UK: Biogenerics: On Route to Regulatory Approval?

The generic drug market is now firmly established as a major part of the European pharmaceutical sector, with generics forming a significant proportion of off-patent drug sales, especially in Germany, the Netherlands and the UK. Generic drugs composed of biopharmaceuticals – so-called ‘biogenerics’ – are yet to make an impact however despite the incentive of what is, potentially, a highly-lucrative market. Several of the world’s biggest blockbuster drugs are biopharmaceuticals and have or soon will lose their compound patent protection. The main European patent on erythropoietin for example, the drug that netted Kirin-Amgen approximately U$4bn in sales in 2003, expired at the end of last year. Furthermore, by 2010 it is estimated that nearly half of all new marketing approvals will be for drugs of biotechnological origin (source: IMS Global), making this a potential market no company in the biopharma sector can ignore.

A biogeneric drug’s route to market is however significantly more difficult than that of a conventional pharmaceutical. The technologies involved are of course highly complex, but the principal obstacle that faces any generics company is obtaining marketing approval for such a product. These difficulties have been such that even the more sophisticated generic companies have failed to obtain drug approvals in Europe and the US. The situation is epitomised by Sandoz’ applications relating to its generic human growth hormone product, Omnitrop, which despite receiving an initial positive opinion was denied marketing approval in Europe. Sandoz is currently challenging this decision in the European court of Justice.

The European regulatory framework has however been revised in recent years, with provisions that are key to biogeneric approvals due to be brought into effect in late-2005, and it is thought that this new regime could lead to the authorisation of the first biogeneric drug in Europe. This article describes the relevant European legislation and its anticipated implementation, and following the first approval of a biogeneric drug in Australia (Sandoz’ Omnitrop), it considers whether the tide has now turned for European biogenerics.

Traditional generic pharmaceuticals are essentially cheaper, ‘copy cat’ versions of branded drugs for which patent protection (at least on the drug compound itself) has expired. The term ‘biogeneric’ is often used to describe a generic drug that is of biotechnological origin – medicinal products containing proteins derived from recombinant DNA and hybridoma techniques for example. Proteins are large, complex and often heterogeneous molecules, and their particular constitution is often determined by their process of manufacture. This is in stark contrast to conventional small molecule drugs, which are inherently more predictable and normally possess a discrete set of characterising properties. There is some debate over the terminology that should be used to describe generic forms of biopharmaceutical drugs, with names such as ‘biosimilars’, ‘generic biologics’, ‘follow-on proteins’ and ‘follow-on biologics’ being floated, and the US FDA is currently grappling with this issue. Whichever term is used however, there is no doubt that biogenerics differ significantly from other generic pharmaceuticals.

Driven by the need to agree the revised legislation before EU enlargement, agreement was finally reached on major reforms of the regulatory framework which governs European marketing approvals in early 2004. This resulted in the adoption of a new Directive (Directive 2004/27/EC) amending Directive 2001/83/EC which lays down a broad range of rules relating to the manufacture, marketing and distribution of medicinal products, and includes provisions on the requirements for marketing authorisation. The new Directive was accompanied by new Regulation 726/2004. That Regulation replaces existing Regulation 2309/93 and relates to the operation of the renamed European Medicines Agency (previously the European Medicines Evaluation Agency though still referred to as the ‘EMEA’).

Broadly speaking, there are three potential routes for a company seeking marketing approval for a biogeneric. First, it could submit a full dossier of clinical and non-clinical data, just as would be submitted by the maker of a new drug, but this is not an attractive option because of the time and expense involved. Secondly, it could seek to demonstrate that its product already has a well established medical use within the Community. However, this route was originally designed to cater for very well established products such as aspirin or evening primrose oil which have been used over a long period of time. It will therefore not be open for many biotechnological products which by their nature are relatively new. It was however the route followed by Sandoz for Omnitrop in Europe in view of the regulatory framework existing at the time of Sandoz’ applications.

The third route to approval, which is the one favoured by most generic manufacturers, is the so-called ‘abridged procedure’. In an abridged application, the applicant seeks to demonstrate to the regulatory authority that its product is essentially the same as (i.e. a "generic" of) a product which has previously received authorisation and is already on the market. If this can be demonstrated, the generic applicant is then permitted to rely on the results of clinical trials already conducted in relation to the originator’s product, rather than conducting its own clinical trials which would, theoretically, generate the same results anyway. The abridged procedure therefore provides generics companies with the quickest and most cost-effective method of gaining a European marketing authorisation, so long as the required degree of similarity can be shown.

The crucial question is just how similar the new product has to be to the originator’s, and this in turn raises the issue of what evidence is required to demonstrate similarity. This question is particularly pertinent for biogenerics because of their inherently complex and variable structures, and the dependence of the nature of the product on manufacturing conditions.

Prior to amendment by Directive 2004/27/EC, Article 10 of Directive 2001/83/EC required that an applicant show that its product was "essentially similar" to the originator’s medicinal product in order to obtain marketing authorisation by the abridged procedure. This term was interpreted by the European Court of Justice (ECJ) in the Generics (UK) case (Case C368/96 in which judgment was given on 3 December 1998) which set out the three requirements for essential similarity. Unless it was apparent in the light of scientific knowledge that the product differed significantly from the original product as regards safety or efficacy, a product would be essentially similar if it:

(1) had the same qualitative and quantitative composition in terms of active principles as the originator’s product;

(2) was in the same pharmaceutical form; and

(3) was bioequivalent.

This was thought by many commentators to be an insurmountable test when it came to biogeneric drugs. Their complex nature meant that it was unlikely to be fulfilled, as did the possibility that even subtle differences in their process of manufacture (compared with the originator’s) could significantly affect the nature of the product.

When the provisions of Directive 2004/27/EC have been implemented and the Regulation comes fully into force (as to which see the section on Timing below), the requirement of essentially similarity will have been removed. The amended form of Article 10 instead permits applications under the abridged procedure for so-called "generic medicinal products"

The definition of generic medicinal products in Article 10 contains similar requirements to those espoused by the ECJ in the Generics case, and it is therefore unlikely that biogenerics will fall within it. However, a key change to Article 10 is the addition of new paragraph 10(4) which states:

This provides a new route by which marketing authorisations could be obtained for biogenerics via the abridged procedure. Where, as would be expected, a biogeneric does not fit into the "generic medicinal product" definition, then appropriate trial results could be provided to supplement the data already held by the authority relating to the originator’s biopharmaceutical product in order to obtain approval.

As well as introducing a new approval route, Directive 2004/27/EC includes a new Article 10(6) which should benefit companies using that route to seek approval for a biogeneric. This article is a ‘Bolar’ type provision which exempts the conducting of studies with a view to such an application from patent infringement. Presently, the status of such studies varies significantly between the Member States of the EU and is a matter of considerable debate. When the new provision is brought into force, it should provide a further incentive to biogenerics companies, allowing them to conduct appropriate trials within the EU with considerably less concern over patent infringement.

Guidance on the sorts of supplementary data envisaged when applying for an approval under Article 10(4) has also been released. Article 10(4) itself states that the data must comply with the criteria set out in the Annex to the Directive (which is in effect the Annex to amending Directive 2003/63/EC). That Annex describes in general terms the scientific and technical requirements for each part of the dossier of information which must be submitted when applying for marketing approval.

More specific Guidance for approval applications for biogenerics has since been released by the EMEA’s Committee for Proprietary Medicinal Products. These include the following guidelines relating to biotechnology derived active substances, which are already in operation:

(a) "Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance – Quality Issues"

This guideline came into operation in December 2003 and is concerned with the comparability of such products where: (i) changes have been made to a manufacturing process (which could potentially affect the safety or efficacy profile of such products); and (ii) applications are made for marketing approval for such products using the abridged procedure. It provides guidance on the comparability exercise which should be carried out in such circumstances.

(b) "Guideline on Comparability of Medicinal Products Containing Biotechnology-derived Proteins as Active Substance – Non-Clinical and Clinical Issues"

This guideline is to be read in conjunction with Guideline (a) above and came into operation in June 2004. It seeks to explore the non-clinical and clinical data which will be required in situations where comparability is an issue, including where applications for such products are made under the abridged procedure, in order to show that a product has a similar profile in terms of quality, safety and efficacy to the original product.

Further important guidelines relevant to biogenerics, drafted by the EMEA’s Committee for Medicinal Products for Human Use, are also in the pipeline, including the "Note for Guidance on Biotechnological/Biological Products Subject to Changes in their Manufacturing Process", which has received final approval and will come into operation in June 2005 and a draft "Guideline on Similar Biological Medicinal Products" which is in the consultation phase. Concept papers on providing guidance on medicinal products containing a number of specific biopharmaceuticals have also been released with a view to their inclusion as annexes to the existing Guideline (a) above. These annexes would lay down specific requirements for demonstrating comparability of such products. The biopharmaceuticals in question are recombinant human insulin, human granulocyte-colony stimulating factor (filgrastim), human growth factor and human erythropoietin, all of which are of great interest as potential biogenerics.

Timing

Directive 2004/27/EC is not retrospective, and has an implementation deadline of 30 October 2005. Exactly when the various provisions take effect is therefore largely dependent upon implementation by the individual Member States – some may choose to implement certain provisions early, and some may already have legislation which complies in some respects. The UK for instance has recently enacted secondary legislation (SI 2004/3224) that brought a limited number of the Directive’s provisions (albeit not those discussed above) into force on 1 January 2005, and the UK regulatory authority has indicated that the remaining provisions are to be brought in by the implementation deadline. Other Member States may not be so expedient though, and the Council and Commission have indicated (in a statement released in March 2004) that extra time may be given for implementation by the ten new accession states. Further, some commentators have highlighted ambiguities in the Directive’s wording which could affect when the new Article 10(4) procedure actually becomes available to generics companies.

Whilst we will have to wait and see just when and how Directive 2004/27/EC will be implemented each of the EU Member States, it is clear that there will be a new abridged procedure providing generics companies with a potential route to marketing authorisations for biogenerics. Guidelines specifically aimed at such medicines are already in operation that will assist them in compiling their dossiers and more are expected to follow. If implementation occurs by the 30 October 2005 deadline, this could become a landmark year for European biogenerics.

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