by Kavitha Gnanasambandan
Health Advances recently organized a panel with industry experts who have first-hand experience in using accelerated pathways within their drug development programs. The discussions were multipronged, touching on key topics such as the impact of accelerated pathways on targeted therapies, the role of patient organizations, qualification criteria and benefits of breakthrough designation (BTD), and scope for accelerated pathways use across clinical areas.
Over the years FDA has created multiple accelerated pathways to fuel innovation in drug development for serious conditions with unmet medical needs. Since the earliest orphan drug program, established in 1983, to the most recent BTD and Qualified Infectious Disease Product (QIDP) designations introduced in 2012, industry sponsors have shown significant interest and activity (Figure 1). As of June 2016, over 500 drugs have obtained orphan status, and 65 drugs have obtained the more recent Breakthrough Therapy or QIDP designations.
Panelists highlighted the impact of accelerated pathways in enhancing mechanistic understanding of disease and diagnosis, thus enabling development of more targeted therapies. Dr. Eric Olson, former Research Vice President for respiratory diseases at Vertex Pharmaceuticals, discussed the case-in-point experience with Kalydeco, which received the first Breakthrough designation in December 2012. He emphasized their targeted drug development strategy, which was tailored to patient populations with specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) rather than the entire patient population. Successful BTD approval of Kalydeco was founded upon demonstrating clear efficacy data in such a precisely defined target population. Jason Meyenberg, former SVP of Commercial Operations at Alexion Pharmaceuticals, spoke on lessons from commercialization of Soliris and other orphan drugs. He emphasized the role of accelerated pathways in improving awareness for accurate diagnosis and precisely defining target populations, particularly for orphan diseases. This in turn necessitates higher investment in disease diagnosis by companies, payers, and providers, to enable better characterization of target population. He stressed that such a targeted and disciplined approach is key to successful commercialization. Further, developing targeted therapies for defined target populations enable more precise strategy development for market planning and product launch.
Eric Olson and Ron Farkas, former clinical team leader in the Neurology division at FDA, acknowledged the increasing role of patient organizations in accelerated drug approvals. They not only represent the patient voice in decision making but also enable better patient characterization for developing targeted therapies. Olson stressed the critical role played by the cystic fibrosis (CF) foundation in defining patient population through mutations, which was possible in large part due to their well-organized patient registries. Farkas discussed the Duchenne muscular dystrophy (DMD) case, where patient feedback on improvement in disease symptoms was not reflected accurately by end point data. This disease area enabled the agency to reconsider safety margins required for accelerated approval and also more precise definition of end points.
The lively audience at the discussion also brought up a question around qualification criteria for breakthrough designation. Based on experience, panelists highlighted at least four key factors that seemed to have supported BTD to-date including: clear efficacy data on primary end points in early clinical trials, precise definition and characterization of target population, biomarker data that show clear treatment effects, and support from patient organizations. Farkas also clarified that the agency is also retrospectively analyzing the implementation of BTD, including the qualification criteria, to improve the program further. A 2015 panel discussion organized by the Friends of Cancer Research (FOCR) and Brookings institution highlights one such effort in that direction.
Panelists also underscored that a key benefit of BTD is easy access to senior officials at FDA enabling more intensive support and consultation on developmental decisions. Seeking BTD as early as possible in clinical development will help companies gain the most benefit and support from FDA. Biomarker data can be particularly helpful in cases where patient reported data becomes difficult to interpret. Jason Meyenberg highlighted the multisystem benefit through BTD in not only getting attention from FDA but also with providers in the pre-marketing stages. A recent paper published by Health Advances presents case studies and data analysis on how companies have successfully used accelerated pathways to maximize market advantage.
To date, the use of accelerated pathways has been concentrated in relatively fewer clinical areas such as oncology, anti-infectives, and certain orphan metabolic disorders (Figure 2). Dr. Farkas pointed out that this pattern was due to better disease understanding in those areas relative to others. Better disease understanding, biomarkers, and target population characterization are all critical to increasing confidence in early efficacy data and enabling accelerated approval. He also highlighted that FDA has laid out clear goals in prescription drug user fee act VI (PDUFA VI) to expand focus of accelerated pathways to other clinical areas potentially by inviting input from the different stakeholders.
Overall, the panelists agreed that accelerated pathways is a welcome gift to medical innovation in the 21st century. Companies should strategize early and develop a disciplined approach to capitalize on the potential of various accelerated pathways for optimizing product development and commercialization.
Kavitha Gnanasambandan is a Senior Analyst at Health Advances.
The 2016 Accelerated Pathways Panel Discussion was moderated by Sheela Hegde, Partner and Sheldon Ng, Vice President.