Innovator products, bioequivalence studies

It is interesting that the in vitro dissolution test (USP) was more sensitive to the piroxicam formulation variables than the biodata. The fast, moderate, and slow products were found bioequivalent to each other and to the lot of innovator product studied [100]. It is possible that either the formulation variables studied did not affect in vivo dissolution and/or the differences were not discernible because of the long biological half-life of piroxicam [146]. 

Another collateral effect of the DESI project was the development of the abbreviated NDA, by which a generic version of the innovator product could satisfy the statutory preconditions for entering the market, without repeating the preclinical and clinical studies of the innovator. This administrative creation, designed to assure that generics were both pharmaceutically equivalent and bioequivalent to the pioneer product, was endorsed by Congress in 1984. As will be seen, this development had a staggering impact on the business model of the pharma industry. 

Bioequivalence studies are required to be conducted in 12 hezilthy male volunteers after getting the protocol and centre duly approved by the DCGI. The product being tested is to be compared to the innovator formulation. 

In the first two cases comparative bioequivalence studies with the standard. If no standard is available, the generic product will be compared with both the original product of the innovator and the product marketed in Israel (three-way cross-over). 

In the case of generics, there are many controversies with the bioavailability and bioequivalence studies. The comparator is very often not registered in the Slovak Republic or is not the product of the innovator. Some applicants insist that in vitro bioequivalence studies without scientific evaluation and evidence be accepted. 

Quite apart from patent protections, innovator products are granted eight years of data protection and ten years of market exclusivity (see above), plus a further year of market exclusivity if a major new indication is registered. This means that a generic medicinal product can be placed on the market only 10 (or 11) years after the original authorization, although experimental activities to prepare the dossier, in particular to conduct bioequivalence studies, can start two or three years earlier. 

The reference standard in a bioequivalence study is a formulation currently marketed with an approved full NDA, for which there are valid scientific safety and efficacy data. The list of reference products is provided in the Orange Book ( Approved Drug Product with Therapeutic Equivalence Evaluations ). The reference product is usually the innovator s brand-name product. The total content of the active drug substance in the test product must be within 5% of the reference product. Usually similar routes of administration are used for the test and reference products unless an alternative route is needed to answer specific pharmacokinetic questions. In some cases the reference material could be a solution, suspension, IV product, or the clinical trial material containing the same quantity of active drug ingredient. 

Please note that the difference between a bioequivalence study and a comparative bioavailability study is that a bioequivalency study compares a drug formulation with a reference standard that is the innovator product. Moreover both formulations must be identical dosage forms. 

Market approval of generic medicines requires pharmacokinetic bioequivalence studies. In bio-equivalence studies, the product to be investigated is compared to an innovator product. Products are regarded as bio-equivalent if the 90 % confidence interval of the AUC-ratio and Cmax are within 80-125 % of the reference product. If the confidence interval is within these limits, this means that the average will deviate far less from the corresponding value found for the innovator product. 

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