Safety differences in clinical trials for biosimilars

Biosimilars/Research | Posted 25/11/2016 post-comment0 Post your comment

Differences in safety evaluations and findings between clinical trials for biosimilars are highlighted by researchers from the University of Massachusetts, USA and Newcastle University in the UK. This they argue is a reason for clinical trial design for biosimilars to be standardized [1].

Health and Safety V15C26

Jonathan Kay and John Isaacs point out that phase III clinical trials comparing biosimilar TNF inhibitors with their originator biosimilars have employed different designs. They give the examples of the infliximab biosimilars Inflectra/Remsima (CT-P13) and Flixabi/Renflexis (SB2), as well as the etanercept biosimilars Davictrel (HD203) and Benepali/Brenzys (SB4).

In trials of the etanercept biosimilars HD203 and SB4 ‘minor differences were detected in the occurrence of adverse events’. The incidence of injection-site reactions (ISRs) with HD203 and SB4 was lower than with originator etanercept (2.0% vs 5.5% and 3.7% vs 17.2%, respectively), although comparison is made more difficult due to the fact that slightly different definitions were used.

Possible explanations for the differences proposed by the authors include a lack of L-arginine in the formulation and of latex in the needle shield. They point out, however, that ‘such differences do not preclude biosimilarity from a regulatory standpoint and are factors that might differentiate between products’.

The incidence of anti-drug antibodies (ADAs) has also been observed to differ between the biosimilar and its originator biological. In the clinical trial of SB4, ADAs were observed in only 0.7% of subjects receiving the biosimilar compared with 13.1% of subjects who received originator etanercept. Differences in immunogenicity, according to the authors, could ‘reflect, for example, subtle differences in glycosylation or other post-translational modifications, aggregates, impurities, and formulation and packaging effects’.

The authors also pointed out that ‘the SB4 study used a highly sensitive electrochemiluminescence bridging assay to detect ADAs, perhaps explaining the higher incidence of ADAs than that historically detected by conventional ELISAs or radioimmunoassays in previous clinical trials of originator etanercept’. ‘Perhaps critically, assays of ADAs were performed more frequently and at earlier time points than in previous studies’. However, in analyses stratified for the presence or absence of ADAs, they remained equivalent.

The authors therefore recommend that ‘since equivalence trials of a particular biopharmaceutical always compare a biosimilar with the same [originator biological], they should be based on the same meta-analysis of double-blind, randomised-controlled clinical trial data comparing the [originator biological] with placebo’.

Conflict of interest
The authors of the research paper [1] reported conflicts of interest, including having received honoraria, research grants or consulting fees from pharmaceutical companies. For full details of the authors’ conflicts of interest, see the research paper [1].

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1. Kay J, Isaacs JD. Clinical trials of biosimilars should become more similar. Ann Rheum Dis. 2016 Aug 25. pii: annrheumdis-2015-208113. doi: 10.1136/annrheumdis-2015-208113. [Epub ahead of print].

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