Breakthrough Therapy Program Exceeds FDA's Expectations

The two-year-old initiative to accelerate the development and approval of highly effective drugs and biologics has enabled a number of important new medicines to reach patients sooner, according to Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER). Twelve breakthrough drugs have been approved over the past two years, for several critical conditions as well as cancer, and dozens more are in the pipeline. The response to the breakthrough program by sponsors has “exceeded expectations,” Woodcock observed last week at a conference sponsored by the Friends of Cancer Research and the Bookings Institution. And this is “good news for patients,” she added.

The program’s success also is noted on Capitol Hill, where Congressional leaders are looking to enact legislation next year to further speed the development of drugs and devices to treat unmet medical needs. House Energy & Commerce Committee chairman Fred Upton (R-Mich) plans to issue a “discussion draft” in mid-January of a bipartisan bill to promote “21st Century Cures,” he said at the conference on cancer research. Upton’s timetable calls for introducing a bill in February, moving it through the E&C Committee in March, and gaining full House approval before Memorial Day. Then it will be up to the Republican-controlled Senate to approve similar legislation with similar speed. The goal is a final bill in 2015 that modernizes clinical trials, promotes digital medicine, attracts more young scientists into biomedical research, and provides added incentives for developing innovative therapies. 

Efficacy key

The breakthrough drug program, which was established by the FDA Safety & Innovation Act of 2012 (FDASIA), should encourage legislative action. Not only is it a boon for industry and for patients, but it has brought about a change in culture at FDA, Woodcock commented. The importance attached to streamlining research and review of highly effective treatments, she noted, sends a signal to review staff that health promotion is equally important as ensuring safety.

An internal analysis indicates that FDA grants the breakthrough designation to only one-third of requests. The magnitude of clinical effect for a new treatment is the main factor in gaining breakthrough status, and is seen clearly in new compounds that achieve a 50% reduced risk of disease progression in clinical trials. Targeted therapies with some genetic component are more likely to be designated; denials occur most often for drugs demonstrating limited efficacy, tested in very few patients, or containing flaws in trial design.

The program’s success, though, means considerable work for FDA. CDER and the Center for Biologics Evaluation and Research (CBER) have vetted more than 200 requests for designation since January 2013 and have granted nearly 70, a process that involves dozens of meetings with sponsors and within the agency. Woodcock noted a high level of concurrence between CDER review divisions and the agency’s Medical Policy Council, which oversees the designation process.

New breakthroughs get “focused attention” from FDA on development programs, which may lead to streamlined clinical trial designs or use of innovative statistical methods. Equally important is assistance in accelerating the manufacturing process and scheduling timely plant inspections for a drug likely to come to market much faster than expected. Drug quality reviewers in CDER work with manufacturers to clarify clinically relevant specifications and to determine what quality testing can occur post-approval.

One way to reduce the extra burden on reviewers is to set clearer standards for what is and what is not a breakthrough to reduce the volume of inappropriate requests. An abbreviated process for writing up rejection reports on “obvious non-starters” could help, as would progress in filling some of the 650 staff vacancies in CDER, many of them for review positions. FDA officials hope that Congress will provide additional funding to support the breakthrough program and other new initiatives that place added demands on staff.

Regulators and researchers anticipate that some promising breakthrough drugs may turn out to have safety problems or more limited efficacy than seen in initial studies. But early approval of such products does not mean that FDA is lowering its standards, Woodcock maintained. She noted that CDER told one sponsor to conduct more studies when problems emerged in initial trials. And she reports no let-up in companies seeking breakthrough status, an indication that the program will continue to grow.