As of Jan. 31, 2014, manufacturers submitted 140 requests for breakthrough status for drugs and biologics; the agency has approved 39 of these, approximately 30%, and denied 76. New approvals in 2013 included three therapies identified as breakthroughs, an impressive payout for a new and complex program. It’s a sign of strong industry interest in developing new drugs with accelerated, abbreviated pathways, even if indicated for small patient populations.
Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), is excited about the emergence of many new drugs “with incredible efficacy for certain subgroups,” but acknowledged that CDER is struggling to provide the resources needed for the breakthrough drug program. Evaluating these very novel therapies requires “a great deal of attention,” she observed at the WCBP symposium sponsored by CASSS in Washington, DC in late January 2014. Demonstrating efficacy is not the problem, she noted; the greater challenge is to ensure quality manufacturing and access to needed diagnostics.
CMC issues
FDA grants breakthrough status for an experimental drug based entirely on data indicating a profound clinical effect. Chemistry, manufacturing, and control (CMC) issues are not considered at this point, although they are important for the product to come to market. Consequently, FDA officials urge manufacturers with a newly designated breakthrough to meet early with CMC reviewers to discuss strategies for ensuring product quality, including development of stability data to support desired shelf life. FDA has adopted an “all-hands-on-deck” approach to dealing with breakthroughs, assigning highly experienced reviewers to work closely with manufacturers to devise clinical programs and to clarify formulation and manufacturing issues.
FDA briefly outlined the basic components of manufacturing development programs needed for approval of breakthroughs in a June 2013 guidance (1). To ensure availability of a quality product at time of approval, FDA advises sponsors to propose a timeline for developing manufacturing capabilities that fits the clinical development program. The plan should consider how estimated market demand would relate to manufacturing facilities, lifecycle process, methods validation, and stability studies. Early submission of CMC information will allow for timely review and for FDA to determine if the potential manufacturing site will require inspection, especially when contract manufacturers are involved.
Emanuela Lacana of CDER’s Office of Biotechnology Products explained further at CASSS’ CMC Strategy Forum (Jan. 27, 2014) that breakthrough drug development requires information on critical quality attributes, potential scale-up strategies, comparability exercises, and validation plans. FDA will want to know how the company will validate manufacturing processes for drug substances and products, will ensure microbial control for sterile drugs, and will handle changes in formulation and manufacturing. There may be a need for bridging studies and for information indicating readiness of test labs and manufacturing sites, she noted.
Because manufacturers will have less experience with lots and manufacturing process, the need for comparability data with suitable analytical methods may increase, pointed out consultant Emily Shacter at the CASSS forum. Analytical methods must be validated to support fast approval of breakthrough products, and critical quality attributes should be identified as early in development as possible.
Stability data are a notable challenge when development timeframes are compressed from seven years to half that timeframe. The same principles and requirements for setting initial shelf life apply to breakthroughs, Shacter noted, so manufacturers should look to identify stability-indicating assays early. It may be possible to use stability data from earlier lots, based on comparability between initial product and commercial therapy and to submit simple stability updates during application review to extend shelf life before commercialization.