Bioequivalence Assessment of Generic Products: An Innovative South African Approach

Concurrent with the implementation of new legislation mandating Generic Substitution in South Africa, a new set of guidelines for bioavailability and bioequivalence have been published. Since one of the main objectives of the new legislation in South Africa relating to Generic Substitution is to ensure that medicines of high quality, safety, and efficacy are made more accessible and more affordable to the wider public, the need to speed up approval of such multi-source products has become a regulatory priority. In order to facilitate this process, various bioequivalence issues have been addressed including important issues such as the acceptance criteria and associated bioequivalence intervals, use of a foreign reference product and the issue of assessing highly variable drugs (HVDs). In addition, dispensations have been made with respect to food effect assessment and variability relating to genetic polymorphism in drug metabolism (genotyping/phenotyping). Furthermore, the use of "old" biostudies submitted in support of an application is subject to expiry date. Acceptance of appropriate data requires that specific criteria such as Cmax and AUC, in addition to the usual considerations, also meet the limits specified by the particular registration authority of the country where such products are intended to be marketed. Generally, these limits require that the 90% confidence interval (CI) for AUC and Cmax test/reference ratios lies within the acceptance interval of 0.80-1.25 calculated using log-transformed data. While such acceptance criteria are, in general, ubiquitous, some differences in acceptance criteria do exist between various countries. The new guidelines for bioavailability/bioequivalence studies developed by the South African regulatory authority, the Medicines Control Council (MCC), makes provision for highly variable drugs and the use of a non-South African reference product. The MCC requires that the acceptance criterion for Cmax ratios be set at 0.75-1.33 while maintaining AUC ratios at 0.80-1.25 using a 90% CI. Furthermore, provision is made to apply scaling based on average bioequivalence assessment and, as an interim measure, consideration has also been given to the use of a foreign reference product provided that equivalence between that product and the innovator product currently available on the South African market can be shown using in vitro testing.