Bioequivalence studies are the preliminary requirement for generic products to enter in the market. The manufacturer (generic) must be in limit with that of innovator (branded) formulation (reference listed drug) within the limits approved by respective governing bodies. As per biopharmaceutical classification system the drugs falls in the category I to IV on the basis of permeability and solubility data. Drugs belonging to the category of poor solubility and poor permeability data uphold bioequivalence issues. Due to this high variability, large sample size may be needed in BE studies to give adequate statistical power to meet FDA BE limits, and thus designing BE studies for HVDs is challenging. Consequently development of generic products for HVDs is a major concern for the generic drugs industry. Major regulatory agencies also considered different approaches for evaluating BE of highly variable drugs. From 2004 onward the FDA started looking for alternative approaches to resolve this issue, and eventually found that replicate crossover design and scaled average BE provides a good approach for evaluating the BE of highly variable drugs and drug products as it would effectively decrease sample size, without increasing patient risk.