The legal framework applicable to biosimilars in the EU
Biosimilars are becoming increasingly important in the European Union’s biopharmaceutical landscape due to the increased growth of biologicals as key therapies and the financial pressure this puts on healthcare budgets.
Both generic and innovator companies are players in the biosimilars market, and such drug products can present potential savings for payers. In certain cases biosimilars have gained over 90% of the market share within one to two years of launch1 . This article examines the process for the approval of biosimilars in the EU; the way in which safety and risk management is conducted; and market access issues.
The approval process Biological products are large molecules that are typically derived from living cells. They are characterised as being highly sensitive to manufacturing and handling processes, which makes them more challenging to produce (and copy) than small molecules. A biosimilar product is defined as a biological medicinal product that is similar to a reference biological product, but that does not meet the conditions in the definition of a generic medicinal product owing, in particular, to differences in raw materials or manufacturing processes.
The approval of biosimilar products has been facilitated since the introduction of a specific provision in the Medicinal Code2 . So far, twenty biosimilar products have been approved via the centralised approval process relating to eight different reference biological products – the most recent being Benepali (etanercept)3 .
The legal basis for the approval of biosimilars, Article 10.4 of the Medicinal Code, sets out the definition of a similar biological product and clarifies that an application for a marketing authorisation for a biosimilar must include the results of appropriate preclinical tests or clinical trials demonstrating similarity with the reference biological product. The goal is to exclude any relevant differences between the biosimilar and the reference product and to confirm comparable clinical performance. This contrasts with the requirements for generic medicinal products, where the applicant need only provide the results of bioavailability studies demonstrating bioequivalence with the reference medicinal product.
The type and quantity of supplementary data to be provided is set out in Annex I of the Medicinal Code and in detailed biosimilar guidelines issued by the European Medicines Agency (EMA)4 . These guidelines consist of: (a) overarching guidelines on similar biological medicinal products, non-clinical and clinical issues and quality issues; (b) product-specific guidelines such as those that include recombinant follicle-stimulating hormone, interferon beta and recombinant erythropoietins; and (c) other relevant guidelines.
From the date of submission of the marketing authorisation application, the approval process for a biosimilar product generally takes between one and one and a half years. The average cost for developing a biosimilar is estimated to range from $40 million to $375 million – this compares with the $4 million price for developing a generic medicinal product.
The first biosimilar product to be approved in the EU was Sandoz’s Omnitrope, containing the growth hormone somatropin, which was approved on the 12th of April 2006. Interestingly, Sandoz had tried to obtain a marketing authorisation for Omnitrope sometime before Medicinal Code 2004/27/EU came into effect using the process for bibliographic applications based on well-established medicinal use, but this approach was rejected by the European Commission.