Breakthrough Therapies Challenge FDA Reviewers, Manufacturers

The development of more complex biopharmaceutical therapies that merit accelerated evaluation and approval has put pressure on FDA to speed up its review process without compromising objectivity and standards.  Yet, consistent and efficient reviews of breakthrough products depend considerably on the quality of the manufacturing process, says Steven Kozlowski, director of the Office of Biotechnology Products (OBP) in the year-old Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER).

Manufacturers of breakthroughs and other innovative therapies need to plan for manufacturing with the same forethought as for clinical, Kozlowski commented at the WCBP symposium in Washington, D.C. last week sponsored by CASSS and FDA. Sponsors should assess how much product will be needed at launch, how they are going to supply the patient population, whether sites are ready, and how to validate the production process.

Talk early with the agency on how to make that happen and have “a real plan for bringing the new product forward,” he advised. His office has seen considerable variation in breakthroughs -- some for tiny orphan populations and developed very quickly, others in development for several years, he commented. His four review divisions can assess these applications very quickly, but “it’s a resource issue,” he noted, as a breakthrough application often needs twice as many people to split up and coordinate the review and to participate in multiple meetings with sponsors.

Kozlowski also observed that some complaints about inconsistent regulatory decisions may arise when a sponsor has limited access to the detailed information about the specific product and its review scenario. Just what is a “good quality review” often is hard to define, he said: There is “no magic formula.”

Seeking flexibility

FDA reviewers at the symposium emphasized that they are trying to be more flexible in accepting less complete data in applications on product specifications, process validation and stability to avoid delaying patient access to needed therapies. Critical product attributes may be set broadly in an application and then tightened down as more experience is gained with a product. FDA says it’s open to retrospective assessment of process validation and has approved several breakthroughs based on manufacturing data from a clinical site, with additional information filed following transfer to commercial production.

Yet manufacturers expressed concern and confusion over just how much process validation needs to be done during development, and what can be confirmed after approval. Some sponsors may feel they’re getting a break, while others complain about being overburdened. Ashley Boam, acting director of OPQ’s Office of Policy for Pharmaceutical Quality (OPPQ), noted that CDER is looking to adopt a more formalized risk assessment process for the “quality space,” similar to how it has examined risk-benefit assessment for safety and efficacy. This involves looking closer at clinically relevant specifications and evaluating quality issues in terms of product performance.

There was agreement among the participants at the Symposium that certain practices that were unacceptable a few years ago, “now are possible.” But less extensive R&D experience with a breakthrough product is “not a license to give FDA less information,” FDA staffers emphasized. Reviewers see many cases where products and processes fail and want assurance from sponsors that the commercial process is reasonably well-controlled and that the company can scale up to manufacture the product to meet quality standards.