Exceeding expectations, the success of the breakthrough therapies program has the FDA and patient advocates calling on industry to exercise self-control in requesting the designation, which grants expedited development and review.

Since the program started in 2012 under the FDA Safety and Innovation Act (FDASIA), the agency's Center for Drug Evaluation and Research (CDER) has received more than 250 breakthrough requests and has more than 80 programs designated as breakthrough. In the first two years of the program, CDER received 203 requests and approved about one-third of them. (See chart below.)

FDASIA offers the designation to drugs that are intended to treat serious or life-threatening illnesses or conditions and that have preliminary clinical evidence indicating they may demonstrate a substantial improvement over available therapies. (Available therapies are drugs that have been fully approved; they do not include drugs that have accelerated approval, according to the FDA.)

The number of requests will continue to grow as industry turns from copycat drugs to breakthrough therapies to fill their pipelines, Richard Moscicki, deputy CDER director for scientific operations, predicted Friday at a Brookings Institution workshop on the breakthrough designation. Moscicki sits on CDER's Medical Policy Council, which reviews all breakthrough requests.

"The age of me-toos is slowly going away," Moscicki said, adding that he expects more breakthroughs as the science in other areas catches up with the science in the oncology space, which accounts for many of the breakthrough designations already awarded.

When the breakthrough program was conceived, the expectation was that maybe two drugs a year would receive the designation, said Ellen Sigal, chairwoman and founder of Friends of Cancer Research. Instead, it "has been a seismic change," she noted.

Perhaps due to those low expectations, the FDA received no additional resources under FDASIA to review breakthrough requests. But sponsors have flooded the agency with requests for drugs that were in development before the designation became a reality. Given the volume of requests, the reviews are taking a lot of senior staff time, diverting limited resources from other programs, said John Jenkins, director of CDER's Office of New Drugs.

Sponsors have nothing to lose in requesting the designation, as there's no fee and the request is part of the confidential investigative new drug (IND) process, Jenkins said. That encourages them to apply for the designation, which can substantially reduce time to market, with some breakthrough drugs being approved months before their priority PDUFA date. The program also provides valuable interaction with senior FDA officials.

Because of the IND confidentiality, there's little transparency in CDER's decisions to grant or deny a breakthrough request. Along with the vague subjectivity of the requirement for "substantial improvement," the lack of transparency has led to confusion and unrealistic expectations among sponsors, Jenkins said.

If there were a sizable user fee and public disclosure of breakthrough requests and decisions, drugmakers might be more careful in consulting with experts on whether their candidates truly represent a breakthrough before requesting the designation, said George Demetri, senior vice president for experimental therapeutics at Dana-Farber Cancer Institute. That would relieve the burden put on the FDA.

Moscicki isn't convinced an "entry price" is necessary for breakthrough designation, but there is a need for industry self-control. "The resource issue is real," he said. For him, the big message from Friday's meeting was communication and how that could save resources for both the FDA and drugmakers, especially if sponsors talked with the agency before submitting a request.

PUTTING THOUGHT INTO IT

Sigal agreed. The designation has proven an incredible tool in speeding the development and approval of much-needed new therapies, she said, "but we have to be thoughtful about how we use it."

To help sponsors be more thoughtful about their requests, FDA staff presented an overview of CDER's breakthrough decisions, along with several case studies demonstrating agency thinking on the data needed to support a request and the magnitude of effect size necessary to be deemed a breakthrough.

Most denials were based on a number of factors, with trial analysis issues cited 72 percent of the time, FDA's Kim Taylor said. Such issues included results being too preliminary, flawed post-hoc analyses, and issues with endpoints, trial design and sample size.

A lack of substantial improvement was cited in more than half the denials. In some cases, no clinical data or incomplete data were available to support claims of improvement, Taylor said. Safety concerns were cited in 11 percent of the denials, and two requests were denied because the intended indication wasn't considered serious or life-threatening.

In some cases, the review team encouraged sponsors to resubmit their requests when they had more data. That happened with Ariad Pharmaceuticals Inc.'s brigatinib. The company requested breakthrough therapy when it had data from an ongoing phase I/II trial showing improvement in 16 patients with anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer. CDER denied the request, saying the company was on the right track but the sample size was too small and the duration of response was limited, Ariad's David Kerstein said.

The Cambridge, Mass.-based drugmaker continued to get more data. When it had about triple the patient experience and more duration, it contacted the FDA again and asked if that would be enough to submit a breakthrough request. The company was encouraged to resubmit, and brigatinib was granted breakthrough status.

In hindsight, Kerstein said it would have been helpful had Ariad engaged with the FDA before making its first request. That's something several FDA staff urged sponsors to do, especially start-ups with little regulatory experience.

Taylor noted that half of the breakthrough requests CDER received from 2012 to 2014 were submitted by small or privately held companies.

Yet those companies received only 25 percent of the approvals. That may be due to lack of regulatory experience and communication with the FDA, Taylor said.

Going forward, FDA officials stressed the need to better define the bar for "substantial improvement." When nothing has worked in the past, is any improvement a breakthrough? Jenkins asked. "You can't sustain a program where everything is a breakthrough," he added.

Speaking for patients, Sigal said they "want things that can work. . . . They want more than hope."

Quoting Jenkins, Kay Holcombe, of the Biotechnology Industry Organization, said breakthrough drugs "should knock your socks off. They should be transformative."