A Prescription for Follow-on Biologics?

As can be seen from other recent articles, changes have recently been made to the route for marketing authorisation for pharmaceuticals in the European Community. These rules are not restricted to standard chemical pharmaceuticals, and this article will address the new rules relating to marketing authorisations for "follow-on" biological medicinal products.

For the purposes of this article the word "biologic" will be used to refer to a biological medicinal product, which is the term used in the legislation. There is no comprehensive legal definition of what a biologic is, but it is generally agreed that a biologic is a medicine that can only be made using a living system or organism, and that contains a substance that has documented biological activity.

With chemical pharmaceuticals, "generic" versions are copies of the original drugs manufactured once the patent and data exclusivity periods have expired. Owing to the simpler nature of chemical pharmaceuticals, making an exact copy of the active ingredient is often, relative to biologics, a straightforward process. However, due to the complex nature of biologics, it is virtually impossible to make an exact copy of a reference biologic. This means that the word "generic" should not technically be used in association with these later biologics, as they will never be exact copies of the original. Instead, it is more usual to refer to these later biologics as "biosimilars" or "follow-on biologics". In order to be a follow-on biologic, a product should: (i) be a later version of, (ii) have the same mechanism of action as, and (iii) have the same therapeutic indication as a reference biologic. The same reference biologic must be used for each point.

The above is important because several blockbuster biological medicines are either already off-patent or coming off-patent in the next couple of years. Some of these products have sizeable markets and patient populations, and prices for biologics are significantly higher than prices for standard chemical pharmaceuticals. This means that the potential production of follow-on biologics is of great interest to generic pharmaceutical manufacturers.

As noted elsewhere in this issue and in previous issues, follow-on pharmaceuticals can be authorised in Europe by one of three routes pursuant to Directive 2001/83 so that manufacturers only need to supply minimal data to prove the efficacy and safety of their products (the "well established use" route, or the "essential similarity" routes with the consent of the innovator or when the data exclusivity period has expired.) However, as already mentioned, with biologics there are difficulties in producing copies of the reference products for the purposes of establishing essential similarity. Unlike chemical pharmaceuticals, biologic medicinal products are always different, as they are "grown" through biological processes, not synthesised through exact chemical reactions. This leads to inherent differences even within the batches produced by the innovative manufacturers, and these differences are amplified when secondary manufacturers attempt to produce copies of these reference biologics. For many biologics, the patents will not explain the whole process, and the production techniques will be closely guarded trade secrets. Thus it will be virtually impossible for a follow-on biologic manufacturer to produce a product that is a copy of a reference biologic. Even with all of the required knowledge, it would be very difficult to produce a biologic product that was "essentially similar", in the technical sense, to the reference product. Small changes in the manufacture of biologics can affect the safety and efficacy of the therapeutic molecule and innovative biotech companies argue that, consequently, the approval of follow-on biologics under one of the essential similarity routes could mean that drugs that could be significantly different from the reference products could be authorised.

Directive 2003/63 was published on 27 June 2003 and replaced the Annex to Directive 2001/83 on the Community code relating to medicinal products for human use as of 31 October 2003. The new Annex provides greater detail on the tests that would be required for approval for medicinal products, and includes a specific section relating to the approval of follow-on biologics. These paragraphs can be found in Part II of the new Annex under the heading "Similar Biological Medicinal Products":

In light of the new legislation, in particular the coming into force of Directive 2004/27 amending Directive 2001/83, the provisions referred to in the Annex will be slightly outdated⁶. Article 10(1)(a)(iii) will no longer exist in Directive 2001/83 and the concept of essential similarity has been replaced by the definition of a putative "generic medicinal product". However, for the purposes of authorisation of follow-on biologics, this should make no difference. Directive 2004/27 also introduces a new Article 10(4) dealing with follow-on biologics, which reads as follows:

Before commencing a discussion of these points, it is necessary to look at the definition of "generic medicinal product" under Directive 2004/27:

As already discussed, the new Article 10(4) will apply most of the time in relation to follow-on biologics as, owing to the inherent difficulties in copying biologics, the follow-on biologic will not meet the definition of generic medicinal products in relation to the reference biological medicinal product. According to Article 10(4), this means that the results of appropriate preclinical tests or clinical trials must be provided. In determining what data will be required, the relevant criteria stated in Annex 1 and the related detailed guidelines will need to be referred to. Annex 1 provides that, in particular, the toxicological and clinical profile shall be provided, and states that the type and amount of additional data will need to be determined on a case-by-case basis. Owing to the diversity of biological medical products, identified studies foreseen in Modules 4 and 5 of the Annex may be required by the competent authorities, taking into account the specific characteristics of each individual medicinal product.

The Committee for Proprietary Medicinal Products ("CPMP") (soon to be known as The Committee for Medicinal Products for Human Use), a part of the European Agency for the Evaluation of Medicinal Products ("EMEA") (soon to be known as the European Medicines Agency), has published two sets of guidelines: first, the Guideline on Comparability of Medicinal Products containing Biotechnologyderived Proteins as Active Substance: Quality Issues (which came into operation in December 2003), and secondly the Guideline on Comparability of Medicinal Products containing Biotechnologyderived Proteins as Active Substance: Non-clinical and Clinical Issues (coming in operation in June 2004). Both sets of guidelines are dealt with below.

The Quality Issues guidelines cover a situation where a manufacturer is seeking approval of a marketing authorisation for a biotechnology-derived product claimed to be similar to one already authorised. They apply when an innovative manufacturer is making changes to his process, and also when a follow-on biologic manufacturer is trying to obtain marketing authorisation for his product through the abridged procedure. The guidelines state that a comparability exercise will be used to demonstrate that two products have similar profiles in terms of quality, safety and efficacy - the three evaluation criteria. Depending on the consequences in terms of quality, safety and efficacy of the intended change, various comparability exercises with different levels of complexity may be required. For example, the comparability exercise could be limited to the strict process validation of the change, could be extended to various quality criteria such as in process controls, stability data etc., or may not be able to be carried out based solely on quality criteria and may need to be further documented as regards in vivo safety/efficacy profile. The content of the comparability studies will depend on the stage of the development where the change is introduced, the potential impact of the change and the suitability and availability of analytical methods to detect potential modifications to the product characteristics. However, with new manufacturers producing new products that are similar to existing products, as would be the case with the follow-on biologics contemplated here, because this situation represents the most complicated case in the view of the guidelines, extensive comparability exercises will be required. The extent of the pre-clinical and/or clinical bridging studies will depend on the nature of the active substance and formulation, and the complexity of its molecular structure, as well as the possible differences when compared to the reference product (including impurities and stabilities, and in some cases the finished product's formulation). This is largely due to the fact that the follow-on manufacturer will generally not have access to the manufacturing process information of the reference product to allow quality comparison in this way. The guidelines make the point that a comparison based on physicochemical or bio-chemical testing/characterisation (eg molecular weights, biological activity, etc.) of the active substance and finished product is not sufficient to establish all aspects pertinent to the evaluation of quality, safety and efficacy for a biotechnology-derived protein.

NON-CLINICAL AND CLINICAL ISSUES The guidance on non-clinical and clinical issues purports to explore which non-clinical and clinical data will be required when either there is a change introduced in the manufacturing process of a similar product or when there is a new application procedure where a product is claimed to be similar to another one already authorised. The guidance states that the data requirements and timing of submission of these data will have to be judged on a case-by-case basis. They will also be affected by, amongst other things, the observed/potential differences between the two products and the clinical experience pertaining to the particular class of product. The guidelines give examples of in vivo studies that consideration should be given to, for example: (a) changes in pharmacodynamic parameters, eg duration of action; (b) changes in pharmokinetic parameters, eg clearance; (c) the immune response, eg antibody titres, neutralising capacity, cross reactivity; (d) areas of specific concern, eg respiratory, renal or cardiovascular parameters; and (e) standard toxicological observations (in life and post mortem). The guidelines state that studies should be designed to detect differences in response and not just the response per se. This would particularly apply in areas such as immunogenicity.

The guidelines also suggest that in vitro studies should take place, in order to assess if any alterations in reactivity have occurred and to determine the likely causative factor. The same reference product should be used for the whole comparability exercise. Generally, demonstration of equivalence concerning bioavailability and pharmacodynamic action using equivalent dosing will be required. Immunogenicity must also always be considered, as almost all biotechnology-derived therapeutic proteins elicit some level of antibody response. The guidelines state that the assessment of immunogenicity requires validated antibody assays and characterisation of the observed immune response, as well as the evaluation of the correlation between antibodies, pharmacokinetics/pharmacodynamics and efficacy and safety.

As can be seen, even though legislation has now been introduced in this area, it is far from clear what hoops a follow-on biologic manufacturer must jump through in order to get its products authorised for use in the EU. As each application will be judged on a case-by-case basis, there will certainly be large financial investment required from the followon biologic manufacturers, not only for the authorisations but also in the design and building of plants that will produce high enough quality products. It seems likely that while the authorities are getting to grips with the potential uncertainties of approving follow-on biologics, many of those follow-on biologics will have to undergo the same trials that the innovative product underwent. However, some follow-on manufacturers may consider this to be a worthwhile investment in light of the potential profits to be had from the sector.

For innovative manufacturers, it will be important to keep their technical know-how and manufacturing process confidential, so that even when the patent on their product expires, the follow-on manufacturers are unable to manufacture a version of the product close enough to enable them to use an abridged procedure without undergoing expensive testing. Recent articles in the press have suggested that whilst some biotechnology-derived proteins may be easier to approve, due to their relatively simple structure, other biological medicinal products are so complex that there may be real difficulties providing any sort of abridged route. The FDA in the USA has also yet to make any definitive pronouncements about the approval of follow-on biologics. So while Europe now has rules in place, it is still very much a question of wait and see.