Biotech Values

[Biowatch]

MNTA FDA concern about low-MW-heparins

Prof. Sasisekharan at MIT co-founded MNTA
His research includes analysis and characterization of LMW heparins.
http://web.mit.edu/tox/sasisekharan/research/index.html
========
Regulatory concern about low molecular weight heparins isn't new:

Hematol Oncol Clin North Am. 2005 Feb;19(1):53-68, v-vi.
Development of generic low molecular weight heparins: a perspective.
Fareed J, Leong W, Hoppensteadt DA, Jeske WP, Walenga J, Bick RL.

Department of Pathology, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA. [e-mail]

It is clear that the introduction of generic versions of low molecular weight heparins (LMWHs) is inevitable; however, it is important that the generic products are manufactured in strict compliance with the manufacturing specification of the branded product. Furthermore, regulatory agencies should require additional data on the chemical biologic, pharmacologic/toxicologic, and dose-response relationship in specific settings. Although there is strong opposition to stop the introduction of these drugs, their development will reduce cost and permit availability to all patients who need them. Some objective guidelines for the proper development of these drugs are needed. Only expert groups and advisory panels to the regulatory bodies can develop these guidelines.
--------
Semin Thromb Hemost. 2004 Dec;30(6):703-13.
Generic low-molecular-weight heparins: some practical considerations.
Fareed J, Leong WL, Hoppensteadt DA, Jeske WP, Walenga J, Wahi R, Bick RL.

Department of Pathology, Loyola University Chicago, Maywood, IL 60153, USA. [e-mail]

It is now widely accepted that various low-molecular-weight heparins (LMWHs) exhibit specific molecular and structural attributes that are determined by the type of manufacturing process used. For example, enoxaparin, which is prepared by benzylation followed by alkaline hydrolysis of unfractionated heparin (UFH), exhibits a double bond at the nonreducing end and the presence of a unique bicyclic structure namely 1,6 anhydromanno glucose or mannose, or both, at the reducing end. Similarly, the other LMWHs, such as dalteparin, nadroparin, tinzaparin, and parnaparin, exhibit specific structural characteristics that may contribute to their own unique biochemical and pharmacological profiles. These unique features may not exhibit any major influence on the routinely determined anti-Xa and anti-IIa activities. However, these may have an impact on the pharmacokinetics and other biological actions such as the interactions with growth factors, blood components, and vascular cells. This is the reason for the initial caution for the noninterchangeability of the anti-Xa adjusted dosing of the different LMWHs. Although the nonanticoagulant biological effects of these drugs are poorly understood at this time, they are now recognized as contributing significantly to the overall therapeutic effects of these drugs. Because some of these drugs have proved to be effective in the management of cancer-associated thrombosis and exhibit improvements in mortality outcome, these LMWHs may also produce several other effects by modulating inflammatory processes, apoptosis, and other regulatory functions related to cellular functions at different levels. Thus, the interactions of these LMWHs with antithrombin and heparin cofactor II are not the only determinants of their biological actions. Release of tissue factor pathway inhibitor (TFPI), regulation of cytokines, nitric oxide, and eicosanoids contribute to their individuality. Such properties are not only dependent on the oligosaccharide sequence and consensus sites but also depend mainly on microchemical and structural attributes in these drugs. European Pharmacopoeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of their molecular and biological profile. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) consider each of these drugs as distinct pharmacological agents. This has prompted the requirement for product-specific clinical data for the approval of their use in various clinical indications. There is a clear concern regarding the development of potential generic versions of branded products and the submissions by generic manufacturers for the regulatory approval of generic interchangeability that refers to the substitution of an apparent chemically identical and bioequivalent versions of the branded LMWHs. Currently, there are no regulatory guidelines or consensus opinions on the acceptance of generic versions of the branded products. Because the LMWHs represent not only a biological entity but also product-specific molecular and structural attributes, the acceptance of a generic version must be based on clearly defined guidelines stipulating minimal molecular and structural, biological, and clinical validation requirements. It is therefore to be stressed that each of the LMWHs is a distinct drug entity that characteristically exhibits a product-based therapeutic spectrum in different thrombotic and nonthrombotic disorders. Thus, until the establishment of valid regulatory guidelines for the generic interchangeability of the commercially available LMWHs is completed, generic substitutes are not recommended.

PMID: 15630677 [PubMed - indexed for MEDLINE]
--------
Clin Appl Thromb Hemost. 2006 Jul;12(3):267-76.

Comment in:
Clin Appl Thromb Hemost. 2006 Jul;12(3):253.

Product individuality of commercially available low-molecular-weight heparins and their generic versions: therapeutic implications.
Maddineni J, Walenga JM, Jeske WP, Hoppensteadt DA, Fareed J, Wahi R, Bick RL.

Department of Pharmacology, Loyola University Medical Center, Maywood, IL 60153, USA.

The currently available brand-name low-molecular-weight heparins (LMWHs) in the United States include dalteparin (Pfizer), enoxaparin (Aventis), and tinzaparin (Pharmion). Other products available, in Europe, include certoparin (Novartis), reviparin (Abbott), nadroparin (GlaxoSmithkline), and parnaparin (Alpha-Wasserman). Each of these LMWHs has a characteristic molecular weight profile and biological activity in terms of an anti-FXa and anti-FIIa potency. The mean molecular weight of these drugs ranges from 4.0 kDa to 7.0 kDa and the anti-FXa:anti-FIIa ratio ranges from 1.5 to 3.5. These agents may also be characterized by the presence of specific chemical end groups such as 2-O-sulfo-4-enepyranosuronic acid at the nonreducing terminus (enoxaparin) or 2,5-anhydro-D-mannose at the reducing terminus (dalteparin). Further, the component oligosaccharide chains exhibit product-specific distribution profiles. It is now widely accepted that individual LMWHs are chemically unique agents and cannot be interchanged therapeutically. Each commercial LMWH has been individually developed for specific clinical indications, which are dose and product dependent. Recently, several generic LMWHs have become available in India (Cutenox and Markaparin) and South America (dilutol, clenox, dripanina), and three companies have filed for regulatory approval of a generic version of enoxaparin in the United States. As the primary aim of a generic drug is to reduce cost without compromising patient care, a generic drug is required to be chemically and biologically equivalent to the pioneer drug. Because LMWHs represent complex natural mucopolysaccharide drugs that have undergone chemical and enzymatic modifications, physicochemical and biological information in addition to molecular weight and anti-FXa:anti-FIIa ratio should be used to determine generic equivalency to the branded drug. We have utilized a previously reported approach to systematically compare three generic versions of enoxaparin obtained from India and Brazil with the branded enoxaparin (Lovenox) available in the United States. Testing included molecular and structural profiling, evaluation in clot-based and amidolytic anti-FXa and anti-FIIa assays, and heparinase-I digestion profiles. While the molecular profiles (4.8 +/- 1.8 kD) and anticoagulant potencies as determined by activated partial thromboplastin time (APTT) were comparable for all four agents, the generic products showed variations in the thrombin time (TT) and Heptest assays. Two generic and the branded enoxaparin were readily digested by heparinase-I, losing most of their anticoagulant activity, but one generic product resisted digestion. This may have been due to a unique structural feature in this product. These studies show that, while generic LMWHs may exhibit acceptable molecular weight and anti-FXa profiles, they can exhibit assay-based differences and digestion profiles. Testing in animal models to determine safety, efficacy, and pharmacodynamic parameters may be important to verify equivalence. In order to assure that the generic LMWHs are equivalent to branded LMWHs such that equivalent clinical results are obtained, there is a need to develop clear stepwise guidelines that will establish equivalency in terms of physical, chemical, biochemical, pharmacokinetic, and pharmacodynamic properties for these anticoagulant drugs.

PMID: 16959680 [PubMed - indexed for MEDLINE]