Biosimilars have been available in the field of rheumatology since 2015. In light of this fact, researchers from the National Health Service (NHS) Foundation Trust and King’s College London, discuss study design for biosimilar trials [1].
It is relatively simple to prove that a chemical small molecule generic is identical to its reference product. It is normally sufficient to show pharmaceutical equivalence (i.e. identical active substances) and bioequivalence (i.e. comparable pharmacokinetics) and clinical efficacy and safety studies are not normally required. This is not the case, however, for biosimilars, which are derived from living cells and therefore demonstrate molecular complexity and heterogeneity.
Biosimilar trials are equivalence studies. They differ from conventional randomized controlled trials that are designed to demonstrate superiority of one intervention over another.
In a trial designed to prove superiority, the ‘intention-to-treat’ analysis is used. In this type of trial all patients randomized to a specific arm are analysed irrespective of whether they complete follow-up or not. This approach is based upon the concept that differential drop out, for example, where more people leave an interventional arm because of side effects, would lead to bias in favour of the treatment if the analysis were limited to only subjects that completed the protocol.
In contrast, an intention-to-treat analysis would bias towards the null hypothesis. However, if you consider that a bioequivalence study is looking to prove the null hypothesis, then in the presence of drop out an intention-to-treat approach would bias towards concluding that the biosimilar is equivalent (effectively reversing type 1 and type 2 errors). For this reason equivalence studies should adopt ‘per protocol’ analysis and present findings with 95% confidence intervals for a difference rather than providing a single p-value. The generally accepted standard to declare equivalence would be if the comparator compound confidence intervals lie within ±15% of the originator estimate.
Conflict of interest
The authors of the research paper [1] declared that there were no conflicts of interest.
Editor’s comment
Readers interested to learn more about biosimilars are invited to visit www.gabi-journal.net to view the following manuscript published in GaBI Journal:
Supporting biosimilarity and extrapolation
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Reference
1. Rutherford AI, Galloway JB. Biosimilars in rheumatology: out of the laboratory and into practice. Expert Rev Clin Immunol. 2016;12(7):697-9.
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