In view of the limited number of patients in preauthorization trials, further information mainly focusing on safety aspects must be acquired through postmarketing investigations [6]. For the FDA, the sample size has been defined based on the evaluation of inhibitor development with the goal of showing one or fewer cases with the upper bound of the two-sided 95% confidence interval (CI) for the product inhibitor incidence rate being below 6.8%, and the calculation based on an intent-to-treat (ITT) population. Of note, Bayesian and Adaptive Design approaches were considered Tanespimycin concentration as alternative statistical models to estimate the value and confidence interval around

the inhibitor frequency, but were not determined to add to the efficiency of the espoused selleck screening library model [7]. Ultimately, in this proposed approach, subject requirement and trial duration are only moderately reduced from the current regulatory requirements, to meet the current standards of acceptable preauthorization product safety determination. The ISTH SSC project group attempts to delineate innovative approaches to the clinical design of new product safety (immunogenicity) trials based on the known epidemiology and immunology of FVIII inhibitor development in congenital haemophilia A. A biphasic ‘epidemic’ and ‘endemic’ pattern defines

the post-exposure inhibitor incidence, and this parameter should be evaluated in the trial design. Specifically, after 20–50 exposure days (EDs) a high peak ‘epidemic’ rate (up 30%) is observed in previously untreated patients (PUPs)

[8], followed by a lifelong low ‘endemic’ incidence of 0.1–0.6% per patient-year, particularly after 150 EDs [9]. Therefore, the ISTH SSC project group discussed how methodology might best inform the traditional design of the single-arm prelicensure study with respect to study duration and subject number. The same considerations should be applied to trial designs in haemophilia B while taking into MCE公司 account two important differences in the study design, namely a lower prevalence and the more rare development of inhibitors. Clinical studies differ in key characteristics, such as in their definition of previously treated patients (PTPs). When preregistration studies are evaluated in PTPs, they should be defined in a way that is most suitable to the study of product-related immunogenicity since the incidence of inhibitor formation declines with increasing numbers of infusions, but never disappears. Patients having approximately 150 EDs or more therefore provide an immunotolerant population in which an unusually high incidence of inhibitor formation, suggestive of neoantigenicity, would be unexpected and relatively easy to detect. Another reason for choosing PTPs is that in developed countries, PUPs are relatively few in number, making their recruitment an obstacle to conducting clinical studies.