Given this, TKI can interrupt signaling cascades evading apop tosis, thereby re sensitizing cancer cells to induction of apoptosis. Figure 1 gives a schematic overview of the molecular mechanisms of action of TKI. Challenges of generic TKI drugs in cancer therapy According to their European Birth Date during the past decade, these substances successively will be running off patent within the next years. From a regula tory point of view, this raises the question how market ing authorization applications should be filed and especially, how therapeutic equivalence should be established for generic applications. In general, demon strated bioequivalence allows generic medicinal prod ucts to refer to the efficacy and safety data of the originator medicinal product.

It is easy to anticipate, that numerous questions in this regard will arise in the near future. Aqueous intravenously applied drug products have a 100% bioavailability directly per defin ition, thus, no BE studies are required for a MAA selleck of such generic drugs. However, for orally applied drug products, BE with the originator product needs to be shown, which may be done using patients or healthy volunteers in re spective in vivo studies or by means of comparative in vitro investigations. Since decades BE acceptance criteria for AUC and Cmax require the 90% confidence intervals being com pletely within 80 125% to assume BE. The acceptance range may be tightened to 90 111% for one or both pharmacokinetic characteristics according to the European BE Guideline in the case of narrow therapeutic index drugs.

In cases of class I and III compounds having identified not to have a narrow therapeutic index specific in vitro dissolution data may substitute for human BE Carteolol assay studies considering also particular requirements on excipients. This concept follows the principles of the biopharmaceutical classifi cation system. It is likely that numerous questions in regard to the ap propriate data package will arise in the near future includ ing questions on the appropriate study design, on the appropriate study population, nutrition status, single or repeated dose design, appropriate BCS classification of the individual compound or the classification as NTID. MAA for new generics may be processed via different regulatory authorizations routes, i. e.

national procedures in European member states, decentralized procedures in volving several European member states or centralized procedures for all European member states. As the latter is an option only for generics for which the originator me dicinal products already obtained marketing authorization from a centralized procedure, this option may receive more attention with the increasing number of medicinal products with centralized authorizations that are running off data protection and patent in the next years.