FDA Creates Breakthrough Designation for Drugs

As a top executive at the FDA, Richard Pazdur, MD, understands that the agency and drug manufacturers have an inherently complicated relationship. Companies are eager to rush their products through clinical trials and sell the new molecules, while the FDA is more cautious and wants to ensure the drugs are safe and effective.

The sides communicate regularly and work together to understand each other’s positions. However, the review process is typically long and filled with potential obstacles, although the FDA considers special circumstances with faster evaluations. 

Last July, as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), the FDA created a breakthrough designation to identify drugs for serious or life-threatening diseases and expedite the review process for those that demonstrate significant improvement over existing therapies. The goal is to make the products available to patients who can benefit from them and do not have any comparable options.

Since the 1990s, the FDA has had similar review processes such as fast track, priority review, and accelerated approval for medications to treat serious or life-threatening conditions. For a drug to receive a breakthrough designation, evidence must indicate the product could potentially offer substantial improvement on a clinically significant end point compared with an existing drug. Drugs can receive fast track or accelerated approval designations based on clinical or nonclinical data.

“The bar is much higher [for a breakthrough designation] than [for] fast track or accelerated approval or priority review,” Dr. Pazdur, director of the FDA Office of Hematology and Oncology Products, said at the American Society of Clinical Oncology’s annual meeting on May 31. “What we are looking for are transformative therapies, therapies that are going to offer patients an option where no other therapy existed or are a dramatic improvement that will transform the course of the patient’s life—both the quality of that life and the quantity of that life.”

From October 1, 2012, to May 31, 2013, the FDA received 51 requests for breakthrough therapies. The agency granted 19 of the requests and denied 14 of them. In each case, the FDA reviewed the requests within 60 days of receipt.

Breakthrough designations granted to date include an investigational direct-acting antiviral combination therapy from AbbVie with or without ribavirin to treat genotype 1 hepatitis C; palbociclib from Pfizer, Inc. for locally advanced or metastatic breast cancer; ibrutinib from Janssen Research & Development, LLC and Pharmacyclics, Inc, for chronic lymphocytic leukemia, small lymphocytic lymphoma, relapsed or refractory mantle cell lymphoma, and Waldenstrom's macroglobulinemia; and ivacaftor from Vertex Pharmaceuticals as a monotherapy or in combination with VX-809 to treat cystic fibrosis.

Of the requests, more than half (26) were for oncology or hematology products. Eight of them were granted. Dr. Pazdur noted that oncology drugs face difficulties in demonstrating efficacy and getting approved because they are more toxic and have more risks than other therapeutic areas. Still, there are approximately 900 cancer drugs in development, and numerous oncology products have been approved in the last few years.

Ten years ago, there were no drugs approved for melanoma, yet in the past 2 years there have been 4 drugs approved for the disease, including Tafinlar^® (dabrafenib) and Mekinist^™ (trametinib), both on May 29.

As treatment strategies for cancer and other diseases change, the FDA must adapt and consider new regulations to understand the trends, Dr. Pazdur said. Dr. Pazdur, who has been with the FDA since 1999, added that the breakthrough designation has been “poorly defined,” but it is generally granted when preliminary clinical evidence finds the drug may demonstrate substantial improvement over the existing options.

The FDA is developing draft guidance on the breakthrough designation. As required by FDASIA, the agency must issue the guidance no later than 18 months following the rule’s implementation date of July 9, 2012.

For now, after a company receives a breakthrough designation, it works closely with the FDA to finalize plans for further clinical trials and prepare for manufacturing the drug so that it is ready to sell soon after the potential approval. When companies submit an application for a drug to be approved, they must not only include safety and efficacy data but also plans indicating how they are going to manufacture and distribute the product.

Throughout the process, the FDA and drug manufacturers will maintain a “continuous dialogue,” according to Dr. Pazdur. He said agency officials communicate with drug manufacturers on a regular basis through teleconferences or in-person meetings to ensure they are on the right path. Both sides will examine preliminary and ongoing results of trials, and the FDA may even recommend changing end points or the participants to include in the studies.

“It is a different way of looking and working with our pharmaceutical sponsors in drug regulation,” Dr. Pazdur said. “ This obviously requires some changes, not only for the FDA but also for the pharmaceutical industry.”