European Union: Biological Medicines And Biosimilars

Last Updated: 4 April 2014
Article by Jennifer Pierce and Christopher Birch

A watershed moment was seen in September 2013 with the grant by the European Commission of marketing authorisations throughout the European Union for the first two biosimilar versions of the monoclonal antibody, infliximab (Remicade®).

In this article we give an overview of biological medicines and biosimilars and looks at why this is such an important event.

What is a biosimilar and how are they regulated?

Because the originating company's cell line and manufacturing processes will be proprietary/confidential to them it is impossible for another company to reproduce a biological medicine in the same way that an identical "generic" version of a chemical medicine can be produced.

A "biosimilar" is therefore a biological medicine which is developed to be as close to the original biological medicine as possible.

Applications for marketing authorisations for all biological medicines, including biosimilars, are required to be submitted to the European Medicines Agency ("EMA") through the European Centralised procedure. In the EU there is a specific regulatory pathway for the approval of biosimilars. However, because of the inevitable differences between the biosimilar and the original biological medicine (the "Reference Medicine") and hence the potential for differences in safety and efficacy, obtaining a marketing authorisation for a biosimilar is still much more complex and costly than obtaining a marketing authorisation for a generic medicine, where a much abridged procedure can be followed.

As the Reference Medicine has been authorised in the EU for several years and its clinical benefit is established, some studies carried out with the Reference Medicine may not need to be reproduced. The main part of the approval process for a biosimilar is therefore a comparison of it against the Reference Medicine to show that there are no significant differences between them in terms of quality, safety and effectiveness. This includes comprehensive comparisons of the structure and biological activity of the active substances and an assessment of differences in their respective benefit and risk. The EMA does not however specifically evaluate whether a biosimilar can be used interchangeably with its Reference Medicine.

Biosimilar manufacturers must provide all of the pre-clinical and clinical data required to demonstrate the similarity of their product with the Reference Medicine. The level of data required is assessed on a case by case basis but it will be less than that required for an original biological medicine. The above can be contrasted with obtaining a marketing authorisation for a generic medicine, where non-clinical studies and clinical trials are not usually required, and the generic manufacturer only needs to demonstrate the bioequivalence of their product against the original product – which is usually a case of confirming that the blood levels of patients taking the generic product given at a certain dose are the same as they would be when taking the original product in a small number of healthy volunteers.

What is a biological medicine?

Biological medicines are medicines which contain active substances made by or derived from a biological source - they are created by biological processes rather than by chemical synthesis. Examples include insulin and growth hormone, both proteins, and monoclonal antibodies.

Biological medicines are far more complex and usually much bigger than medicines produced by chemical synthesis. This and the way that they are produced means that it is harder to reproduce biological medicines exactly. The fact that they are produced by complex manufacturing processes using living systems means they show considerable variability compared to chemical medicines. Differences in the cell line used and minor variations in conditions during the manufacturing process can result in significant variation in the properties of the biological medicine. Variability therefore occurs between batches in particular but can also occur within a single batch.

Significance of these approvals

The authorisation of these infliximab biosimilars (Remsima and Inflectra) is of great significance because monoclonal antibodies are particularly structurally complex substances that can locate and bind to specific molecules, and this is the first time that the biosimilar concept has been successfully applied to such a complex molecule.

The European Generic Medicines Association has described this approval as the beginning of a new era of biosimilar medicines. It has long been argued by originators that the biosimilar concept carries higher risk for patients. In the case of these biosimilars the EMA applied regulatory criteria which required the products to be subjected to extensive testing, including phase III trials, before marketing authorisation could be granted. It is hoped that the fact that such a robust process has resulted in a positive outcome, with Remsima and Inflectra being authorised for the full range of indications Remicade is authorised for, will set a precedent for future biosimilar antibody approvals.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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Christopher Birch
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