The oncology drugs LDK378 and ibrutinib have both been granted Breakthrough Therapy status by the U.S. Food and Drug Administration. This designation is intended to expedite the development and review of drugs that treat serious and life-threatening conditions and that have demonstrated substantial improvement over available therapies on at least one clinically significant endpoint.

New program is intended to speed the path to approval by boosting company–FDA interactions

Swiss drugmaker Novartis announced in mid-March that its investigational compound LDK378, an inhibitor of anaplastic lymphoma kinase (ALK), received a “Breakthrough Therapy” designation from the U.S. Food and Drug Administration (FDA) for treatment of patients with ALK-positive metastatic non–small cell lung cancer who cannot tolerate crizotinib (Xalkori; Pfizer) or whose disease progressed while taking it.

Novartis is the second company to reveal that one of its oncology drugs was granted the special status. In February, Janssen and Pharmacyclics received 2 Breakthrough Therapy designations for ibrutinib, a Bruton tyrosine kinase inhibitor under investigation for the treatment of patients with relapsed or refractory mantle cell lymphoma who have received prior therapy, and also for patients with Waldenstrom macroglobulinemia.

The Breakthrough Therapy program, introduced last summer under the mandate of the FDA Safety and Innovation Act, is intended to expedite the development and review of drugs that treat serious and life-threatening conditions and that have demonstrated substantial improvement over existing therapies on at least one clinically significant endpoint. Companies whose drugs earn this status are entitled to interact more frequently with the FDA to discuss the clinical trial design, ensure the collection of appropriate data, and streamline the drug development program.

As of March 13, the FDA had received 32 requests for Breakthrough Therapy designation, of which 9 have been granted and 10 denied; the remainder are pending review. The program is open to all types of drugs.

“Breakthrough Therapies allow us to take the most promising drugs—those that will have a transformative effect on the practice of oncology, the crème de la crème drugs—and task our review staff to move these applications quickly and have frequent interactions with the company,” explains Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.

The new program is the fourth to be introduced to make the drug approval process speedier and more fluid:

  • The Fast Track designation, reserved for drugs that treat serious diseases and fill an unmet need, includes more frequent meetings and correspondence with the FDA and rolling review of sections of its application for approval.

  • Accelerated Approval hastens approval of drugs for serious diseases that fill an unmet need through the use of surrogate endpoints in trials; later confirmatory trials must verify the anticipated clinical benefit.

  • Priority Review status may be granted to drugs that offer significant advances in treatment or provide a treatment for a condition for which no adequate therapy exists. The FDA aims to complete a Priority Review in 6 months rather than the standard review timeline of 10 months.

  • Breakthrough Therapy status conveys all the benefits of the Fast Track program and even more intensive FDA guidance.

The various designations are not mutually exclusive. For example, a drug can be declared a Breakthrough Therapy and receive Accelerated Approval and Priority Review.

Although the FDA will likely be more discriminating about which drugs receive the designation than it is with the Fast Track distinction, the specifics of the program aren't entirely clear yet, says Christopher-Paul Milne, DVM, MPH, JD, director of research at the Center for the Study of Drug Development at Tufts University in Boston, MA.

By law, the FDA must issue a draft “guidance document” before the end of 2013. The lack of such guidance now, however, isn't likely to deter many in industry from seeking the designation.

“It really shouldn't cost them much in the way of resources to apply,” other than a relatively small investment of time, notes Milne.

The designation may also boost a company's value. When the FDA takes that level of interest in a candidate drug, says Milne, “it certainly helps maintain investor interest.”

Suzanne Rose, with additional reporting by Megan Scudellari

What makes a “Breakthrough”?

The FDA has not yet issued guidance on what constitutes “substantial treatment effects” or the amount of data required for a drug to be considered a Breakthrough Therapy. Public data on 2 oncology drugs that have received the designation—LDK378 (Novartis) and ibrutinib (Janssen and Pharmacyclics) may offer some insight.

At last fall's European Society of Medical Oncology annual congress, researchers presented a phase I study of LDK378 in patients with ALK-positive malignancies. Data showed an 80% response rate in patients with non–small cell lung cancer whose disease had progressed despite treatment with crizotinib (Xalkori; Pfizer).

Ibrutinib was tested in a phase I trial of 56 patients with various B-cell lymphomas; 7 of 9 patients with mantle cell lymphoma and 3 of 4 patients with Waldenstrom macroglobulinemia responded to the drug. Data from a phase II trial of the drug in patients with mantle cell lymphoma were presented at the American Society of Hematology Annual Meeting in December 2012. Among the 110 patients who were evaluated for their response to treatment, 68% experienced a complete or partial response to the drug.

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