The therapeutic equivalence of complex drugs☆
Introduction
This paper is based on the presentations and discussion during the TI Pharma workshop on the therapeutic equivalence organized in Leiden, 7 October 2009. A follow-up workshop is organized during the EUFEPS/AAPS meeting in New Orleans in 2010. The aim of the workshops and follow-up discussions with stakeholders including the manufacturers of original products as well as generics and biosimilars is a consensus paper about the scientific issues involved in showing therapeutic equivalence of complex drugs to support the development of harmonized regulatory pathways for generic/similar of these drugs.
This paper intends to give a global view about the difficulties involved in assessing the therapeutic equivalence of complex drugs by some examples and also outlines also a possible regulatory framework. The paper is not the consensus of the Leiden workshop but only reflects the opinion of the authors and want to contribute to the ongoing debate. The issues are highly controversial and are currently discussed at many levels, including most regulatory agencies. A number of guidelines are under development and official opinions have been made public, showing some fundamental differences between the approach by the FDA and the EMA.
Section snippets
The generic paradigm
When the patent of a classical small molecule drug expires generics may be marketed if their therapeutic equivalence to the original drug has been established (Al-Jazairi et al., 2008, Chen et al., 2001, Meredith, 1996). Conventional generics for an orally administered drug are considered to be therapeutically equivalent to a reference once pharmaceutical equivalence (i.e. identical active substances) and bioequivalence (i.e. comparable pharmacokinetics) have been established in a cross over
Therapeutic proteins
Therapeutic proteins are the clinically most widely used class of drugs for which the classical generic paradigm cannot be used (Crommelin et al., 2005, Schellekens, 2005). The molecular mass of most of the therapeutic proteins varies from 5 to 150 kDa, which is 25–1000 times larger than the average small drug molecule. Nearly all therapeutic proteins are produced by living cells and these cells in general make mixtures of different proteins, e.g. by variation in the process of post-translation
Low molecular weight heparins (LMWH)
The complexity of LMWHs is given from the starting material. UFH (unfractionated heparin) is an incompletely characterized heteropolymer of 48 theoretical disaccharide variants (building blocks), extracted and purified from animal mucosa. LMWHs are obtained through specific and proprietary depolymerization processes of UFH with each process resulting in a distinct end product. LMWHs are comprised of a mixture of thousands of oligosaccharides (complex sugars) also incompletely characterized and
Liposomal drugs
Liposomes have been discovered more than 40 years ago, and represent a successful example of a particulate drug delivery system and a lot of literature is available. A list of recommended literature is added in the list of references (Maurer et al., 2001, Gabizon et al., 2003, Zuidam et al., 2003, Gregoriadis, 2007, Drummond et al., 2008).
Liposomes are vesicles composed of one or more phospholipid bilayers surrounding an aqueous compartment and can be formed from a great variety of lipid
Complex iron–carbohydrate (“iron–sugar”) drugs
Venofer® (iron–sucrose [IS]) is the main representative of the iron-oxyhydroxide carbohydrate drugs, a class of colloidal IV iron preparations (Crichton et al., 2008). For the treatment of iron deficiency anemia associated with chronic kidney disease (dialysis and pre-dialysis), in pregnancy, through malabsorption, autologous blood donation and other conditions, mostly with high prevalence in the population.
The physico-chemical properties and thus the pharmacological activity of these high
Glatiramoids
The prototype glatiramoid is Copaxone® approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), containing the active substance glatiramer acetate (GA), which is classified as a chemically synthesized active substance. GA is a complex heterogeneous mixture of polypeptides with immunomodulatory activity (Aharoni et al., 2000, Schrempf and Ziemmsen, 2007, Sarasella et al., 2008, Hestvik et al., 2008, Begum-Haque et al., 2008, Liu et al., 2007). Until recently GA was the only
A regulatory framework for complex products
The regulatory approach for the authorization of generic products is based on the principle that two small molecule drugs are considered therapeutically equivalent if their active substance is shown to be structurally identical and their PK characteristics are equivalent. In this report we have discussed whether this classical generic paradigm applies to complex drug classes of biologics, the LMWH, glatiramoids and iron–carbohydrate complexes.
For biologics the EMA has pioneered a comprehensive
Acknowledgments
The authors of the paper want to acknowledge the contributions of the participants of the TI Pharma consensus meeting: Bioequivalence of Complex Drugs 7 October 2009, Leiden, the Netherlands. The meeting was sponsored by Teva, Sanofi-Aventis and Vifor-Pharma.
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Based on the discussions during the TI Pharma Consensus Meeting: Bioequivalence of Complex Drugs, 7 October 2009, Leiden, The Netherlands.
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