Bioequivalence and Bioavailability Forum

Hi

Thanks for a comprehensive reply, We are focusing WHO regulations and as per WHO there is another approach for highly variable drug (HVD) i.e. sequential design approach

Some regulatory agencies (Canada [2], Japan [3], and the World Health Organization (WHO) [4]) permit ‘add-on’ designs. With these designs, if the failure to declare the two formulations bioequivalent appears to be due to insufficient power, it is permissible to add additional subjects and pool results of the additional subjects with the original trial. For example, the WHO and Japanese guidelines allow an add-on study provided the additional sample size is at least 50% of that of the original study. Potvin D, Diliberti CE, Hauck WW, Parr AF, Schuirmann DJ, and RASmith: Sequential design approaches for bioequivalence studies with crossover designs; Pharmaceut Statist 7/4, 245–62 (2008)

Reference WHO

If the bioequivalence study was performed with the appropriate number of subjects but bioequivalence cannot be demonstrated because of a larger than expected random variation or a relative difference, an add-on subject study can be performed using not less than half the number of subjects in the initial study, provided this eventuality was anticipated and provided for in the study protocol. Combining data is acceptable only in the case that the same protocol was used and preparations from the same batches were used. Add-on designs must be carried out strictly according to the study protocol and SOPs, and must be given appropriate statistical treatment

my query: Which one will be the most appropriate approach for BE of Sofosbuvir?

1. Sequential Design Approach (initially conducted on 24 subjects and if bioequivalence cannot be demonstrated than an add-on subject will be done as per guideline)

OR

2. Reference Scaled Average Bioequivalence (RSABE), a full replicate 2 × 4 cross-over design Which can be conducted on minimum of 22 subjects?

Thanks

Dr. Hashmi
Technical Coordinator