Zelda Pickup and Andrew Whitworth

CMS Cameron McKenna

With the threat of patent expiry looming ever nearer for a number of biopharmaceuticals, 1 generic manufacturers are looking to seize the potentially great commercial rewards in this unexploited territory. It is predicted that by 2010 nearly 50 per cent of all new approved pharmaceuticals will be biopharmaceuticals and that $60 billion worth of biopharmaceuticals will be going off patent in the next few years. 2 As an inevitable consequence, there will be a developing market in tandem whereby generic manufacturers produce ‘copy-cat’ versions of these products, which are known as ‘biogenerics’. 3

The development and marketing of biogenerics is not as straightforward as may initially be thought. There are some crucial differences between the development of biogenerics and ‘traditional’ chemical-based medicines. Biopharmaceuticals are inherently different and more complex in character than small chemical molecules. They may exhibit a range of toxicological properties and elicit a variety of responses from the human body, some of which are dependent on the structure of the biopharmaceutical. One of the more important responses is from the body’s immune system, known as ‘immunogenicity’.4 The larger and more complex the biopharmaceutical, the greater the chance that even the slightest variation in manufacture or assembly of the biopharmaceutical could provoke an immunogenic response. Some of these differences may produce irrelevant harmless responses, whilst others may produce significant adverse events and even potentially fatal results.

It is against this background that the European Medicines Agency 5 (‘the EMEA’) has issued guidelines to assist generic manufacturers in obtaining regulatory approval for biogenerics. Quality control and production are more complicated for a biopharmaceutical than for chemical-based medicines and the EMEA’s Committee for Medicinal Products for Human Use (‘CHMP’) 6 has also released guidelines 7 in respect of this, which fall outside the scope of this article.

Producing generic versions of an off-patent original chemical-based medicinal product will generally be cheaper because a generic manufacturer does not need to invest heavily in discovering a new substance. Instead a generic manufacturer can rely on the results of the pre-clinical and clinical tests, which would have been carried out by the original manufacturer when initially trying to secure regulatory approval for the medicinal product. The generic manufacturer can rely on the originator’s data by making an ‘abridged application’. In order to make an abridged application a generic manufacturer must demonstrate that the generic product is ‘essentially similar’ to the original medicinal product (in accordance with Directive 2001/83). 8 ‘Essentially similar’ products should have the same qualitative and quantitative compositions in respect of active substance and the same behaviour in the human body. However, there is great difficulty in trying to prove ‘similarity’ between biopharmaceuticals due to their complex nature and their elaborate manufacturing processes.

In order to overcome these hurdles, the CHMP has released various guidelines including one entitled ‘Comparability of Medicinal Products Containing Biotechnology Derived Proteins as Active Substances – Non-Clinical and Clinical Issues’. 9 These guidelines came into operation in June 2004. The overriding aim of the guidelines is to set methods of demonstrating or justifying that a biogeneric has a similar profile to the original biopharmaceutical in terms of quality, safety and efficacy.

The guidelines are to apply either when a change is introduced in the manufacturing process of a biopharmaceutical (either before or after the grant of its marketing authorisation) or, of more relevance, when a biogeneric is claimed to be similar to an original biopharmaceutical. The guidelines explore the types of clinical and non-clinical data required for verification, although due to this area being unchartered territory, assessment as to the types of data required will be made on a case-by-case basis. The criteria for both non-clinical and clinical data, as outlined in detail in the guidelines, will be discussed in summary below.

Non-clinical Data
The guidelines highlight that non-clinical data can flag up potential therapeutic differences between the biogeneric and the original biopharmaceutical, especially if the data provide a direct comparison of the biogeneric and the original biopharmaceutical. The guidelines suggest, by way of example, physico-chemical characterisation studies, which could be used to review the potential impact on the safety and efficacy of the biogeneric in terms of its biological activity, metabolism, kinetics and immunogenicity as possible markers.

In vitro studies (such as receptor-binding studies) are suggested as a method of ascertaining whether there has been any alteration in the activity of the biogeneric as well as determining the causative agent if such a change in activity of the biogeneric occurred. Similarly, in vivo studies of the biogeneric’s safety in animals may be used to research any concerns into the safety of the biogeneric in human patients. The guidelines place greater reliance on in vivo studies where the same species is used for in vivo studies both with the biogeneric and with the original biopharmaceutical. Such in vivo studies should be performed in such a way as to detect differences in responses to the biogeneric and the original biopharmaceutical rather than just detecting responses per se.

Non-clinical data may also be used where there are case-specific safety concerns (that is, tolerance, new excipients used in the biogeneric’s formulation, and so on), and may allay any concerns surrounding the administration of the biogeneric to human patients in clinical studies.

Clinical Data
Clinical data can be used to predict accurately the behaviour of a biopharmaceutical in vivo. Indeed, the guidelines specify that certain aspects of a biogeneric, such as immunogenicity, can only be addressed through clinical data.10

The guidelines specify important issues which should be taken into account when designing a clinical programme to produce comparative data in respect of the biogeneric and the original biopharmaceutical. These include:

• the stage of development of the biogeneric;
• the therapeutic area of the biogeneric relationship between dose/exposure and efficacy/safety of the biogeneric;
• the availability of surrogate markers which can be used in the clinical studies of the biogeneric and their relationship to dose/exposure of the biogeneric;
• the drug/receptor(s) interaction(s) of the biogeneric;
• the disease-specific mechanism(s) of action of the biogeneric;
• the mode of administration of the biogeneric; and
• the pharmacokinetic properties of the biogeneric.

The guidelines highlight two particular situations where there may be differences between the biogeneric and the original biopharmaceutical. The first situation is where there are differences between the two, but these cannot be characterised. It is still the case that the efficacy and safety of the biogeneric needs to be confirmed and characterised against the original biopharmaceutical and so it is suggested that pharmacokinetic and pharacodynamic studies using surrogate markers are conducted to verify the similarity and efficacy of the two products. If no surrogate markers are available, an equivalence trial using clinical endpoints may suffice to meet this requirement.

The second situation envisaged is where there are well-characterized differences between the biogeneric and the original biopharmaceutical. Where the differences are not major and there is no change in in vitro biological activity, comparable bioavailability data and/or pharmacodynamic studies may be sufficient. However, where the differences are major, clinical equivalence studies will be necessary, unless other background clinical data can justify this.

It is a key concern of a biogeneric manufacturer whether it will have to conduct clinical studies in respect of the biogeneric. Clinical studies will be expensive and have a huge bearing on the timing of launch and any profit margin. It is of particular interest that the guidelines highlight that it may not be necessary to repeat all safety and efficacy studies, where it can be demonstrated that:

• 1) it is possible to characterise the biogeneric in detail with respect to physico-chemical properties and in vitro activity; and
• 2) comparability can be shown from a chemical-pharmaceutical perspective.

It will obviously be in a generic manufacturer’s interest to use this exemption from having to conduct such studies.

Post-marketing Considerations
The guidelines also highlight the possibility that the safety profile of the biogeneric may be different from the original biopharmaceutical, depending on the clinical population exposure of the biogeneric. This difference in safety may only be noticeable in a larger post-marketing population rather than in smaller populations used in pre-marketing authorisation clinical studies. In relation to immunogenicity, for example, the guidelines recommend that due to the unpredictability of onset and incidence, post-marketing monitoring of antibodies at predetermined intervals for at least a year takes place. In line with existing EU legislation and pharmacovigilance guidelines and in order to capture any adverse events which may only emerge in larger populations, the guidelines require enhanced post-marketing surveillance of the biogeneric. The EMEA would want to see proposals for a pharmacovigilance plan, which would implement such systems and procedures in respect of the biogeneric.

Conclusion
The guidelines aim to achieve an appropriate balance between opening up the potentially large biogenerics market to community populations and ensuring that such products are both safe and efficacious for the patient receiving them. By setting out the principles in the guidelines, the EMEA has moved towards clarification of this unchartered area, and whilst it is estimated that initial uptakes of the biogeneric approval mechanisms will be slow, it is expected that the biogenerics industry will become fully established after 2010. 11

1) Examples of biopharmaceuticals that are facing patent expiry include Amgen’s erythopoietin product (Procrit & Epogen) which faces patent expiration in 2004 and Amgen’s Neupogen (filgrastim) with a patent due to expire in 2006. The combined global sales of these products are approximately $8 billion in the United States alone according to the Generic Pharmaceutical Association, US. Other products include Genentech’s Protroprin and Activase, both with a patent due to expire in 2005.
2) Quoted from Biogenerics, ‘A Difficult Birth by IMS Health’, available at www.ims-global.com/insight/news_story/0405/ news_story_040517.htm.

3) Certain commentators have suggested that the term ‘biogeneric’ is misleading due to the inherent variations of a biopharmaceutical arising from its large size and complexity. Other terms that have been suggested include ‘Biosimilars’ and ‘Off-Patent Biotechnology Products’ (‘OPBPs’) (John Thomas, ‘Generics and Biogenerics’, American College of Toxicology Newsletter, March 2004, Vol. 24, No. 1).

4) The immunogenicity of a biosimilar may be caused by a variety of factors, not only by the properties of the active substance and finished product. Other potential causative factors include the manufacturing process, the patient’s genotype and concomitant diseases, exposure to other therapeutic proteins, and the route and manner of administration.

5) Previously known as the European Medicines Evaluation Agency but still using the same acronym.

6) Previously known as the Committee for Proprietary Medicinal Products (‘CPMP’).

7) These guidelines are entitled ‘Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins As Active Substance: Quality Issues’. These can be obtained from the EMEA’s website at www.emea.eu.int/pdfs/human/bwp/320700en.pdf. This came into operation in December 2003.

8) A copy of EC Directive 2001/83/EC can be obtained from the Europa website at http://pharmacos.eudra.org/F2/pharmacos/docs/Docs200 nov/Codifications/Human Code 2001-83/2001-83en.pdf.

9) The guidelines entitled ‘Guidelines on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins An Active Substance: Non-Clinical and Clinical Issues’ can be obtained from the EMEA’s website at www.emea.eu.int/pdfs/human/ewp/309702en.pdf

10)The guidelines state that the issue of immunogenicity must always be considered when making a comparison between a biopharmaceutical and a biogeneric. The assessment of immunogenicity requires validated antibody assays, characterisation of the immune response and a correlation to the efficacy and safety of the biogeneric. A rationale should be presented for the proposed antibody-testing strategy and such testing should use standard methods and international standards where possible. The duration of such studies should be sufficiently long.

11)N. Lamble, Therapeutic Proteins: Strategic Market Analysis and Forecasts to 2010 (Datamonitor plc, Charles House, London, 2000).

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