Background The global development of a biosimilar product is methodologically complex, presenting potential design pitfalls and operational challenges with the risk of failing to demonstrate equivalence. The clinical development of anti-TNF biosimilars presents an additional challenge of selecting the most appropriate therapeutic indication(s) for the pivotal clinical trial(s) among those approved for the originator molecules.
Objectives By reviewing the clinical development programs of biosimilars of adalimumab, etanercept and infliximab, we aimed to highlight the key features of pivotal clinical trials in terms of both study design and most suitable indications.
Methods We performed a search of completed or ongoing Phase III global clinical trials for anti-TNF biosimilars in different clinical trials databases1–3 as well as a search of literature on Medline for anti-TNF biosimilar clinical trials, and summarized the main features of study design of the retrieved trials.
Results The pivotal efficacy and safety trials for anti-TNF biosimilars were either in rheumatoid arthritis (RA) or in psoriasis (PsO). In only a few cases, both indications were pursued for the same product in two pivotal trials. For etanercept and infliximab biosimilars, the most frequent indication of the pivotal trial was RA. For adalimumab either RA or PsO indications were investigated in approximately the same number of trials, with the most recent trials being all in PsO. All studies have an equivalence and not a non-inferiority design. However, considerable differences exist among these studies regarding key design elements such as the target patient population, background therapy, blinding, stratification, switch from originator to biosimilar product, primary dependent variable, and selection of equivalence margin. The differences of the study design of the Phase III biosimilar studies are summarized and discussed regarding the potential impact on demonstrating comparability and operational feasibility.
Conclusions Most of the sponsors are conducting or have conducted the pivotal Phase III studies of anti-TNF biosimilars in one disease indication only, with a preference for PsO in most recent trials. This may suggest that PsO has become the indication of choice for pivotal trials for anti-TNF biosimilars. Potential advantages include 1) the greatest placebo-adjusted response rate is in PsO for the various TNF inhibitors among the licensed therapeutic indications4,5, consistent with the need for a smaller sample size to demonstrate equivalence; 2) the primary study endpoint at week 16 or Week 12 for PsO compared to week 24 of RA allows for a shorter study duration; 3) a more favorable competitive environment leading to a faster trial execution; and 4) a more sensitive model to investigate immunogenicity compared to RA since PsO patients do not receive any immunosuppressive drug for the duration of the study.
Disclosure of Interest None declared