Trialing plasma protein therapies for rare disorders: Thinking outside the box

The application of evidence-based medicine to the indications addressed by plasma protein therapies is problematic. So-called Level 1 evidence in the form of randomized clinical trials using classical designs to demonstrate efficacy is seldom possible, because the small numbers of patients denies the appropriate level of power from being built in the trial design. In addition, patient accrual is difficult because of understandable patient resistance and “fatigue” at the number of trials. Efforts to address this by regulating agencies over the past years have yielded promising policies in some areas, which recognize the inherent problems and outline practical solutions. The use of patient registries to accrue safety and efficacy data, while rapidly becoming accepting an accepted component as a basis for pre-market review and approval, is also promising as a basis for the incorporation of post-market data, through Phase 4 surveys, of approved therapies. As such, innovative thinking to address the problem of rare disorders may also lead to desirable reform in all aspects of regulation, with a shift from pre- to post-market review.