Biopharmaceutical companies are eager for FDA to designate potential test therapies as “breakthrough drugs” that offer exceptional promise in treating patients with serious medical needs. Such designation brings considerable FDA assistance in developing accelerated test protocols and in speeding an application through the review process. The designation also plays well on Wall Street, which is particularly important for smaller biotech companies.
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.
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.
Developing breakthrough products requires a new approach to process development and commercial launch, said Earl Dye of Genentech at the CASSS forum, in describing the company’s program to develop CMC/GMP strategies and “manufacturing readiness plans” for both large- and small-molecule breakthrough products. This involves assessing timelines around formulation and process validation and ensuring that all manufacturing sites are GMP compliant. If there are no changes in formulation, it may be easier to leverage stability data from early development, Nye noted, adding that it’s important to determine as early as possible if the clinical manufacturing facility can produce drug substance and drug product for launch. If no transfer of production is needed, that will save a lot of time, he observed, but all facilities have to meet standards.
FDA has established many standards and requirements to ensure quality manufacturing, but often allows for variation in how a firm demonstrates a product’s “fitness for use,” Woodcock pointed out at the CASSS symposium. She noted that a patient facing only a few months life expectancy is not that worried about a product’s expiration date. And if a companion diagnostic is not fully tested, FDA may decide to approve a drug without the test product. “We have to think about what’s necessary,” she observed.
FDA officials acknowledge ongoing discussions at the agency on ways to exercise flexibility in terms of quality requirements for products demonstrating high clinical benefits. The regulator understands that evaluations based on limited stability data and provisional specifications could mask safety issues and that permitting manufacturers to shift more CMC analysis and final stability testing to the postmarketing timeframe raises concerns about ensuring that a quality product is available to patients on a reliable basis. FDA is intent on avoiding situations where it approves a high-demand breakthrough, only to see the firm unable to scale up sufficiently to meet demand, or to run into quality problems that require a recall or production halt. Treatment followed by product withdrawal can be devastating to patients with life-threatening conditions, and availability to patients is a crucial concern, Lacana emphasized.
Nye of Genentech looks to work with FDA to assess the risks of providing less CMC information at time of filing vs. the benefits of early access to a needed medicine. But he and others understand that it’s important to assess whether delays in process validation would compromise patient safety and to commit to providing more confirmatory data during review and post approval.
For the long term, FDA would like to see companies adopt innovative manufacturing strategies that can accelerate quality production, such as continuous manufacturing systems. Agency officials note that there can be advantages in using a clinical manufacturing site for initial commercial production or producing clinical supplies at a commercial site.
FDA reviewers are “doing triple backwards somersaults to facilitate development of breakthrough products,” Shacter commented. They are looking to be flexible whenever possible, provided that quality is assured. To do this, manufacturers need to demonstrate control over the process and product, to justify specifications, to ensure that sterile products are free of adventitious agents, and that there is adequate stability data to ensure product quality on the market.
1. FDA, Expedited Programs for Serious Conditions-Drug and Biologics, Draft Guidance(June 2013), accessed Feb. 7, 2014.