Calls are growing for biosimilar manufacturers to publish their data in the public domain, particular when developing versions of monoclonal antibodies (mAbs) that are associated with potential survival benefits [1-3].
MAbs are large, multi-subunit proteins with complicated patterns of post-translational modification. Commercial mAb production is complex and involves the culturing of large batches of cells, and considerable pre-production effort to ensure that the cell line is stable, uncontaminated and of sufficient quality . Examples of originator mAbs are Herceptin (trastuzumab), Avastin (bevacizumab) and MabThera (rituximab), all of which have shown survival benefits across various haematological and solid tumours. The physicochemical and biological methods for mAb characterisation have become increasingly sophisticated and clinical equivalence can therefore not be assumed. Hence, there is a need for biosimilar manufacturers to be totally transparent with their data.
Dr Janice Reichert* is a Senior Research Fellow at the Tufts Center for the Study of Drug Development, Boston, USA, studying innovation in the pharmaceutical and biotechnology industries. She is also Editor-in-Chief of mAbs, an international, peer-reviewed journal that focuses exclusively on topics relevant to mAb research and development. Her opinion on the matter is clear: ‘The most critical, ‘non-negotiable’ issue [for mAb biosimilar manufacturers] is to have substantial data to prove that there are no clinically meaningful differences in terms of safety, purity, and potency to the reference product. Perhaps more importantly, such data, and particularly discussion of the significance of any such differences in the clinical setting, should be presented in the public domain. Currently, little such data are available publically, with innovators guarding the particulars of their cell lines, purification, and fermentation processes closely.’ .
It is not just the public interest that Dr Reichert believes will be enhanced with such data publications, she also foresees benefits for the manufacturers themselves: ‘Publication of biosimilar study results would be in everyone’s interest, particularly helping to increase physician comfort about using biosimilars. In addition, with high development costs, complex manufacturing, and numerous legal obstacles to overcome, the development of biosimilars is not a low cost proposition and data publication may pave the way to make claims of superiority to the reference product.’ .
Many other biosimilar experts agree. Writing in mAbs, Dr Joseph Miletich and colleagues argued: ‘Over the next decade, a new and advanced tranche of biosimilars will be developed for complex reference products, including medicines used in the treatment of cancer and autoimmune diseases. The products developed in this period should exhibit high levels of fidelity to the reference products and should be rigorously evaluated in analytical, non-clinical and clinical comparisons. Additionally, biosimilar manufacturers should strive for transparency in their labels and take proactive strides to be accountable to providers and patients for the quality of their products. An important opportunity now exists for the healthcare community, industry and regulators to work in partnership to outline the appropriate standards for these products to facilitate increased access while meeting patients’ needs.’ .
Contrary to expectations, biosimilars have not been rapidly adopted by physicians in the EU. For 2010, Amgen estimated that erythropoietin biosimilars had penetrated only 4% of the European market –a sure sign that clinicians’ perceptions that biosimilars might not be 100% as safe and effective as the originator biological have yet to be changed.
The transparent publication of biosimilar clinical data would undoubtedly help to improve this situation, and given that the European regulatory authorities are insisting on these data anyway, the process of sharing these data should not be too difficult. Indeed, the most recent EMA draft guideline on similar biological medicinal products containing mAbs clearly outlines its clinical data requirements for mAb biosimilars which claim to be similar to an already marketed product .
The guidance states that a comparative pharmacokinetic study in a sufficiently sensitive and homogeneous study population (healthy volunteers or patients) should form an integral part of biosimilar mAb development, with a parallel-group design being preferred due to the long half-life of mAbs and potential interference of immunogenicity .
In terms of safety and efficacy data, the guideline recommends that similar clinical efficacy should be demonstrated in adequately powered, randomised, parallel-group comparative clinical trials, which are preferably double-blinded. To establish biosimilarity, it states that deviations from disease-specific guidelines issued by the Committee for Medicinal Products for Human Use, for example, choice of endpoint, timepoint of analysis of endpoint, nature or dose of concomitant therapy, etc.; may be warranted, but that the focus of the biosimilarity exercise would be to demonstrate similar efficacy and safety compared to the reference product, and not patient benefit per se which would have already been shown for the reference product. Applicants are also asked to choose clinically relevant markers and provide sufficient reassurance of clinical safety, particularly immunogenicity .
The question to biosimilar manufacturers is this: given that many influential clinicians want to see supporting data before they will consider using a treatment, and given that such supporting studies already exist, why wouldn't you publish them?
Please feel free to share your thoughts via email at firstname.lastname@example.org or in the comments section below. What are your views on biosimilar manufacturers publishing biosimilar study results? Do you think that this would help to improve adoption rates for biosimilars in the EU?
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*Dr Reichert is a member of the International Editorial Advisory Board of GaBI Journal.
1. Vulto A. Biosimilars, Information gap, and barriers to substitution. 9th EGA International Symposium on Biosimilar Medicines; 2011 Apr 14; London, UK.
2. Wiatr C. Transparency will be key to success of biosimilars. inThought Research. 23 August 2010. Available from: www.in-thought.com/resources/Biosimilars-23Aug.pdf
3. Miletich J, et al. Biosimilars 2.0: guiding principles for a global ‘patients first’ standard. mAbs 2011;3(3):318-325.
4. Committee on Methods of Producing Monoclonal Antibodies, Institute for Laboratory Animal Research, National Research Council. Monoclonal antibody production. Washington, DC: National Academy Press; 1999. Available from: grants.nih.gov/grants/policy/antibodies.pdf
5. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies. EMA/CHMP/BMWP/403543/2010. 18 November 2010. Available from: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdf