TRIbune Fall 2014 - The FDA’s Breakthrough Designation: Two Years of Fun
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The FDA’s “Breakthrough” Designation: Two Years of Fun

Breakthrough” Designation: Two Years of Fun

In July 2012, the Food and Drug Administration (FDA) began reviewing the most promising new investigational therapeutics in order to decide which one best qualified to receive “Breakthrough Therapy” designation and enter into an expedited development pathway. Nearly two years later, on May 6, 2014, representatives of the FDA, pharmaceutical companies, and nonprofit organizations convened at the Hart Senate Office Building to recount the history of the Breakthrough designation, to celebrate its successes, and to offer a frank assessment of its challenges and future plans.


To expedite development and review of investigational drugs under clinical development, the FDA has made use of programs including Fast Track designation, Accelerated Approval, and Priority Review. The specifications distinguishing these programs are subtle, and they largely hinge upon differences such as addressing a serious indication/meeting unmet medical needs (Fast Track) or favorable evaluation of surrogate endpoints (Accelerated Approval). The Breakthrough designation meets all of the Fast Track requirements in addition to receiving significantly more intensive drug development guidance from the FDA; a forthcoming article in The TRIbune will examine the various mechanisms in further depth.


The Breakthrough designation enjoyed strong bipartisan support in Congress, having first been introduced as a separate bill, and later incorporated in 2012 as an amendment to the fifth authorization of the Prescription Drug User Fee Act (PDUFA V), a part of the FDA Safety and Innovation Act (FDASIA). However, according to Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research (CDER), its roots lie within the FDA itself, as an idea first put forth by Richard Pazdur (Head of the Office of Hematology and Oncology Products) and other program directors. After convening an initial panel, the FDA reached out to industry, patient groups, and researchers, finding enthusiastic support.


Breakthrough designation is intended for those therapies with “game-changing” potential in a serious disease; that is, whose early clinical results show evidence of dramatic effect above and beyond other comparable therapies. Agents meeting this standard are assigned an FDA committee which is specifically dedicated to working with the company to bring that agent to market as rapidly as possible. The committee is typically chaired by an FDA clinical officer, and may also consist of experts in pharmacology/toxicology and chemistry, manufacturing, and controls (CMC). These experts are tasked with constantly identifying any immediate issues that stand in the way of development. The committee meets regularly (typically on a weekly basis) with the company developing the agent, and will make clear to the company what is expected, both from week to week as well as in the long-term.


Sandra Horning of Genentech and Urte Gayko of Pharmacyclics provided the industry perspective on this arrangement, noting that while the compressed timeline leads to some difficult demands (such as FDA requests on Friday requiring a Monday response), the program has inspired a “can-do” spirit of cooperation that makes the demands feel achievable. Having passed the early high-bar for efficacy, companies are also freed from some of the pressures involved in gathering and presenting that data for re-review. Even so, the overlaying of this new system onto the FDA’s standard processes has led to some inefficiencies: for example, mid-cycle meetings mandated by PDUFA were rendered largely redundant, with little to discuss that hadn’t already been covered by the weekly conferences. The FDA has been discussing strategies with industry to alleviate such problems, such as designing “lite” mid-cycle meetings with fewer preparatory burdens, and developing clearer milestones relative to the PDUFA deadline. At this point, the most significant hurdle appears to be the need for more resources within both the FDA and industry, particularly for companies scrambling to get their manufacturing processes up to speed in time to meet the accelerated deadline.


Regardless of initial difficulties, all panelists agreed that the program has been an overall success. The pace of review has been much faster than anticipated, and as of the panel meeting reviewed herein, 44 agents had been granted Breakthrough status. Of those, six therapies were subsequently approved by the FDA, including Pharmacyclics’ targeted cancer therapy ibrutinib (PCI-32765, Imbruvica™). Dr. Gayko recalls that the FDA was so impressed with their initial application, demonstrating such solid phase 1 efficacy data in various B cell lymphomas, that they asked whether the company could send their final submission package even sooner than the mandated PDUFA deadline. Since its accelerated approval for mantle cell lymphoma (MCL) in November 2013, more than three months before the PDUFA deadline, Dr. Gayko estimated that “thousands” of MCL patients have been able to receive the drug. The agent has been so successful in other B cell malignancies that it was also granted additional breakthrough designations for chronic lymphocytic leukemia (CLL) and Waldenström’s macroglobulinemia (WM); it received accelerated approval for CLL in February 2014.






Gazyva™ (obinutuzumab)

Chronic lymphocytic leukemia


Imbruvica™ (ibrutinib, PCI-32765)

Mantle cell lymphoma, Chronic lymphocytic leukemia

Pharmacyclics/Johnson & Johnson

Sovaldi® (sofosbuvir)

Hepatitis C


Kalydeco™ (ivacaftor)

Cystic fibrosis


Arzerra® (ofatumumab)

Chronic lymphocytic leukemia


Zykadia™ (ceritinib)

Non-small cell lung cancer


Panelists also discussed noteworthy trends, such as the fact that the greatest number of breakthrough designations (41%) was for cancer therapies, followed by treatments for infectious disease (24%). Dr. Woodcock also noted that while the Center for Biologics Evaluation and Research (CBER) was a full partner with CDER in this effort, so far only one biologic therapy (Bexsero®, a meningitis B vaccine) has been granted Breakthrough status. Applications to CBER for the designation are usually either for vaccines, where it can be difficult to determine “game-changer” status early in the development cycle; or are very experimental, warranting additional caution. Still, this does not mean that such therapies are automatically off the table, and more breakthrough biologics may be on the horizon.


Overall, it is undoubtedly true that the Breakthrough track has already brought several important therapies to market much faster than they would have otherwise. As the fledgling program “finds its equilibrium,” in the words of Dr. Woodcock, it is possible that the pace of approvals may accelerate even further in the coming years. All participants seemed more than enthusiastic about taking up the challenge, and are extremely optimistic about the future of Breakthrough drug development.

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About the Author

Dr. Tim Schulz, Medical Writer & Clinical Research Specialist for CTEP, has 16 years of experience in biomedical and clinical research. He holds a Ph.D. in Pharmacology from the University of Virginia.


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