Are There Real-World Benefits to the Critical Path Initiative?

Since the FDA released its "Innovation or Stagnation" report in March 2004, there has been much interest from all concerned—given that it attempts to modify the current situation where, in FDA's words, "...the costs of product development have soared over the last decade. Because of rising costs, innovators often concentrate their efforts on products with potentially high market return. ...[manufacturers] are forced to use the profits from a decreasing number of successful products to subsidize a growing number of expensive failures." and there is "growing concern...the biomedical revolution may not deliver on its promise of better health."¹

Timothy Pratt, PhD

FDA contends that the above is 1) a result of applied sciences not keeping up "tremendous advances" in basic sciences, 2) causing a stagnation of innovation, and 3) not in the public interest for the development of low cost/low profitability/safe therapies. FDA goes on to suggest a number of strategies and working groups that can assist in addressing the problem, including Bayesian statistics, surrogate endpoints, etc. I tend to be frequentist in general approach as Bayesian models are not without their problems—this goes some way in explaining why I feel the Critical Path Initiative, if successful and as laudable as it may appear to be, will create as many problems as it solves.

In my view, the Critical Path Initiative pays insufficient attention to the ongoing utilization and monitoring of drugs and devices in the real world. It is well known, especially in the realm of heavily utilized drugs, that the performance of a therapy when market-approved rarely matches that found in the clinical trial. The highly controlled and monitored environments of clinical centers of excellence unfortunately are not reflective of general practice at large, and thus, postapproval problems arise, such as those seen with antidepressants, COX2 inhibitors, and most recently with implantable cardioverter-defibrillators (ICDs).

Meaningful mechanisms needed

If the critical path is to function effectively, it must provide a truly meaningful mechanism to assure access to quality care throughout the continuum of a therapy's life-cycle—and include an emphasis on real-world registries, Phase IV studies, and prospective product performance monitoring. We already see CMS heading in this direction, albeit with a different agenda, with increasing numbers of "Coverage with Evidence Decisions" for a variety of agents—most recently, for medical devices such as stents. CMS clearly states that they often find the trials that gain FDA approval for a product are not adequate to predict performance in the noninvestigative world. Thus, it could be argued that getting more products approved faster will in fact exacerbate the problem of failure in the marketplace, as opposed to failure to gain approval, the latter being the subject focus of the Critical Path Initiative. This would in fact merely shift the cost burden from upfront development to postmarket lawsuits, of the type currently being evidenced in the ICD arena.

Is the initiative merely a first step?

Perhaps the Critical Path Initiative is merely a needed first step. It must not end at product approval however; it must incorporate more mandated postmarket chronic performance studies for the benefit of the real-world population as a whole. A useful and important side-effect of such well-constructed real-world initiatives would be a wealth of meaningful data about the broader therapy population that Bayesians could incorporate in their modeling to make frequentists both a little more comfortable with smaller study populations and a little more confident of predicted results; this may well facilitate more predictable approvals—the whole point of the critical path.

Timothy Pratt, PhD, Chief Marketing Officer & Principal Scientific Advisor, MedNet Solutions, Inc.

References

1. March 2004 "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products," US Dept. of Health & Human Services, Food and Drug Administration.