Down the Critical Path: Who Should Lead?

In March 2004, FDA issued a provocative white paper: Innovation and Stagnation—Challenge and Opportunity on the Critical Path to New Medical Products. The Critical Path was identified by FDA as those parts of the R&D continuum that constitute bottlenecks in the drug development process. These bottlenecks are the cause of rising clinical costs, stagnating development times, decreasing success rates, and inconsistent productivity. FDA acknowledges that there are inefficiencies in the current system for developing new medicines. Because most sources of variability in human response are not understood and thus cannot be controlled for, demonstrating medical utility is highly empirical. The degree of uncertainty inherent in current techniques can result in the setting of overly conservative safety standards. FDA has provided the following three rationales to justify its initiative: 1) the FDA's mission is to protect the public health by promoting medical innovation; 2) the agency has a critical role in setting standards, which in turn guide development programs in the industrial sector; and 3) the FDA is in the best position to evaluate objectively what works well and what doesn't work well in the drug development process.

Christopher-Paul Milne, DVM, MPH, JD and Kenneth I. Kaitin, PhD

The FDA has called for an aggressive collaborative effort to create a new generation of performance standards and predictive tools to improve the efficiency of the three development and review dimensions of the critical path: ensuring product safety; demonstrating medical utility; and improving the industrialization process. FDA's Acting Commissioner refined the FDA role as one in which FDA would take information developed by industry, NIH, and academia and formulate it into generalized principles to guide development and review. FDA took the lead by announcing the development of a Critical Path Opportunities List, in consultation with stakeholders, and internal changes to support high-priority critical path research efforts. FDA acknowledged that it has little in the way of resources to address what will inevitably be a massive and coordinated undertaking to avoid wasting time and money.

It has now been well over a year since the FDA released the Critical Path Initiative. In the intervening months, Vioxx was withdrawn amid considerable media and congressional scrutiny. FDA resources were diverted to addressing whether its new drug review standards were adequate, whether it had the capability to monitor spontaneous drug safety reports, and whether its relationship with industry had become too "cozy" in the decade since passage of the Prescription Drug User Fee Act (PDUFA). FDA's Critical Path initiative was back-burnered in order to address these and other issues. The Critical Path Opportunities List, which was to be the showpiece on which FDA would demonstrate its commitment to the initiative, has now been delayed at least six months. Understandably, industry buy-in has been lukewarm. They are on the outside looking-in and getting a very fuzzy picture of the shape of things to come. FDA is sending a mixed message, and leading many to question, "Is the agency willing to lead, or only cheerlead?"

It is worth noting that FDA has taken some small steps to date, by establishing a docket to collect comments from stakeholders, forming several inter/intra-agency working groups, and cooperating on small projects with academia. FDA will have to manage how best to turn confidential data into lessons learned, but it already does that at workshops and public meetings, as well as when it develops guidances or responds to stakeholders' commentaries and queries. A bigger challenge for FDA, however, will be to implement its grand plan for the way forward, which calls for the agency to specify the work needed, prioritize opportunities, coordinate the Initiative, work on new tools and regulatory guidance, and update stakeholders to identify unmet needs and opportunities. These tasks highlight the critical need for a point person at the agency to ensure that progress is being made, and a formal partnership with industry and academia.

It would be unreasonable to assume that FDA, which is short on resources, can take the Critical Path Initiative very far on its own. Unfortunately, it's a catch-22 situation. FDA is unlikely to find enough friends in Congress in the current climate to get a targeted appropriation to fund the Initiative until the agency has at least a program and process in place. Industry and academia, for their part, also have resource constraints. Furthermore, they must justify how and when those resources are allocated, and they will want a place at the table when the talk turns to priority-setting.

If FDA leads by example, industry and academia will have some direction along the Critical Path and some confidence that it is going somewhere. FDA should publish their own roadmap to show the way, create a formal public–private partnership to demonstrate commitment, and assign a point person who will lead the effort. FDA's Acting Commissioner Lester Crawford hailed the initiative as "unique in FDA's history...a ground-breaking shift in the agency's role." That can still be true!