EU Healthcare: The European Medicines Agency publishes draft guidelines on biosimilar products containing monoclonal antibodies

The European Medicines Agency (“EMA”) published its long-awaited Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies (the “Biosimilar mAb Guideline”) in November of last year. This sets out requirements for the non-clinical and clinical studies which should be carried out in relation to products containing a monoclonal antibody (“mAb”) claiming to be similar to another such product already marketed. The deadline for commenting on the draft guideline is 31 May 2011.


The biological medicinal market is lucrative and is expanding. According to IMS Health, worldwide sales of all biologic drugs reached $130 billion in 2009. With further patents for biological products due to expire in the next few years, this significant market is opening up to increasing generic competition.

The concept of biosimilar products, as distinct from ordinary generic products, was introduced into EU legislation in 2005 by Directive 2004/27/EC. In turn, that amended Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use, and introduced a new Article 10(4) regarding biosimilar products. Article 10(4) provides that the results of appropriate pre‑clinical tests or clinical trials relating to differences in raw materials or manufacturing processes of the biosimilar and the reference product must accompany any application for a marketing authorisation for that biosimilar. However, the results of other tests and trials from the reference product’s dossier need not be provided. Since 2005, the EMA has introduced a number of detailed guidelines regarding biosimilar products. These include a guideline on non-clinical and clinical issues relating to biotechnology-derived proteins and a guideline on production and quality control of mAbs. The Biosimilar mAb Guideline is another such scientific guideline.

Key points arising from the Biosimilar mAb Guideline

The Biosimilar mAb Guideline covers both non-clinical and clinical requirements. In relation to non‑clinical development, a risk-based, case-specific approach is recommended. Comparative in vitro pharmacodynamic studies should be carried out to assess the difference in biological activity between the biosimilar and the reference product, and to determine the extent of what, if any, in vivo work will be required. If these comparability studies are considered satisfactory and no factors of concern are identified, an in vivo animal study is not considered necessary. Further, if in vivo studies are considered necessary, whilst it is recognised that the relevant species for toxicology studies are usually non-human primates, large comparative toxicological studies in such species are discouraged.

Pharmacokinetic clinical studies are considered by the guideline to be an integral part of biosimilar mAb development, primarily to show comparability to the reference product. The population of such studies should be sufficiently sensitive and homogenous, to reduce variability and sample size. Further, it may be sufficient to carry out single dose studies, if adequate justification is provided, and applicants are not generally required to investigate the pharmacokinetic profile in all clinical indications (unless distinct therapeutic areas are involved). Clinical efficacy trials, which would normally include the clinical safety studies, should be conducted if pharmacodynamic studies cannot be performed to show comparability in a clinically relevant manner. As with pharmacokinetic studies, the guideline recommends that such studies are conducted using the most sensitive clinical model in a homogeneous patient population, again, to reduce variability and sample size: “[t]he focus of the biosimilarity exercise is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been established by the reference product”.

Additionally, the Biosimilar mAb Guideline suggests that, if justified, extrapolation of clinical efficacy and safety data to other indications of the reference mAb is possible, although it is acknowledged that scientific justification would be more challenging for indications which are very different from one another.


The European Generic Medicines Association has said that “the proposed guideline appears to strike the right balance between high level data requirements and the need for the development of biosimilar medicines, and is based on the broad expertise gained over more than 10 years from reviews of many originator mAb products as well as from biosimilar medicines’ applications in general”.  However, it has been suggested by numerous commentators that the requirement to conduct additional clinical trials (estimated by some to cost around $100 million per product) will limit the competition from the generic sector to only a few well‑funded companies, rather than opening the market up to numerous generic manufacturers. Meanwhile, some companies and industry bodies consider that mAb products are too complex for meaningful comparability testing to be conducted and that the Biosimilar mAb Guideline is not sufficiently stringent.

If you have any further questions or would like to discuss further, please contact:  Nigel Jones on + 44 207 456 5804 or