Totality-of-the-Evidence

For approval of a proposed biosimilar product, the FDA requires that totality-of-the-evidence be provided to support a demonstration that the proposed biosimilar product is highly similar to a US-licensed product. The FDA recommends a stepwise approach for obtaining the totality-of-the-evidence for demonstrating biosimilarity between the proposed biosimilar product and the reference product The stepwise approach starts with similarity assessment in critical quality attributes (CQAs) in analytical studies, followed by the similarity assessment in pharmacological activities in pharmacokinetic and pharmacodynamic (PK/PD) studies and similarity assessment in safety and efficacy in clinical studies. Basically, the following assumptions are made for the stepwise approach for obtaining the totality-of-the-evidence: (i) analytical similarity is predictive of PK/PD similarity, (ii) analytical similarity is predictive of clinical outcomes, and (iii) PK/PD similarity is predictive of clinical outcomes. The validity of assumptions (i–iii) is critical for the success of obtaining totality-of-the-evidence for assessing biosimilarity between the proposed biosimilar and the reference product. This chapter investigates the validity of these assumptions and the relationships among analytical, PK/PD, and clinical similarity assessment for an overall assessment of biosimilarity between the proposed biosimilar product and the reference product.