Solution
The two-stage design or add on design approach is accepted by regulatory agencies and should be predefined in the protocol with stoppage rule. Based on our knowledge, very few CROs have used this design approach and is not among their favourite approach since this consumes more time than conventional two-way crossover study. Two stages or add on also gives a second chance to modify sample size with some statistical penalty but it also helps when earlier pilot or pivotal data is not available or when intra subject variability is not known. Add-on designs, group sequential designs and adaptive two-stage sequential designs are currently accepted to demonstrate bioequivalence in various regulations. Designing such studies with different approaches are acceptable to regulatory agencies but needs good statistical understanding, confidence and knowledge on guidelines. Most important close relations with CRO is also required since study involves two stages with stop and start process which consumes time. Pharmadesk has conducted such type of studies successfully for EU and TGA submission with interim statistical analysis capability of conducting interim analysis, sample size re-estimation, power & different two stage methods.
