Originally published March 2005

Introduction

Follow-on biologics, being copies of biologic drugs manufactured by innovative pharmaceutical companies, have been covered in the Life Sciences Newsletter previously, most notably in Issue 22 (June 2004), where various pieces of European legislation and guidance were discussed.

As an update to that discussion, on 16 November 2004, the Committee for Medicinal Products for Human Use ("CHMP"), a part of the European Medicines Agency ("EMEA"), issued a document entitled "Guidelines on Similar Biological Medicinal Products". This Guideline remains a draft and is subject to consultation.

Draft guidance

It was widely hoped that these draft guidelines would flesh out the legislation, and provide an indication of what additional testing would be required to be filed by follow-on biologic manufacturers in order to gain marketing authorisation. However, the draft guidelines largely reiterate what was already known, and only add limited information about the application of the "Biosimilar" test. The most useful part of the guidance is the section relating to the "Biosimilar" approach, and this is summarised below.

The Biosimilar approach

The key points that the draft guidance makes about the "Biosimilar" approach are:

  • All applications for approval for a "follow-on" biologic will be treated on a "case-by-case" basis.

  • Biological medicinal products are more difficult to characterise than chemically derived medicinal products, and significant alterations may be effected by "minor" changes in the manufacturing process. Thus, the safety/efficacy profile is highly dependent on the robustness and the monitoring of quality aspects.

  • Due to the complexity of biological products, demonstration of bioequivalence with the referenced medicinal products by bioavailability studies is not appropriate. Instead, comparability exercises will be used.

  • These comparability exercises are more likely to be applied to highly purified products which can be thoroughly characterised, for example, biotech derived products, as opposed to those arising from extraction from biological sources and/or those for which little clinical and regulatory experience has been gained, such as gene and cell therapy products. The draft guidelines state that satisfying the test for immunologicals for example, vaccines will be difficult, and for blood or plasma derived products impossible.

  • Success in gaining approval will be dependent upon:
    • the ability to characterise the product

    • the degree of molecular complexity, eg 3D structure, amount of acido-basic variants or post transitional modifications

    • the state of the art for the relevant analytical and manufacturing processes

    • other factors.

  • By definition, follow-on biologics are not generic medicinal products, and it is to be expected that there will be subtle differences between a follow-on product and the reference product. These differences may not become fully apparent until further experience has been gained with them, and therefore, in order to support pharmacovigilance monitoring, the specific product given to a patient should be clearly identified.

The draft guidelines are accompanied by four concept papers relating to:

  • recombinant human growth hormone

  • recombinant human insulin

  • recombinant human erythropoietin

  • recombinant human granulocyte colony stimulating factor.

These papers in themselves indicate the kind of products for which the EMEA considers there is a reasonable prospect of success.

The key message from these draft papers is that potential applicants should contact the EMEA as early as possible to obtain guidance on the applicability of the biosimiliar route and the comparability testing required.

Consultation on the draft guidelines and concept papers continued until the end of February 2005.

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.