Should Generic Versions of Low Molecular Weight Heparins Be Considered As Generic or Biosimilar Drugs. A Regulatory Dilemma

Abstract 4328

The patent protections for the low molecular weight heparin (LMWHs) enoxaparin, dalteparin and tinzaparin have expired and their generic respective versions are available. Despite widespread clinical use the global regulatory pathways to develop and approve these products remain unclear. In South America and Southeast Asia generic versions of LMWHs are available without adequate regulatory oversight. The EMEA has considered these agents as biosimilars and require both pharmaceutical and clinical data for approval. Unlike the EMEA, the US FDA requires data on the basic, chemical, and pharmacologic profiles without any clinical validation. In July 2010, the FDA approved a generic version of enoxaparin for all of the clinical indications for which the branded enoxaparin is approved. On the other hand, Initially the FDA had approved the different branded LMWHs as distinct drug entities, requiring clinical trials for each individual clinical indication. Generic enoxaparins from various manufacturers are marketed under different trade names even when they are manufactured by the same company. Although in the pharmacopeial assays these agents exhibit comparability, in the pharmacodynamic studies assay based differences have been reported. In a study conducted on two batches of Sandoz’s enoxaparin and Lovenox®, while no differences were noted in the molecular profile and anti-FXa activity, significant differences were noted in other assays such as thrombin generation inhibition and PF4 titration. Moreover, pharmacodynamic differences in primates after sc administration were also noted which were more obvious in the release of tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor assays (TAFI).As the manufacturing process of these agents may differ from manufacturer to manufacturer it is likely that certain compositional variations are not detectable by chemical methods. Thus the requirement of clinical trials to assure the safety and efficacy of these agents is an important consideration. Of concern is the disharmonization of pathways between different regulatory bodies which contribute to the complexity of this issue. It is proposed that the EMEA, FDA and other regulatory bodies develop some common global guidelines for the rationale development of these drugs.