The European Medicines Agency (EMA) uses a totality of evidence approach in its regulatory review process for biosimilar approval. As part of this, the biosimilar should demonstrate that it does not have clinically meaningful differences from the originator biological, based on comparative clinical studies.
In their article , authors from the Paul-Ehrlich-Institut, EMA and the Federal Institute for Drugs and Medical Devices (BfArM), discussed the totality of evidence approach for biosimilars in the European Union (EU) using case studies to illustrate biosimilars for which differences were observed in different parts of the comparability exercise and on the justification for why these differences did not preclude regulatory approval.
To date (October 2019), five trastuzumab products have been approved in the EU , three based on a pivotal comparability study in early breast cancer (EBC) and two in metastatic breast cancer with different endpoints and equivalence margins depending on the indication, backbone therapy and reference studies.
In the case of two of the trastuzumab biosimilars, the phase III study in patients with human epidermal receptor-2-positive (HER2+) EBC/locally advanced breast cancer did not formally meet the upper bound of the predefined equivalence margins for the primary endpoint (pathological complete response [pCR]), confirming non-inferiority but not formally excluding the possibility of superior efficacy.
Overall, structural and functional similarity was shown in a comprehensive head-to-head comparison. However, slightly reduced antibody-dependent cell-mediated cytotoxicity (ADCC) activity of some more recent batches of the reference product, Herceptin, used in the clinical trial, were observed, an observation also described in the literature. The observed difference in pCR was considered at least partly confounded by the small shift in ADCC activity in the Herceptin batches. Overall, it was considered doubtful that a shift as small as the one observed would have any significant impact in terms of clinical outcomes.
In both cases, no clinically meaningful differences in the safety profile were found, notably no differences in cardiac toxicity as measured by left ventricular ejection fraction and incidence of symptomatic heart failure, which could be of concern with truly increased efficacy. In addition, pharmacokinetic (PK) comparability between the biosimilars and the reference product was demonstrated in healthy volunteers.
Given the totality of data submitted, similarity between the two trastuzumab biosimilars and the reference product was considered sufficiently established.
In the case of a rituximab biosimilar, shifts in some quality attributes, e.g. charge variants, glycan structures, ADCC, were noted for the EU reference product and US Rituxan.
Similar efficacy and safety of the biosimilar and the reference product was concluded based on the comparative clinical trial in patients with previously untreated, advanced-stage follicular lymphoma who received rituximab-cyclophosphamide, vincristine, prednisone (CVP) combination treatment.
However, at the time of data cut-off, more patients in the biosimilar group than in the reference product group had progressed or died. For EMA’s Committee for Medicinal Products for Human Use (CHMP), these figures suggested immature progression-free survival (PFS) data as 30.3% and 25.4% of patients had < 6 months and 6–12 months of PFS follow-up, respectively, and considering that the majority of PFS events occurred during the maintenance phase of the trial.
In conclusion, the difference in PFS was considered to be due to patient heterogeneity or random data variation rather than a real treatment effect.
In the case of another rituximab biosimilar, the pivotal efficacy trial was an equivalence trial conducted in patients with rheumatoid arthritis, and a second, supportive study was performed in patients with advanced follicular lymphoma. Although the primary endpoint was met in both trials, in the supportive trial, the secondary endpoints of PFS and overall survival were inconclusive at the time of analysis.
Based on the totality of the evidence, this did not preclude approval in the EU but led to additional requests by the US Food and Drug Administration.
The authors of the research paper  declared that the views and opinions expressed in the paper are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agencies with which the authors are affiliated.
Conflict of interest
The authors of the research paper  declared that there was no conflict of interest.
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1. Wolff-Holz E, Tiitso K, Vleminckx C, Weise M. Evolution of the EU Biosimilar Framework: past and future. BioDrugs. 2019 Sep 20. doi: 10.1007/s40259-019-00377-y. [Epub ahead of print]
2. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Nov 4]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
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