Brussels Report

Jacques Chirac and Tony Blair don't exactly see eye-to-eye on how to make Europe more competitive, but they share the same comfortable privilege of being able to discuss it theoretically. And discussing it in theory is just what they and their fellow leaders from the other 23 member states of the European Union (EU) did in Brussels in March, as they nodded their agreement to a series of measures designed to boost the EU's economy over the next 5 years.

Agency requirements

"Europe must renew the basis of its competitiveness," EU leaders agreed at their Brussels summit meeting on 22–23 March, placing the emphasis on innovation and research. Their new bid to improve Europe's economic prospects through support to sectors such as high technology pharmaceuticals included a long list of proindustry factors, ranging from assistance to innovative smaller firms and high-tech start-ups, to promoting joint research between business and universities, effective intellectual property protection, elimination of unnecessary red tape, and improved access to risk capital.

EU leaders also agreed to keep aiming for an overall 3% investment level in research and development, with tax incentives for private investment, better leveraging by public investment, and modernized management of research institutions and universities. The new European research programme now under preparation will be geared to stimulating private investment and helping to fill the technology gap. A European Research Council and a European Technology Institute are to be created to support cutting-edge research, and a new mechanism established for financing innovative smaller firms with high growth potential.

The new plans include public–private technology partnerships and platforms to consolidate Europe's industrial fabric and to set long-term research agendas at national and European level. The EU's own investment bank is to be given a mandate for extending financial support for R&D, and for innovative technology-transfer networks.

Proof of Pudding

But attractive though all these concepts are, they tend to fall into the "jam tomorrow" zone of action. If they happen, they will be nice, but they haven't happened yet.

By contrast, the European pharmaceutical industry is already giving proof of a substantial pudding ready for eating. Across a broad range of activity, it is developing new products that help patients, push out the frontiers of knowledge, promote a strong research base, assure jobs, and maintain the buoyancy of Europe's exports into world markets.

That is why drug companies are now being asked to give their views on how to regulate "biosimilars" — copy products of biopharmaceuticals. At the same time as EU leaders were haggling over the theory of competitiveness in Brussels, the European Medicines Agency in London (UK) was releasing a draft note for guidance on the key factors in assessing this new area of pharmaceutical technology — in essence, generic medicines containing recombinant DNA-derived proteins. And companies have until the end of June to tell the agency what they think of the new rules.

The emergence of biosimilars — a concept that has come into common usage only over the last year or so — is itself a demonstration of the competitiveness of the pharmaceutical industry. Innovation by some has naturally led to emulation by others: and because the make-up of biotechnology-derived products is so much more complex than classic chemical-derived products, there are some delicate questions to be answered about how far generic copies can rely on data from the original product to support a marketing authorization application.

As the draft guideline points out, a company may choose to develop a new biological medicine claimed to be similar in terms of quality, safety and efficacy to an original, reference medicine product which has been granted an EU marketing authorization; but similar biological medicines are manufactured and controlled according to their own development, taking into account such factors as manufacturing processes, product characteristics, stability and comparability data. So in most cases, only limited comparison can be made against official data such as pharmacopoeial monographs or against other published scientific data.

The biosimilar product is defined by its own specific manufacturing process for both active substance and medicinal product, and this process should be optimized taking into account state-of–the-art information on manufacturing processes (such as expression system/cell substrate, culture, purification and viral safety) and consequences for product characteristics. And because each product is defined by the molecular composition of the active substance resulting from its process, there is a risk of process-related impurities being introduced. So, reasons the agency, the biosimilar product is defined both by the characteristics of the molecule (including product related substances/impurities), and by its process. Each applicant will be required to demonstrate the consistency and robustness of his own process.

Comparisons at the level of active substance and finished product are not going to be sufficient for a full evaluation of biosimilarity, the Medicines Agency says, so an extensive comparability exercise will be required to demonstrate that the biosimilar and reference products have similar profiles in terms of quality, safety and efficacy. And only when supported by sufficiently sensitive analytical systems can the demonstration of comparability at the quality level connect the biosimilar product to the nonclinical and clinical data previously generated with the reference product, it warns.

A full quality dossier is required, supplemented by a demonstration of comparability — an additional element to the normal requirements of the quality dossier. The standard quality overall summary in the application should also deal with comparability issues in separate sections to facilitate review, cross referencing the appropriate separate sections of the dossier that contain the relevant data.

Formulation studies should be considered in the course of the development of a suitable dosage form, even if excipients are qualitatively and quantitatively the same as the reference product, to demonstrate suitability with regard to stability, compatibility with excipients, diluents and packaging materials, and biological and physico-chemical integrity of the active substance for its intended medicinal use.

Quality Comparisons

It is not expected that the quality attributes in the biosimilar and reference products will be identical: minor structural differences in the active substance such as variability in post-translational modifications may be acceptable (although they must be justified). The impurity profile in the product should also be fully justified, and will be assessed on a case-by-case basis.

Although the biosimilarity exercise will be easier when the pharmaceutical form, formulation, or strength of the biosimilar product are the same as the reference medicinal product, other approaches may be considered by the applicant. In any case, a clear scientific justification of the criteria followed to select the reference medicinal product should be provided, with specific attention to its critical parameters and quality attributes. The same reference medicinal product should be used for the quality, safety and efficacy parts of the application dossier.

There are no short cuts available to copyists. The comparison of the biosimilar active substance to a publicly available standard as a reference (such as European Pharmacopoeia or World Health Organization) is not going to be sufficient to demonstrate biosimilarity of the active substance, because safety and efficacy profiles may not be sufficiently defined. In addition, the biosimilar manufacturer generally has no access to the originator active substance, so cannot directly compare his active substance to the one used in the originator's medicinal product. Still, the biosimilar manufacturer has to demonstrate, using state-of-the-art analytical methods, that the active substance used in the comparability exercise is representative of the active substance present in the reference medicinal product.

There are situations where the analytical tools used for characterization may not be capable of directly comparing the biosimilar active substance versus the active substance present in the reference medicinal product. In these situations, the applicant will have to use other approaches to obtain representative reference active substance derived from the reference product, so as to perform the comparative analysis at the active substance level. This approach will have to be appropriately validated to demonstrate the suitability of the sample preparation process, and will have to include the comparison of the biosimilar active substance with active substance material derived from the reference and the biosimilar medicinal products.

Here in a nutshell are all the elements of a competitive Europe: an industry that can and does innovate in high-technology areas, that is keenly geared to rivalry in pursuit of markets, that is able to cope with the most arduous levels of regulatory control as a part of product safety and guarantees of customer satisfaction, and very largely self-sustaining, generating most of its funding for innovation from its own sales in tough markets.

If EU leaders would just step down for an afternoon from their Olympian heights, and spend some time in the laboratory and on the shop-floor, they would soon see that what they like to discuss as future theory is already current practice in European pharmaceutical technology.