Bioregnum, FDA

Does the FDA’s ‘breakthrough’ drug program need to be reformed? Harvard skeptics say yes

Of all the expedited review programs that the FDA has set up, none are as popular as the “breakthrough” therapy designation. And a group of high-profile skeptics says that has created some problems that need to be addressed.

Jonathan Darrow

Writing in the New England Journal of Medicine, Harvard’s Jonathan Darrow, Jerry Avorn and Aaron Kesselheim spell out how the BTD program has taken hold in the nearly 6 years since it was created by Congress, with each passing year scoring higher on the percentage of new drug approvals going to a breakthrough therapy.

It’s not hard to see why. They write:

In carrying out its directions from Congress, the FDA developed policies that were applicable to breakthrough-designated therapies: the agency created well-defined staff responsibilities, shortened its response times, and offered intensive guidance to corporate applicants. For example, under this program, the FDA has advised sponsors about interim analyses, methods for data bridging between studies, study-size reduction, and custom-designed end points. The FDA response timelines are 60 days or less for many breakthrough-related submissions, and discussion of certain topics, such as proprietary names, manufacturing inspections, and postmarketing studies, can begin earlier in the development process.

Jerry Avorn

And that approach has delivered big gains for biopharma companuies. In a field where shaving off a few months in the development cycle can be a big advantage — worth well over $100 million for the companies that buy priority review vouchers — the BTD program can slice years off the process. The authors cite one report underscoring an average 4.8-year development period for breakthrough drugs, compared to 8 years for non-expedited therapies.

Increasingly, the critics note, the agency is approving breakthrough drugs on less and less data, leaving their relative value over current therapies untested and uncertain. (This is something I wrote about earlier related to the FDA’s increased eagerness to stamp an OK on a drug after a single study, rather than rely on the twin study standard that has been the hallmark of an R&D gold standard.)

Overall, of the 31 breakthrough-designated therapies, 16 (52%) (including 12 [75%] of 16 oncology drugs) were approved on the basis of phase 1 or phase 2 data, 14 (45%) (including 12 [75%] of 16 oncology drugs) were supported by only a single pivotal trial, and 13 (42%) (including 10 [63%] of 16 oncology drugs) were approved on the basis of either non–concurrently controlled or dose-comparison trials.

Aaron Kesselheim

And the authors say that calling these drugs breakthroughs has spurred the popular press to seize on these new therapies as groundbreaking game-changers, even cures, when they are anything but. In fact, given that the agency often hands out these designations early on, the drugs they deem worthy of VIP service don’t measure up.

Case in point: Acadia’s pimavanserin.

The “breakthrough” drug was approved after it failed two studies, then barely passed muster in a pivotal program. The primary reviewer turned thumbs down on the drug. But it was approved in any case after a majority of FDA experts on the advisory committee felt the benefits outweighed the risks. That’s not much of a breakthrough, and they cite other examples of the same stripe.

So the three say it’s time to call the “breakthrough” program something else that won’t be so easily misinterpreted.

But that’s not going to happen. 

Jacqueline Corrigan-Curay

In an accompanying letter, FDA officials led by Jacqueline Corrigan-Curay, director of the Office of Medical Policy within the Center for Drug Evaluation and Research, concluded that while not every BTD lives up to its promise, the agency has not set the bar too low — and they warn against setting it too high.

The FDA needs the tools to identify and accelerate the approval of drugs that can substantially improve the lives of patients with serious or life-threatening diseases who have inadequate options. Fast-track and breakthrough-therapy designations have done just that — while not without challenges, certainly without compromising the thoroughness of our review or the standards of evidence to support approval. 

The discussion goes on. But FDA commissioner Scott Gottlieb has made it clear that he wants all of the agency to embrace the breakthrough program with the same fervor that the oncology group has shown. And the president has endorsed faster approvals, not higher standards.

For now, BTD isn’t going anywhere.


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