herper post at Forbes: The FDA Is Basically Approving Everything. Here’s the Data to Prove It. The data comes from an analysis that Forbes commissioned at BioMedTracker.
When FDA approves 23 out of 24 drugs, it should make news. However, we are seeing headlines that could generate an instant myth that FDA is a rubber stamp. Like the headline, the body of the Forbes post contributes to this impression: “And there’s even more data to back up the contention that the FDA is basically providing a rubber stamp.”
It is important to remember that phase 2 testing, not FDA review of NDAs, has accounted and still does account for most clinical development failures. A January 2014 article in Nature Biotechnology, also based on data from BioMedTracker, reports that 67.6% of drugs that enter phase 2 fail to progress to phase 3. Of those that make it to phase 3, 39.9% fail to produce an NDA or BLA (Biologics License Application) for FDA to review.
How Can a Rubber Stamp Be Rigorous?
The term “rubber stamp” calls to mind a cartoon character who literally stamps documents without examining content. Anyone engaged in drug development understands that FDA still reviews every program rigorously at multiple steps, starting with pre-IND meetings. Nothing has changed about the close attention that FDA devotes to ensuring patient safety, determining product efficacy and serving patients with serious unmet medical needs. FDA rigorously reviews trial protocols, with particular attention to issues such as excluding bias and ensuring that end points reflect meaningful clinical benefit. At end-of-phase-2a meetings, FDA scrutinizes sponsor plans for proceeding to phase 2b and selecting an appropriate dose and for phase 3 trials to confirm phase 2 results. Sponsor-FDA interaction at earlier stages naturally contributes to higher success rates later. However, FDA-sponsor disagreements about such issues as appropriate end points, population size and requirements for substudies are commonplace. In cases where sponsors consider FDA requirements unrealistic and unreasonable, one thing they would not call FDA is a rubber stamp.
It is also important to note other factors that contribute to higher NDA approval rates. Higher rates likely reflect industry progress toward the goal of failing faster, before costly and futile phase 3 trials. The advent of targeted therapies, especially in rare indications, also plays a role. FDA is reviewing more new drugs in rare and orphan indications where development programs benefit from biomarkers that are predictive of patient response, making it much easier to demonstrate patient benefit. In addition, there have been no effective therapies in many rare indications. This increases the urgency of approving drugs that can provide some benefit to patients with serious unmet medical needs.
The Importance of Doing Our Jobs Right in Phase 2
In summary, when FDA is approving NDAs or BLAs for 23 out of 24 drugs, these are the survivors – roughly 80 other drugs failed at earlier stages of clinical development. Any of a thousand missteps and disappointments along the way can raise questions that lead sponsors to decide against filing an NDA. It is no myth that designing and executing successful phase 2 trials is at once a science, an art and a management challenge.
Despite headlines to the contrary, this is no time for drug developers to lose sight of the importance of doing our jobs right in phase 2 to maximize chances of beating the odds and someday filing an NDA or BLA that withstands rigorous FDA review.