A key question for the developers of biosimilars is the studies needed to support interchangeability with the reference biologic. A new FDA Guidance Document, released this week, provides the current rationale for the need for a Comparative Efficacy Study (CES). This draft guidance describes updated scientific considerations regarding a comparative clinical study with efficacy endpoints intended to support a demonstration of biosimilarity.
The new draft guidance builds on the foundation of the April 2015 guidance, “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”. That initial guidance recommended that a comparative clinical study would be necessary if there was residual uncertainty about whether clinically meaningful differences existed between the proposed biosimilar and the reference product, based on earlier comparative studies (analytical, toxicity, PK, PD, and immunogenicity). The guidance also stated that a sponsor should provide a scientific justification if it believed that a comparative clinical study is not necessary.
However, since the 2015 publication, the FDA has gained significant experience evaluating analytical differences and their impact on clinical performance. This growing experience has led to an important realization: Comparative Analytical Assessments (CAA) are generally more sensitive than a CES for detecting differences between two products that may preclude a demonstration of biosimilarity. Accordingly, the FDA’s scientific approach is evolving as to when a CES may inform a demonstration of biosimilarity.
The fundamental difference lies in their purpose and sensitivity. Comparative Analytical Assessment (CAA) is a highly specific, science-based evaluation conducted in vitro (in a lab setting). It uses modern, highly sensitive analytical technologies to structurally characterize the proposed product and compare its physicochemical and functional attributes (like purity, structure, and biological activity) directly against the reference product. A CAA is generally more sensitive than a CES to detect even minor differences between products. Comparative Efficacy Study (CES) is a clinical trial conducted in vivo (in human patients). It compares a clinical efficacy outcome or other relevant therapeutic effect between the proposed biosimilar and the reference product. However, a CES often lacks the sensitivity of a CAA. This is because clinical trials commonly use a therapeutic dose range chosen to reach pharmacologic target saturation and the therapeutic plateau, which can mask minor differences in product potency (known as floor and ceiling effects).
The new draft guidance outlines a streamlined approach for determining when a CES may not be necessary to support a demonstration of biosimilarity. The key take-home message is that if the robust CAA supports a demonstration that the proposed biosimilar is highly similar to its reference product, then a streamlined clinical package focusing on an appropriately designed human pharmacokinetic (PK) similarity study and an assessment of immunogenicity may be sufficient. This is based on the statutory requirement to demonstrate that there are no clinically meaningful differences between the products in terms of safety, purity, and potency.
A sponsor should consider this streamlined approach when the reference product and proposed biosimilar product are manufactured from clonal cell lines, are highly purified, and can be well-characterized analytically. The relationship between quality attributes and clinical efficacy is generally understood for the reference product, and these attributes can be evaluated by assays included in the CAA. The sponsor should also consider whether a human pharmacokinetic similarity study is feasible and clinically relevant. A CES may still be necessary in certain circumstances, such as for locally acting products (e.g., intravitreally administered products) where comparative pharmacokinetics is not feasible or clinically relevant. The final determination is based on the totality of the evidence submitted in the biologics license application.
This guidance represents the FDA’s current thinking on the topic. It represents a mature regulatory stance that leverages the power of modern analytical technology over less sensitive clinical trials. This shift towards a scientifically-justified, risk-based approach promises to speed up the development of safe and effective biosimilars, ultimately benefiting patients worldwide. Developers should proactively discuss their plans with the Agency early in product development to leverage this updated framework.
