Delhi Summit 2007 - Introduction
Recently the generic versions of oral anticoagulants (eg. coumadin), low molecular weight heparins (eg. dalteparin and enoxaparin), antithrombin agents (eg. argatroban), antiplatelet drugs (eg. clopidogrel) and thrombolytic drugs (eg. streptokinase) have been introduced. Regulatory compliance guidelines from WHO, US FDA, EMEA and other agencies for the manufacture of these drugs are unclear and thus the generic versions of these drugs are not manufactured using the stringent biological and chemical controls applied to the branded products. Moreover, several non-WTO member countries do not acknowledge the intellectual property protection rights of the innovator company for the purpose of patent protection. Generic products are manufactured by uncontrolled means and may result in compromised quality and undesirable clinical implications. Moreover, substandard products may impact on the safety and efficacy of these critical drugs.
The oral anticoagulant drugs such as warfarin exhibit a narrow therapeutic index and show a non-linear pharmacokinetics. Moreover, these agents are not only bound to proteins (>98%) but are subject to individual metabolic variations. Small changes in the patient's condition and pathophysiologic predispositions can result in considerable changes in the anticoagulant responses. Recently, several generic versions of branded LMWHs such as enoxaparin and dalteparin have become available. A comparison of generic and branded LMWHs has shown noticable pharmacological difference despite chemical equivalence amongst some of the products. Generic versions of antiplatelet drugs like clopidogrel have weak antiplatelet activity and require additional dosing of this drug. Such differences are further magnified with the interaction of clopidogrel and aspirin. Clopidogrel also has profound interaction with other drugs which can be further amplified in the case of generic drugs. Variation in generic thrombolytic agents have also been noted. In a comparative study, 21 samples of generic streptokinase were tested and only 3 samples were found to perform as per the information listed on the label. This striking discrepancy between claimed and actual performance of these critical drugs may result in life threatening situations for severely ill patients. To address these important issues a defined preclinical screening program is in place in various laboratories. In the future, peer review and group consensus will be required to develop guidelines for the acceptance of generic antithrombotic drugs. Until that time the interchange between generic and branded anticoagulant, antiplatelet and antithrombotic drugs should be considered with caution.
Several commercially available LMWHs are now widely used in the management of thrombotic and cardiovascular disorders. Although derived from porcine mucosal heparin, these drugs are manufactured by distinct chemical and enzymatic methods with products, which can be differentiated in chemical and biologic assays. The pre-clinical pharmacological profile of these products are also distinct and profoundly impact on their therapeutic actions. More recently several generic versions of Enoxaparin and Dalteparin have been introduced in some Asian and South American countries. In addition, numerous generic suppliers have applied for the approval to sell the generic versions of Enoxaparin and Dalteparin in the US and European Union. Neither the US FDA nor EMEA have any guidelines for the generic interchange of branded products at this time. The current pharmacopeial guidelines are inadequate to accept the generic version of the branded LMWHs since these apply the older guidelines. The LMWHs represent a hybrid of the biologic and chemical manufacturing processes. The European Pharmacopeial description of each of the individual LMWHs is incomplete and US Pharmacopeia is working towards developing monographs for such drugs as enoxaparin and dalteparin. Considering the complexities related to chemical and biologic profiles of LMWHs, additional guidelines for the therapeutic and generic interchangeability are warranted. Product characterization and structural equivalence are not adequate to validate the generic versions of branded LMWHs. Data obtained on the currently available generic versions of LMWHs show that while these products exhibit similar molecular and pharmacopeial profile, marked differences in their in vivo pharmacology are noted. Thus, animal studies and qualified clinical trials may be needed as acceptance criterion for the generic LMWHs. Moreover, process controls including starting material and pharmacodynamic characterization in valid models may be needed. The IUA, ICATH and SASAT has played a role in the biologic standardization and characterization of LMWHs, it is timely that a update on this topic along with expert opinions and discussions will provide a platform for the development of specific guidelines for the requirements to accept a generic version of the branded product. This Summit is organized to openly discuss important issues and generate a white paper for publication in SASAT, IUA and ICATH sponsored publications. Other public forum such as the NATF will also be used for disseminating the information generated during the Summit.
J. Fareed - Chicago, USA