There is no single method that is solely decisive for a conclusion on biosimilarity of a
certain candidate. But we can talk about streamlining the demonstration on biosimilarity.

Demonstrating Biosimilarity

According to the FDA, the approval of a biosimilar should be based on the integration of different information using a totality-of-evidence approach.

The totality-of-evidence paradigm describes the sum of analytical, non-clinical and clinical studies conducted to justify regulatory approval of a biosimilar.

The foundation of this approach is an extensive analytical comparison of both biosimilar and
reference products to establish molecular similarity using physicochemical and functional assays.

A problem with reliability

Performing comparability assessments using classical statistical approaches can be difficult to perform.

Any product characterisation exercise should be based on a comprehensive set of analytical techniques. Typically, that’s what it’s called an analytical package.

These analytical packages include different types of data for multiple quality attributes derived from several analytical techniques. To handle this using a univariate approach is an overwhelming and time-consuming task.

Effectively streamlining the demonstration on Biosimilarity

When you consider the concepts of fingerprint-like similarity and of residual-risks, you need to extensively compare the complete domains of the biosimilar and reference products.

Thus, we use multi-parametric and multivariate approaches.

This stepwise and risk-based approach supports the comparability exercise and considers both the impact and uncertainty of each quality attribute on clinical outcomes.


The result is a mitigated residual uncertainty and an assessment of the minor differences. This helps to determine if they are clinically meaningful, establishing the link between analytical and clinical domains.

The robustness of this approach is also strengthened because it is fully aligned with FDA’s totality-of-evidence and, therefore, it helps streamlining submission processes to regulatory agencies.

Related topics

Interested in biosimilars interchangeability? If so, we think you’ll enjoy our work on the topic. Just click here!