Rethinking FDA's Breakthrough Therapy Designation

cancer patient: cancer patientThe FDA's breakthrough therapy designation (BTD) for expedited drug approval has been a boon for cancer patients. According to data presented at a webinar sponsored by the Friends of Cancer Research (Friends), since 2012 the FDA has received more than 1,000 requests for BTD from drug sponsors, granting more than 400 of these. Of this number, BTD has led to the timely development and approval of 205 new products, 61 percent of which are oncology therapies. BTD has shortened the time from submission to approval for 60 original applications (not previously approved) for oncology therapies by a median of 2.3 years compared to oncology products without BTD—a potentially lifesaving time period for some cancer patients. The BTD expedited pathway is intended for drugs and biologics for serious or life-threatening illnesses for which there is preliminary clinical evidence demonstrating that the investigational therapy may offer substantial improvement on a significant endpoint or endpoints over available therapies. In addition to BTD, the FDA has three other expedited approval pathways: priority review, accelerated approval, and fast track. Now it is time to take a look at the BTD pathway and see how it might be further enhanced to help patients, noted Ellen Sigal, PhD, Founder and Chair of Friends. “The success of this program is clear in the numbers,” she said. While the program has been invaluable in advancing scientific research, she stated that like all scientific programs “there are opportunities for improvement.” “There is still more work to do,” agreed Sen. Michael Bennet (D-CO), who introduced the bipartisan legislation that led to the BTD pathway. This legislation was signed into law in 2012 with strong support from the Friends. “We did not anticipate how significant the bill would be,” said Bennet. While the BTD pathway has brought help to many Americans, he noted it is indeed time to re-examine the BTD and minimize barriers to its effectiveness. Breast cancer survivor and patient advocate Katherine Couvillon, recipient of a drug approved through the BTD pathway, stressed how vitally important the timeliness of this expedited FDA approval process is for cancer patients. “We are always waiting for that next drug in the pipeline,” she said. The Friends organization released a pre-webinar draft white paper, which contains specific recommendations for attaining the full benefit of the BTD pathway for drug development and approval. The white paper is based on contributions from more than 20 commercial sponsors that varied in company size and range of experience with BTD, in order to identify challenges with BTD and solutions for improving its use. The draft white paper's recommendations addressed the following needs: clarify expectations for necessary evidence to receive BTD; enhance communications between drug sponsors and the FDA; support interdisciplinary coordination and improve transparency in oncology; and provide additional support to address rate-limiting steps in drug development. What is needed is to take advantage of the flexible and adaptable communication with the FDA that BTD brings, said Tina Kim-Hafken, MS, Senior Director for Regulatory Affairs at Seagen in Seattle. She cited the importance of multidisciplinary discussions, especially for new molecular entities. Upfront discussions and proactive planning lead to a smoother product review under the BTD pathway, she noted. Agreeing was Sandra Horning, MD, Professor of Medicine at Stanford University and former Chief Medical Officer and Global Head of Product Development at Roche and Genentech. “We're always dealing with a changing standard of care,” she said. “We need to be thinking of this as a partnership.” Enhanced communication across the various centers that make up the FDA will help to improve use of the BTD pathway, agreed Giuseppe Randazzo, MS, Director of Global Regulatory & Development Policy at Novartis. “How can the centers work together early and often?” he asked. “We don't want to slow industry down. Nor do we want to slow the FDA down.” What is needed, he said, is a better pacing cadence to achieve alignment between the drug sponsor and the FDA. Agreeing on the need for enhanced communication between sponsors and the FDA was Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence. He said what is needed is “a very early, comprehensive discussion with the sponsor” on what constitutes the entire therapy package for expedited approval. He also emphasized the importance of confirmatory trials of BTD therapies, which he said must be done with the same diligence that was used for the pivotal registration trial. Pazdur said rethinking the BTD pathway might lead to simplification of the FDA's expedited approval processes. Should there be an early breakthrough therapy designation and a late breakthrough designation? He noted that simplifying the various expedited therapy approval pathways at FDA is warranted. “I don't think even practicing physicians know what all these designations mean,” Pazdur said. “I think it would be better for everyone.” He added that he is always open to discussing expedited approval pathways at FDA. “I think it's high time to look at simplification,” said Michelle McMurry-Heath, MD, PhD, President and CEO of the Biotechnology Innovation Organization. She noted this simplification would be good for both patients and drug sponsors. The BTD approval pathway has led to a shifting role for regulators toward more of a creative problem-solving role, said Martha Donoghue, MD, a pediatric oncologist who is Clinical Team Leader for FDA's Gastrointestinal Cancer Team, Division of Oncology Products 2, Office of Hematology and Oncology Products. She is excited about the draft white paper's suggestion (contained in an appendix) of a drug development snapshot template on clinical pharmacology (dose and administration). This template includes supporting evidence and clinical evidence. Sample questions in the suggested template include the following: Is the therapeutic product a small or large molecule? Or another platform? What is the mechanism of action? What is the recommended dose, schedule and route of administration? For BTD therapies, it is very important to establish the new product's clinical pharmacology, stressed Nam Atiqur Rahman, PhD, Director of the FDA's Division of Cancer Pharmacology II, Office of Clinical Pharmacology. After conducting its survey, the Friends organization convened focus groups with key stakeholders, including FDA staff, to identify possible ways to make the most of the BTD pathway. Peggy Eastman is a contributing writer. Draft White Paper for a Breakthrough Therapy Designation Pathway Optimize the timing of breakthrough therapy designation (BTD) and improve communication on expectations for data necessary to receive and maintain BTD. This includes providing additional clarity regarding the criteria for BTD to optimize the timing for submission of a BTD request. The draft white paper notes that there can be uncertainty among sponsors on the level of clinical evidence required to meet the criteria for BTD, for example. The paper states: “Inclusion of annotation in the preliminary BTD teleconference template to describe the type and scope of preliminary evidence that are generally needed to support a BTD request submission for an oncology product could help to facilitate preparation of documents and meaningful preliminary BTD teleconference discussions, while also reducing the number of preliminary BTD teleconferences that clearly lack sufficient data.” Improve mechanisms to enable meaningful discussions between FDA and sponsors that clearly align with key decision points during a new therapy's development course. Enhance oncology communication tools and optimize processes to support interdisciplinary communication within and between the FDA and product sponsors. Provide a roadmap for addressing key pressure points for products with BTD. This includes facilitating timely discussions of dose selection, exposure-response analyses, and study design. It also includes encouraging early collaboration, alignment, and prioritization between pharmaceutical and device sponsors and FDA's centers, including the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research.