The guidance aims to assist sponsors in determining how to demonstrate biosimilarity when developing or submitting a marketing application for a proposed biosimilar product. It outlines the information needed surrounding the structural, physicochemical and functional attributes of a reference product and lists the requirements necessary to establish meaningful similarity acceptance criteria.

The FDA issued a draft guidance document to assist with the marketing application submission for biosimilar products. As part of the application, sponsors must include data from analytical studies demonstrating that the biological product is highly similar to the reference product. When conducting an analytical similarity assessment of quality attributes, the agency recommends using a risk-based approach. This approach consists of determining the quality attributes that characterize the reference product in terms of its structural/physicochemical and functional properties, ranking the quality attributes according to their risk of potential clinical impact, and evaluating the attributes/assays according to one of the following three tiers of statistical approaches:

  • Tier 1: The agency recommends equivalence testing for quality attributes with the most elevated risk ranking. This should include assays evaluating the clinically relevant mechanisms of action of the product for each indication for which approval is sought.
  • Tier 2: The agency recommends the use of quality ranges for quality attributes with lower risk rankings.
  • Tier 3: The agency recommends the use of visual comparisons for quality attributes with the lowest risk ranking.

The guidance notes that sponsors should develop an analytical similarity assessment plan describing the lots available for similarity testing, making efforts to address all factors that could impact whether the proposed biosimilar is determined to be highly similar to the reference product.

The document makes recommendations concerning the quantity and quality of both reference product and biosimilar lots needed to evaluate analytical similarity. The agency recommends a minimum of 10 biosimilar lots be included in the analytical similarity assessment. To establish meaningful similarity acceptance criteria, the agency also recommends that a minimum of 10 reference product lots be sampled, each of which should be selected with the goal of representing the variability of the reference product. Sponsors should account for all the reference product lots available to them and should also select lots with remaining expiry spanning the reference product shelf life.

The FDA notes that applications should include a list of all lots that were evaluated in any manner — regardless of whether a particular lot was used in the final similarity assessment — along with the specific physicochemical, functional, animal and clinical studies for which each lot was used. Furthermore, in the case of biosimilar lots being manufactured with different processes, data should be provided to support comparability of any materials manufactured with the different processes and/or scales.

The FDA recommends that the analytical similarity assessment plan be developed in four stages, corresponding to the development of the risk ranking of the reference product’s quality attributes based on the potential impact on the clinical performance categories, the determination of the statistical methods to be used, the development of the statistical analysis plan, and the finalization of the analytical similarity assessment plan.

The guidance goes on to state that analytical similarity acceptance criteria will ideally be derived using data from an analysis of the U.S.-licensed reference product, and the similarity assessment should be based on a direct comparison of the proposed biosimilar product to the U.S.-licensed reference product. Sponsors who wish to use data derived from products approved outside of the U.S. are encouraged to discuss their plans with the FDA prior to submitting a marketing application.

The FDA notes that the draft guidance document is being distributed for comment purposes only.