By Sara W. Koblitz –
Earlier this week, FDA published another in its series of guidance documents devoted to implementing the Biologics Price Competition and Innovation Act (“BPCIA”). The objective of the new guidance, entitled Statistical Approaches to Evaluate Analytical Similarity Guidance for Industry, is to assist sponsors in demonstrating analytical similarity to support licensure under section 351(k) of the PHS Act. This guidance is intended to serve as a companion document for Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to Reference Product (we blogged about this guidance here).
According to the guidance, analytical similarity involves the comparison of structural or physicochemical and functional attributes using multiple lots of the proposed biosimilar product and the reference product. Under PHS Act § 351(i), “biosimilar” means that the biological product is “highly similar” to the reference product licensed under PHS § 351(a) – even if there are minor differences in clinically inactive components, as long as there are no clinically meaningful differences between biosimilar and reference product safety, purity, and potency. This must be demonstrated based on “analytical studies.” In this guidance, FDA details its current thinking on these analytical studies, including challenges a sponsor may encounter.
FDA first addresses the challenges that may arise in attempting to demonstrate analytical similarity. These include a limited number of appropriate or representative reference product or biosimilar lots and the large number of attributes that can be compared to evaluate quality but may not actually be meaningful.
Thus, FDA recommends a risk-based approach in analytical similarity assessment of quality attributes. This approach involves an Analytical Similarity Assessment Plan. A successful Analytical Similarity Plan will be based on testing with a minimum of 10 reference product lots, 10 biosimilar lots, representative samples of reference product variability (including expiry), U.S.-licensed reference lots only, and lots manufactured with different processes or scales.
The Analytical Similarity Assessment Plan itself should be based on a several step approach:
Step 1: Determine the quality attributes that characterize the reference product in terms of structural/physicochemical and functional properties.
Step 2: Rank these quality attributes according to risk of potential clinical impact.
Step 3: Evaluate these attributes based on three tiers of statistical approaches.
The intent of the analysis is to examine the potential impact on clinical performance and the degree of uncertainty around a clinical attribute in terms of risk to product similarity. Beyond risk, the level of impact of the attribute, the assays used for the attribute, and the types of attributes evaluated should all be carefully considered.
Once the attributes are identified and ranked, the sponsor should determine the appropriate statistical methods to be used based on risk ranking. Tier 1 testing, or formal statistical equivalence testing, should be used for those quality attributes determined to have the highest potential clinical impact. Tier 2 (called the Quality Metric approach), involves setting ranges of acceptable quality attributes and is best used for medium-impact attributes. Finally, Tier 3, Visual Displays, involves subjective assessment through observation and should be used for those attributes with either the lowest risk of potential clinical impact or those attributes that are important but not amenable to formal tests or quantitative evaluation.
FDA notes that final assessment of “highly similar” is made upon the totality of evidence rather than the passing or failing of the analytical similarity criteria of any one tier or any attribute. This demonstrates FDA’s willingness to show flexibility in applying a complex concept, which is necessary given the range of sizes and types of molecules eligible as biologic reference products. Further, establishing biosimilarity is not a one-size fits all process, and this guidance is indicative of FDA’s case-by-case approach. As with all drug development, both small and large molecule, FDA will be involved in the development program from the start – but this guidance gives industry the broad strokes to allow more productive planning conversations.