Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany
Biopharmaceuticals are medicinal products containing biotechnology or biology-derived substances (proteins or polysaccharides) as their active ingredients. Many biopharmaceuticals are proteins that are manufactured using recombinant DNA technology, a process that involves inserting a specific gene into a host cell to produce a particular protein.
These complex molecules represent a distinct regulatory class of medicine compared to chemically synthesised medicines. The development of these biological therapies has helped improve treatment outcomes in many diseases, including cancer, rheumatoid arthritis, multiple sclerosis, diabetes and anaemia.
Patents for the first generation of approved biopharmaceuticals have either expired or are about to expire, providing opportunities for the development of similar versions of these medicines. The advent of these agents, referred to in Europe as biosimilars, offers potential benefits to patients, physicians and healthcare providers by offering improved access to high-quality biopharmaceutical treatments at reduced cost.
Biopharmaceuticals are typically complex high-molecular-weight recombinant proteins that are produced in living systems. As such, the development and manufacture of biosimilars is considerably more complex than that of traditional generic chemical medicines. Also, unlike generics, biosimilars are comparable but not identical to their reference product.
Because of this, biosimilars require a specific regulatory framework and authorities across the world are in the process of developing approval pathways. The European Medicines Agency (EMA) has led the way in developing guidelines for the evaluation and approval of biosimilars and has approved several biosimilar proteins on the basis of comparable quality, safety and efficacy with their reference product.
EMA guidelines address quality issues such as manufacturing processes, analytical methods to assess comparability with a reference product, and physicochemical and biological characterisation. The guidelines also outline the requirements for pharmaco-toxicological assessment and clinical development, and evaluation of potential immunogenicity.
In addition to these general guidelines, product-class specific guidelines have been issued for the development of biosimilars based on erythropoietin, somatropin, granulocyte colony-stimulating factor (G-CSF), insulin, interferon alpha and low molecular weight heparins (LMWH). The EMA have also recently published draft guidelines for the approval of biosimilar monoclonal antibodies and additional guidelines are in development for other product classes.
Although approval of all biosimilars is based on comparability with a reference product, exact data requirements may differ between products. For example, the regulatory requirements are more stringent for recombinant erythropoietins than for the other recombinant proteins.
Lower regulatory barriers
Other countries (e.g. Australia, Japan) have adopted guidelines based on those in Europe. However, the regulatory barriers to market entry for biosimilars are not as high in some other regions, such as South America and Asia. As a result, different versions of biopharmaceutical products have launched in these markets. These copies of biopharmaceuticals cannot, however, be considered to be biosimilars, as they have not been approved by a regulatory process as stringent as that employed in Europe.1
Analysis of epoetin copies produced by manufacturers in Argentina, Brazil, China, Korea and India has shown that these products differ widely in composition, do not always meet self-declared specifications with regard to erythropoietin content and bioactivity, and exhibit considerable batch-to-batch variation. As well as the failure to show comparability on the basis of analytic data, clinical studies conducted have not been sufficiently rigorous to show equivalent safety and efficacy.2
The pathway to approval of biosimilars in Europe requires far more rigorous testing than is needed for a conventional generic drug or for a change in production process by the originator company. The EMA has now approved several biosimilars in the EU, the first, in 2006, being a recombinant human growth hormone (somatropin), Omnitrope (developed and marketed by Sandoz), a biosimilar version of Pfizer’s Genotropin. Subsequently, another biosimilar somatropin (Valtropin by Biopartners) has been approved in the EU.
Two biosimilar versions of recombinant human erythropoietin have also been approved in Europe, which are marketed under five different brand names. HX575, marketed as Binocrit (Sandoz), Epoetin alfa HEXAL (Hexal AG) and Abseamed (Medice Arzneimittel), is a biosimilar version of the reference product, Eprex (epoetin alfa).
The second biosimilar epoetin approved in Europe is SB309, marketed as Retacrit (by Hospira) and Silapo (by STADA). In addition, three biosimilar filgrastim products, marketed under various different brand names, have been approved for the treatment of neutropenia. Ratiograstim/Filgrastim ratiopharm (both by Ratiopharm GmbH), Biograstim (by CT Arzneimittel GmbH), and Tevagrastim (by Teva Generics GmbH) are produced by the same manufacturer and are biosimilar to the reference product Neupogen. More recently, two more biosimilar filgrastim products, Zarzio (by Sandoz)/Filgrastim Hexal (by Hexal AG) and Nivestim (by Hospira) have been approved.
Not all successful
Not all applications for marketing approval of biosimilars have been successful. In 2006, the EMA rejected an application for approval of a biosimilar interferon product due to concerns regarding product characterisation, manufacturing and quality control. This highlights that the approval pathway for biosimilars is not straightforward, with products requiring assessment on a case-by-case basis.
Because biosimilars are complex to develop and manufacture, it is important that those producing such medicines are experienced in protein production and design their processes so that product quality is the primary goal. It is very apparent that quality cannot be tested into a product after manufacture, but must be integral to the design of the entire manufacturing process.
The development and approval of biosimilars provides an opportunity for manufacturers to consider the quality of the product during the whole development process. This concept of quality by design is central to the development and manufacture of high-quality biosimilars. Indeed, the use of state-of-the-art technology to produce biosimilars may compare favourably with the production of originator biopharmaceutical products. A recent analysis has found that the quality of certain biosimilar epoetins may exceed that of the original product.3
The biosimilar approval pathway in Europe is a scientifically rigorous and robust process involving several stages, the aim of which is to demonstrate comparable product quality, safety and efficacy of the biosimilar with its reference product in order to achieve approval by the EMA. The exact requirements differ between products, but approval is based upon a comparability exercise involving physicochemical and biological protein characterisation, pre-clinical testing, phase I pharmacokinetic and pharmacodynamic studies and phase III evaluation of clinical efficacy and safety.
Extensive physicochemical and biological characterisation of the biosimilar protein to demonstrate comparability to the reference product is a key aspect of the European approval process. This characterisation includes an array of standard and advanced tests for primary and higher-order protein structure, isoforms, aggregates, receptor binding and biological activity.
Protein characterisation has become increasingly feasible in recent years because of rapid advances in analytical methods and provides important evidence on protein identity, purity, stability and bioactivity. For example, the primary protein structures of biosimilar filgrastim (Zarzio) and its reference product (Neupogen) were shown to be identical by peptide mapping with UV detection and mass determination.
Circular dichroism and nuclear magnetic resonance (NMR) spectroscopy demonstrated that the two products have comparable secondary and tertiary structures. Reversed-phase high-performance liquid chromatography and other methods showed that the products have similar purity profiles. Comparable affinity with the G-CSF receptor GCSFR/CD114 was shown by surface plasmon resonance spectroscopy, and comparable in vitro bioactivity was shown in a cell proliferation assay.4
Biosimilar approval also requires demonstration of equivalence with respect to pharmacokinetic and pharmacodynamic profiles, as well as clinical efficacy and safety data. The development of the biosimilar erythropoietin Binocrit included three phase I studies in healthy adult volunteers. Two of these studies confirmed pharmacokinetic and pharmacodynamic bioequivalence of Binocrit with its epoetin alfa reference product (Eprex) after subcutaneous (SC) and intravenous (IV) administration, while in the third study comparability was shown with epoetin beta.5,6,7
In addition, comparable efficacy and safety of Binocrit with its reference product was shown in two randomised, double-blind phase III studies; one in patients with chronic kidney disease and one in patients with cancer.8,9
Assessing products individually
The clinical development of the biosimilar filgrastim Zarzio was focused on the pharmacodynamic response in healthy subjects rather than a comparative phase III study. This is in accordance with the EMA guidelines for the demonstration of clinical efficacy of a biosimilar G-CSF and highlights the need to assess products on an individual basis. Studies in healthy volunteers may be especially useful to evaluate the haematopoietic effect of filgrastim, since their bone marrow is more responsive to G-CSF than that of patients with cancer undergoing chemotherapy.
In four comparative phase I studies, Zarzio and its reference product Neupogen had comparable effects on absolute neutrophil count (ANC) and CD34+ cell count (used as surrogate markers of efficacy) with confidence intervals within predefined equivalence boundaries.10 Pharmacokinetic parameters also showed bioequivalence. In addition, Zarzio was effective and well tolerated in a supportive non-controlled phase III study in patients with breast cancer receiving cytotoxic chemotherapy.10
Like all new medicines, biosimilars need to be carefully monitored in the clinical setting after marketing authorisation has been granted. Post-approval studies and extensive pharmacovigilance will help provide further evidence of their efficacy and safety in clinical practice.
Major growth area
Biopharmaceuticals are a major medical growth area. In addition to over 150 existing agents, several hundred more biopharmaceuticals are under development, mostly in the fields of oncology, infectious disease, autoimmune disease and respiratory disorders. Targeted biological therapies are also predicted to dominate drug development over the next decade. These medicines are increasing clinicians’ ability to fight diseases, and improving outcomes for millions of patients worldwide.
However, biopharmaceuticals can be expensive. In 2008, sales of biopharmaceuticals amounted to around €60 billion in Europe. The increasing demand for biopharmaceuticals will place increasing cost pressures on healthcare providers. The development of biosimilars may result in less expensive alternatives to original products, thereby widening patient access to treatments. It has been estimated that a 20% price reduction of five off-patent biopharmaceuticals as a result of biosimilar competition could save the EU in excess of €1.6 billion a year.11
In conclusion, the development of biosimilars in Europe involves a scientifically robust process within a specific regulatory framework designed to show comparability with a reference product with regard to quality, safety and efficacy. This process, together with post-marketing surveillance and safety assessment of products, should ensure that only high-quality rigorously tested products reach the hospital formulary. The availability of biosimilars may provide benefits to patients and healthcare providers by increasing choice and improving access to biopharmaceutical medicines.
*All EMA guidelines and data leading to approval of the respective products are available from the EMA website: http://www.ema.europa.eu
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- Oldham T. ‘Strategy options for entering the biosimilar market’. In: Biosimilars – Evolution or Revolution?