Over recent years, the landscape of blockbuster medicines in Europe has been changing, moving from small molecule drugs to biologicals. Biologicals, mainly biotechnology-derived proteins, now dominate the top 10 list of best-selling medicinal products in Europe: currently, eight of the top 10 best-selling medicinal products are biologicals. As the patents for all of these blockbuster biologicals have either already expired or will expire by 2022 at the latest, these blockbuster biologicals are targets for biosimilars developers. To date, 20 biosimilars have been granted a marketing authorisation by the European Medicines Agency ("EMA").
However, a major problem with protein-based therapeutics is their immunogenicity, in other words, their tendency to trigger an unwanted immune response against themselves. Immunogenicity can be influenced by various factors, such as patient or disease-related factors and also product-related factors. The consequences of an immune reaction to a therapeutic protein range from a transient appearance of antibodies without any clinical significance to severe life-threatening conditions.
As a consequence, the current guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins (the "Guideline") states that immunogenicity assessment should be part of the clinical trial process. In addition, they state that immunogenicity should always be addressed in the Risk Management Plan – which should be included within the scope of the marketing authorisation application.
However, the Guideline will shortly be revised. This revision will be of particular interest for manufacturers and applicants of marketing authorisations for biotechnology-derived proteins, as it is expected to provide valuable guidance on the marketing authorisation application process.
The concept paper on the proposed revision of the Guideline was published for public consultation in February of this year. It is anticipated that the draft revised Guideline will be released for consultation in the fourth quarter of 2014.
The proposed revisions to the Guideline
Currently a high number of biological products – mainly biotechnology-derived proteins – are being developed. Therefore, the knowledge on the assays required to be performed in order to obtain a marketing authorisation, the risk factors associated with biologicals and, the occurrence of potential unwanted immune responses has increased. As a result, improved assays, which detect the level of antibodies raised against a specific biological, have been developed so that the extent of immunogenicity can be more specifically determined.
The concept paper on the proposed revised Guideline highlights that the Committee for Medicinal Products for Human Use ("CHMP") has regularly raised questions related to the assays used by marketing authorisation applicants and the data generated on the clinical correlation of the induced antibodies. Such questions pertained to the sensitivity of such assays and the use of ligand-binding and cell-based assays to demonstrate the presence of neutralizing antibodies. Since many risk factors relating to immunogenicity are currently known, it may be possible to estimate the risk level of a given biological product. Such analysis can be used to justify the selected immunogenicity strategy, i.e. the development of a suitable set of assays and the detection and clarification of the clinical significance of the observed anti-drug-antibodies both pre- and post-marketing.
The concept paper notes that most marketing authorisation applications lack a clear strategy when considering the approach to immunogenicity. Such a strategy should be based on a comprehensive analysis of all data that may be related to the immunogenicity. Therefore, the requirements of the immunogenicity assays may need to be defined more clearly. Quality issues, such as impurities, aggregates, xenogeneic structures need to be assessed. The dose, frequency, duration and route of administration, the underlying disease as well as concomitant medication may also modify the risk of immunogenicity arising.
With respect to biosimilars, the concept paper highlights that when carrying out comparisons of the immunogenicity of two forms of a product or two independent products (for instance a biosimilar and its reference product), certain specific features must be considered.
The concept paper mentions that the knowledge regarding the immunogenicity of the reference product may help to estimate the level of tolerance towards a particular protein. However, this needs care as the immunogenicity of the proposed biosimilar product may not be similar to the reference product. This has to be demonstrated as part of the comparability assessment.
Moreover, the concept paper states rather ominously that the regulatory consequences of a different degree of immunogenicity (both increased and decreased) need to be considered. This element in the concept paper raises questions about the degree of difference in immunogenicity which justifies such a 'regulatory consequence'.
At this stage, it cannot be estimated yet whether the aforementioned is a prelude to the introduction of new regulatory hurdles for applicants of marketing authorisations for biosimilars. In any case, it demonstrates the need for clear directions on the assessment and presentation of data regarding the absence or presence of differences in immunogenicity. Considering that normally only a restricted number of patients are available for studies in the pre-authorisation phase, post-authorisation studies may become more important.
Within this perspective, the question of whether the regulatory concept of conditional approval could possibly play a role here, may be a legitimate one. Conditional approval entails the granting of a conditional marketing authorisation even though comprehensive clinical data referring to the safety and efficacy of the medicinal products have not been supplied. Obviously such marketing authorisations will only be granted if specific requirements are met, for example, the availability of the medicinal product should fulfil an unmet medical need.
Finally, the EMA clarifies that the aim of the revision to the Guideline is not to increase the number of studies on immunogenicity, but rather to increase the quality of studies and their clarity to the assessors.
Unwanted immunogenicity remains an important concern for all biotherapeutics. It therefore is and will remain an important and much discussed topic in relation to biologicals and biosimilars.
As the knowledge on immunogenicity continues to evolve, the revision and updating of the Guideline is recommended. In particular, more specific guidance with respect to the presentation of immunogenicity data, requirements of data on antibody assays and a risk-based approach to immunogenicity and clinical data is needed. Furthermore, the comparative immunogenicity studies and post-authorisation immunological studies require attention.
As the EMA states that most marketing authorisation applicants lack a clear strategy to approach immunogenicity, applicants and other interested parties should carefully monitor the developments with respect to the revision of this Guideline. It is anticipated that the draft revised Guideline will be released for consultation in the fourth quarter of 2014.
Furthermore, it is unclear at this stage whether the revised Guideline will provide clear directions on the assessment and presentation of data substantiating the absence or presence of a difference in immunogenicity and which regulatory consequences may come into play. Within this context, post authorisation studies and conditional approval may gain more interest in the near future.
This article is part of the International Life Sciences Update for October 2014
 Go to www.ema.europa.eu, click on 'Find medicine', select Human medicines, then: 'browse by type' and select 'biosimilars'.
 Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. EMEA/CHMP/BWMP/14327/2006.
 Article 14(8) of Regulation (EC) No. 726/2004, as amended.
 Given that the applicant is able to demonstrate being unable to provide comprehensive data under normal conditions of use which is based on one of the grounds as set out in Annex 1 of Directive 2001/83/EC (as amended), page 153 and 154. For instance:
— the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or
— in the present state of scientific knowledge, comprehensive information cannot be provided, or
— it would be contrary to generally accepted principles of medical ethics to collect such information, marketing authorisation may be granted subject to certain specific obligations.