Differences in efficacy assessment in clinical trials for biosimilars

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

Clinical trial design should be standardized according to researchers from the University of Massachusetts, USA and Newcastle University in the UK [1]. They argue that a ‘standard clinical trial design be adopted for all biosimilars of a particular [originator biological] in a given disease’.

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In clinical trials for the infliximab biosimilars Remsima/Inflectra (CT-P13) and Flixabi/Renflexis (SB2), as well as the etanercept biosimilars Davictrel (HD203) and Benepali/Brenzys (SB4) the authors note that, although the primary endpoints for all the biosimilars were similar, the phase III clinical trials for the different biosimilars all used different time points for efficacy evaluations. The phase III trial for CT-P13 evaluated efficacy at 14, 30 and 54 weeks. While the phase III trial for HD203 evaluated efficacy at 12, 24 and 48 weeks. These time points, according to Kay and Isaacs, fall during the plateau phase of the time–response curve. In contrast, the phase III trials for SB2 and SB4 evaluated efficacy at several earlier time points.

Kay and Isaacs believe that ‘since potential differences in efficacy are more likely to be detected during the rapid rise phase of the time–response curve compared with the plateau phase, assessment of efficacy at early time points is a more sensitive way of comparing a biosimilar with its bio-originator.’ 

Equivalence margins
To demonstrate two-sided therapeutic equivalence of a biosimilar to its originator biological in a clinical trial, the 95% confidence interval (CI) for the mean absolute difference in the primary endpoint between the biosimilar and the originator biological must fall within a predefined equivalence margin (δ). But, already here, differences start to emerge. The European Medicines Agency suggests the use of a 95% CI, while the US Food and Drug Administration prefers use of the narrower 90% CI for demonstration of therapeutic equivalence. 

These differences become apparent when considering the examples of HD203 and SB2. In the study comparing HD203 to originator etanercept an equivalence margin of ±20% was used, whereas in the trial of SB4 an equivalence margin of ±15% was employed. 

Assuming an absolute risk difference of 40.49%, the authors concluded that ‘an equivalence margin of ±20% preserves 50% of the therapeutic effect (1−ε, where ε=δ/δap=0.5), whereas an equivalence margin of ±15% preserves 62.5%’. The equivalence margin used for a specific originator biological could, according to the authors, be standardized ‘since δap is derived by analysing historical data from the same placebo-controlled trials of the [originator biological]’.

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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