Too Many Breakthroughs?

The FDA program to expedite the development and approval of innovative drugs for serious and life-threatening conditions is a great success, but determining whether an experimental compound has real transformative potential is proving to be a challenge for sponsors and for the agency. Expert

Jill Wechsler

review teams in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are meeting deadlines and goals for assessing breakthrough designation requests and for expediting reviews of these products, but the process is resource intensive and raises questions about how FDA can keep up with the deluge in candidates.

When the breakthrough program was established as part of the FDA Safety and Innovation Act of 2012, advocates envisioned about 2-3 designations a year. As of the end of May, the agency had received 308 requests for breakthrough status and had granted the designation for 90. Nearly 15 important new therapies have come to market more quickly as a result, contributing to the recent rise in new drug approvals. FDA acting commissioner Stephen Ostroff pointed out at the annual meeting of the Food & Drug Law Institute (FDLI) in April that two-thirds of the new drugs approved last year took advantage of at least one FDA expedited review program. 

The popularity of the breakthrough drug initiative is not surprising, as it offers extensive hand-holding by FDA experts that can cut years off development, and the agency is approving market applications for certain “home run” treatments in less than six months. This helps patients gain faster access to life-saving therapies and treatments for serious conditions. The breakthrough imprimatur, moreover, is particularly important to small firms seeking to attract attention in the investment community.   

Sustainable program?

The large number of breakthrough requests and a denial rate of more than 50%, however, is prompting FDA and stakeholders to weigh options for refining and clarifying breakthrough criteria to create a more manageable program. The agency is examining past designation decisions and why it turned down certain requests to see if the bar is too high or too low and how to better educate industry on which promising experimental products really qualify for breakthrough status.

FDA “can’t sustain a program where everything is a breakthrough,” commented John Jenkins, director of CDER’s Office of New Drugs, at an April workshop on breakthrough therapy designation criteria organized by the Brookings Institution. Really fast development should be possible for true breakthrough candidates that demonstrate large treatment effects and can be easily measurable in small populations. But FDA has to devote extensive resources to evaluating designation requests and to supporting the development and accelerated review of breakthrough candidates. Kay Holcombe, senior vice president of the Biotechnology Industry Organization (BIO), agreed that some products are “more breakthrough than others,” and that clearer definition of “substantial improvement” and what is “transformative” would be helpful.

CDER deputy director for science operations Richard Moscicki offered the possibility that FDA could either limit the number of breakthrough candidates, or strive to evaluate these products more efficiently. FDA is working with stakeholders to assess the reasons for designation denials and to encourage companies to limit breakthrough requests to therapies that offer truly substantial improvements in patient care. In addition, industry may provide specific funding to support the unexpectedly large breakthrough program, an issue that is slated for discussion as part of the next round of drug user fee negotiations.

An internal FDA assessment of breakthrough designation requests and denials for 2012-2014 indicates that large biopharma companies are more successful than small firms in gaining designations; that most submissions provide data from a single Phase I or Phase II clinical trial; and that submissions with a prognostic biomarker do relatively well. Randomized clinical trials are not necessary to gain breakthrough status, and trial size depends on the specific indication and nature of the product. Denials of breakthrough designations are more closely linked to problems with the design and analysis of clinical data, as opposed to a failure to show substantial improvement over available treatment.

Sponsors also withdraw about 15% of breakthrough designation requests before they receive the agency’s decision. This occurs for a range of reasons, and further analysis could help improve program processes and reduce wasted efforts on all sides.

Karin Van Baelen, head of global regulatory affairs for Janssen Pharmaceuticals, noted at the Brookings workshop that her company had a very positive experience with the breakthrough designation process, but also

received a denial on a project that perhaps was “overly ambitious” and based on a too-small sample size. "The experience has helped us better understand the breakthrough criteria," she commented, and provided “very valuable feedback” on developing that compound further. Companies should exercise some self control, she added; submitting everything for breakthrough status wastes the firm’s resources as well as FDA’s.

Meanwhile, programs to accelerate approval of important new drugs are expanding globally. Japan, for example, has established the SAKIGAKE designation program for innovative medicines and medical devices that are developed first in Japan and offer “radical improvement” over existing therapies to treat critical diseases, explained Yoshihiro Matsuda of Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), at a CMC workshop in April sponsored by the Drug Information Association (DIA). Matsuda described a greatly accelerated development and approval process for such therapies, combined with stronger post-marketing oversight.

Refining FDA’s breakthrough program is challenging, as the agency finds wide variation in trial characteristics, patient populations, and available therapies for different treatment areas. Thus, FDA analysts can only approximate a “substantial improvement threshold,” but hope to better identify patterns and characteristics that will signal therapeutic success.

Jill Wechsler is Pharmaceutical Executive's Washington correspondent. She can be reached at jwechsler@advanstar.com