The EMEA guidelines cover a range of issues including manufacturing, measurement of comparability, physicochemical and biological analyses and clinical trial requirements. In addition to the pharmaceutical, chemical and biological data normally required for a generic drug application, applications for the market approval of biosimilar products require additional toxicological and other non-clinical and clinical data. The goal will be to demonstrate that the biosimilar product is similar to the reference product in terms of quality, safety and efficacy. Products will be dealt with on a case-by-case basis, which reflects the complexity and diversity of the products under review. Updates to the guidelines will be published on the EMEA website (www.emea.europa.eu).

EMEA/CHMP issued an overarching biosimilars guideline to set the scene and guidelines for the development of biosimilars covering quality, non-clinical and clinical issues, and immunogenicity for both biosimilars and innovator products that undergo a manufacturing change. In addition, EMEA/CHMP released four product class-specific guidelines or concept papers.

Brief details of the EMEA guidelines
The Guideline on similar biological medicinal products, which came into effect in October 2005, had the purpose of “introducing the concept of similar biological products, outlining the basic principles to be applied and providing applicants with a ‘user guide’ showing where to find relevant scientific information in the various CHMP guidelines, in order to substantiate the claim of similarity”.

The Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues came into effect in June 2006. The aim of this document is to “lay down the quality requirements for a biological medicinal product claiming to be similar to another one already marketed”. Importantly, this guideline addresses the requirements regarding manufacturing processes, analytical methods to assess comparability, factors to consider when choosing a reference product, and physicochemical and biological characterization of the SBMP.

The Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues also came into effect in June 2006. This guideline “lays down the non-clinical and clinical requirements for a biological medicinal product claiming to be similar to another one already marketed”. The non-clinical section addresses the pharmaco-toxicological assessment. The clinical section addresses the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies, with emphasis on the evaluation of immunogenicity of the SBMP.

The Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins came into effect in April 2008. This guideline provides a broad overview of the immunogenic issues that biopharmaceutical companies must adequately address for the approval of a biosimilar product or when a manufacturing change occurs. The guideline discusses factors that might influence immunogenicity and the potential consequences of immunogenicity; the development, design and interpretation of non-clinical and clinical assays to evaluate the immunogenic potency of a product and its comparability to other products; and the implementation of a risk management plan. Many of the concepts discussed in the guideline will likely need to be adapted on a case-by-case basis.

Four product class-specific guidelines were issued for the development of biosimilars containing recombinant erythropoietin (EPO), somatropin, human insulin and human granulocyte colony-stimulating factor. These documents outline pre-clinical and clinical data requirements for marketing approval, describing the size of the trials required and the best indication for demonstrating equivalence for each product, in comparison with a reference product.

One example of the product-specific guidelines is the EMEA Annex to the guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues; guidance on similar medicinal products containing recombinant erythropoietins. This guideline was effective from July 2006 and “lays down the non-clinical and clinical requirements for EPO-containing medicinal products claiming to be similar to another one already marketed”. Interestingly, the regulatory requirements are more stringent for EPO than for the other recombinant proteins, reflecting its greater molecular complexity and clinical history, i.e. antibody (Ab)-mediated pure red cell aplasia (PRCA). Equivalent therapeutic efficiency with the reference product must be demonstrated in at least two randomised, parallel-group clinical trials, which are preferably double-blind. The document also states that patients with renal anaemia would be the best study population and that after an initial titration phase the comparative phase should be at least 12 weeks, followed by a maintenance study of at least three months. Therapeutic equivalence must be demonstrated for both pre-dialysis and haemodialysis chronic kidney disease patients, and by both the intravenous and subcutaneous routes of administration. Clinical trials should involve at least 300 patients, and at least 12 months of immunogenicity data should be provided.

Recently, both France and Spain adopted legislation preventing the automatic substitution of a biological medicine for a biosimilar. This decision transposes into French law the European Directive 2004/27/EC governing the definition of generic and biosimilar medicines. Thus, French and Spanish law now forbids the replacement of one biological medicine for another at the pharmacy without the express consent of the prescribing physician.

Post-marketing surveillance
The onset and incidence of immunogenicity is unpredictable; therefore, extended post-marketing surveillance (pharmacovigilance) to monitor potential immunogenicity is very important. Biosimilar guidelines from the EMEA state that a pharmacovigilance plan to address immunogenicity and potential rare adverse events should be included in the data package submitted for the product approval. The term ‘pharmacovigilance’ describes the detection, assessment, understanding and prevention of adverse effects after the launch of a product onto the market. As already discussed previously, there are important lessons to be learned from the experience with Eprex and Ab-mediated PRCA. Although the innovator product had been in use for years, it was some time before the link between the relatively small modification in the product formulation and the increase in the number of PRCA cases was established.