The therapeutic equivalence of complex drugs

doi:10.1016/j.yrtph.2010.09.021

Regulatory Toxicology and Pharmacology

Volume 59, Issue 1, February 2011, Pages 176-183

https://doi.org/10.1016/j.yrtph.2010.09.021 Get rights and content

Abstract

When the patent of a small molecule drug expires generics may be introduced. They are considered therapeutically equivalent once pharmaceutical equivalence (i.e. identical active substances) and bioequivalence (i.e. comparable pharmacokinetics) have been established in a cross-over volunteer study. However this generic paradigm cannot be applied to complex drugs as biologics and a number of other therapeutic modalities. For copies of biologics the European Medicine Agency and other regulatory agencies have introduced a new regulatory biosimilar pathway which mandates clinical trials to show therapeutic equivalence. However for other complex drugs such as the iron–carbohydrate drugs, low molecular weight heparins (LMWHs), liposomal drugs and the glatiramoids regulatory guidance is still mostly lacking. In this paper we will discuss (therapeutic) experience obtained so far with these different classes of ‘complex drugs’ and their specifics to provide scientific arguments and criteria for consideration for a regulatory framework for the market authorization for these type of 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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The therapeutic equivalence of complex drugs☆

Abstract

Introduction

Section snippets

The generic paradigm

Therapeutic proteins

Low molecular weight heparins (LMWH)

Liposomal drugs

Complex iron–carbohydrate (“iron–sugar”) drugs

Glatiramoids

A regulatory framework for complex products

Acknowledgments

Drug Discov. Today

J. Neuroimmunol.

Am. J. Kidney Dis.

Pharmacol. Ther.

J. Pharm. Sci.

Eur. J. Pharm. Sci.

J. Am. Coll. Cardiol.

Autoimmune Rev.

Specific TH2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1

PNAS

Brand and generic medications: are they interchangeable?

Ann. Saudi Med.

Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications

PNAS

Down-regulation of IL-17 and IL-6 in the central nervous system by glatiramer acetate in experimental autoimmune encephalomyelitis

J. Neuroimmunol.

Pharmacokinetics and red cell utilization of iron(III) hydroxide–sucrose complex in anaemic patients: a study using positron emission tomography

Brit. J. Haematol.

Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography

Brit. J. Haematol.

Acute injury with intravenous iron and concerns regarding long-term safety

Clin. J. Am. Soc. Nephrol.

Widespread coronary inflammation in unstable angina

New Engl. J. Med.

Bioavailability and bioequivalence: an FDA regulatory overview

Pharm. Res.

Glatiramer acetate induces a TH2-biased response and cross reactivity with myelin basic protein in patients with MS

Multiple Scler.

Iron Therapy with Special Emphasis on Intravenous Administration

Pharmaceutical evaluation of biosimilars: important differences from generic low-molecular weight pharmaceuticals

Eur. J. Hosp. Pharm. Sci.

Pharmacokinetics and red cell utilization of ⁵²Fe/⁵⁹Fe-labelled iron polymaltose in anaemic patients using positron emission tomography