Clinical trials of biosimilars should become more similar.

Since the approval of the infliximab biosimilar, CT-P13, by the Korean Ministry of Food & Drug Safety (MFDS) on 23 July 2012, biosimilars to treat inflammatory diseases have become available to patients in many countries around the world. The European Commission (EC) approved CT-P13 on 10 September 2013, and, subsequently, it has been granted marketing authorisation by regulatory agencies in many other countries, including the USA. CT-P13 is now marketed in >70 countries worldwide as Remsima, Inflectra and Flammegis. Several other biosimilars of tumour necrosis factor (TNF) inhibitors have also received regulatory approval and are commercially available. HD203 was the first etanercept biosimilar granted marketing authorisation by the Korean MFDS on 11 November 2014 and was marketed as Davictrel in South Korea. However, because the facility where it was manufactured was sold, its licence could not be retained and it was withdrawn from the market upon the request of its manufacturer on 30 September 2015. Another etanercept biosimilar, SB4, which received approval by the Korean MFDS on 8 September 2015 and by the EC on 14 January 2016, is marketed as Brenzys in South Korea and as Benepali in the European Union (EU) and in the European Economic Area (EEA) member states of Norway, Iceland and Liechtenstein. 6 SB2, another infliximab biosimilar, was granted marketing authorisation by the Korean MFDS on 4 December 2015 and by the EC on 26 May 2016, and is sold as Renflexis in South Korea and as Flixabi in the EU and EEA member states. 7 In this issue, Bae et al report the results of the phase III clinical trial of HD203 (etanercept biosimilar), Emery and colleagues report the results of the phase III clinical trial of SB4 (etanercept biosimilar) and Choe et al report the results of the phase III clinical trial of SB2 (infliximab biosimilar). The European Medicines Agency (EMA) was the first to establish a pathway for the regulatory approval of biosimilars in 2005, in which a biosimilar is compared with its reference product or originator biological, hereafter referred to as bio-originator. This occurs in a series of analytical, in vitro, in vivo, pharmacokinetic, pharmacodynamic and clinical studies according to a stepwise approach. Other regulatory agencies have followed suit and established similar regulatory pathways. In 2012, the US Food and Drug Administration (FDA) issued draft guidance regarding its pathway for the review and approval of biosimilars and articulated a ‘totality-of-the-evidence’ approach to evaluating the data generated by all of these studies. The purpose of a clinical trial comparing a biosimilar with its bio-originator is to reduce residual uncertainty following extensive analytical, in vitro and pharmacokinetic analyses. Efficacy of the bio-originator already has been proven in the pivotal clinical trials that were conducted to gain regulatory approval and by subsequent experience in clinical practice. Thus, if equivalence of the biosimilar to its bio-originator can be demonstrated, there is no need to re-establish its clinical benefit. The clinical trial of a biosimilar therefore can be viewed as a bioassay to demonstrate that it exhibits a clinical effect comparable to that of the bio-originator in patients with a disease for which the bio-originator is approved. Similar principles permit subsequent regulatory extrapolation to other licensed indications of the bio-originator, provided that therapeutic efficacy relies on a similar mechanism of action in the extrapolated indications. Phase III clinical trials comparing biosimilar TNF inhibitors with their bio-originators have employed different designs. Although their primary end points were similar, the phase III clinical trial of CT-P13 evaluated efficacy only at 14, 30 and 54 weeks, 14 and that of HD203 evaluated efficacy only at 12, 24 and 48 weeks, each of which is a time point during the plateau phase of the time–response curve. In contrast, the studies of SB2 and SB4 also evaluated efficacy at several earlier time points. 10 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. This aspect of clinical trial design should be standardised for future studies of biosimilars. Indeed, it could be argued that a ‘standard’ clinical trial design be adopted for all biosimilars of a particular bio-originator in a given disease. To demonstrate two-sided therapeutic equivalence of a biosimilar to its bio-originator in a clinical trial, the 95% CI for the mean absolute difference in the primary end point between the biosimilar and the bio-originator must fall within a predefined equivalence margin (δ). This equivalence margin is often derived from a meta-analysis of the therapeutic effect of the bio-originator in the original placebocontrolled clinical trials, calculated as the risk difference in the end point of interest between active drug (a) and placebo (p), often referred to as the ‘delta’ (δap). Whereas the EMA suggests use of 95% CI, the US FDA prefers use of the narrower 90% CI for demonstration of therapeutic equivalence. A one-sided equivalence (non-inferiority) study would be inadequate to demonstrate biosimilarity since it cannot exclude the possibility that the test treatment might be a ‘bio-better’. In order to preserve a proportion (1−ε) of the therapeutic effect of the biooriginator, δ should be a relatively small fraction (ε) of the difference between biooriginator and placebo in the metaanalysis of placebo-controlled trials (δap). 16