Implementation of the Anchor-Based Indirect Comparison Method for Equivalence Margin Derivation in Biosimilar Development

TL;DR

This paper introduces a new method for deriving equivalence margins in biosimilar development using indirect comparisons when direct data is unavailable.

Contribution

The paper proposes an anchor-based indirect comparison method for equivalence margin derivation in complex treatment scenarios.

Findings

The anchor-based method estimates the treatment effect of Reference vs. Placebo using available indirect data.

Sensitivity analyses help validate the method's assumptions and support regulatory acceptance.

A case study demonstrates the practical application of the method in biosimilar efficacy trials.

Abstract

Background/Objectives: To derive the equivalence margin (EQM), typically, a “classical” meta-analysis on direct within-trial estimation of the effect size of the reference drug compared to the placebo or standard of care is performed: a certain factor of the 95% confidence interval for the pooled treatment effect compared to placebo is used. However, treatment regimens in many indications are becoming more complex (e.g., combination treatments), and for most of these clinical study data, direct comparisons are not available. On the other hand, data for the comparison of the common treatment to the reference treatment in one study and to the placebo in another study are available in some situations. Methods: In such situations, an anchor-based indirect comparison can be applied to estimate the treatment effect of Reference vs. Placebo. This treatment effect (Reference vs. Placebo) can be estimated by calculating the difference of the two treatment effects and the variance as the sum of both variances. The 95% confidence interval of this estimated treatment effect can then be used to derive the EQM. To alleviate any concerns about the underlying assumptions of transitivity and consistency, multiple sensitivity analyses can be performed. Results: We present a case study for deriving the EQM using the anchor-based indirect comparison along with sensitivity analyses (i.e., direct comparison against similar reference drug, the impact of variation of treatment effect on Comparator, and effect size Reference vs. Placebo, including trial data with slightly different population characteristics) for a planned efficacy trial in the biosimilar setting. Conclusions: An anchor-based indirect comparison for EQM derivation is an approach health authorities can agree to if sufficiently supported through other means, e.g., relevant sensitivity analyses.

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