The role of biostatistics in drug development has been evolving since the 1962 Kefauver-Harris drug amendments. Those legal amendments were driven by the poor state of clinical trial research that had been conducted in prior decades as well as the outcomes from numerous safety failures of existing products at the time. The new regulations included the need for future drugs to be shown to be efficacious, and thus controlled trials were necessary to support those claims of efficacy. In the succeeding decades, rigorous clinical trial methodology became the norm rather than the exception with prospectively defined endpoints, hypotheses that were being tested and then rigorous statistical analysis plans that were pre-specified in such a manner that ‘efficaciousness’ could be reasonably demonstrated. Biostatistics had been found to provide the backbone upon which development companies could provide data, in a thoughtful and pragmatic manner, in order to obtain approval for marketing of new drugs and biologics. Hundreds of products have been approved using both classical (eg, simple t-tests) and novel (eg, mixed models) statistical methods.
The Orphan Drug Act of 1982 was introduced in order to encourage drug companies to develop products for rare diseases. Because the underlying populations for many orphan diseases are exceptionally small (with total world-wide prevalence measured in the hundreds for many of these indications), the application of classical biostatistics methodologies (as has been performed for therapeutic indications where the patient prevalence supports the underlying theory behind many of the statistical procedures applied to drug development) may not be appropriate. Thus, biostatisticians working in the area of orphan disease must allow themselves flexibility in terms of how they think about the design of these studies as well as the analysis of the resulting data. Further, the biostatistician must understand that the FDA may view these orphan programs as opportunities for a greater flexibility, particularly in the areas of the number of trials and patients required, the design of the trials and even the tolerability of certain adverse effects or risk-benefit ratios.
Many orphan diseases have only been studied by a small number of investigators and the natural progression of the disease may not be fully understood. Further, as most orphan diseases do not have approved treatments available, precedent regulatory pathway is rarely provided. Thus, one of the key aspects of any orphan Investigational New Drug application is the discussion of the proposed endpoints to be used in the program and the determination of the appropriate regulatory pathway. The biostatistician's role in determining the optimal endpoint must start early in the program at the pre-IND stage when the overall development plan is being drafted. Topics such as selection of potential endpoints or surrogate markers, initiation of natural history studies (in order to describe the course of disease in the patient population as part of the overall regulatory pathway), and even determination of what a clinically meaningful effects might be needed will require input by the biostatistician from the early stages of the program through the New Drug Application process. Companies pursuing an orphan indication are therefore encouraged to involve an experienced biostatistician as early in the development process as possible.
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