A biosimilar is “a product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and their reference product in terms of the safety, purity and potency of the product,” said Emanuela Lacana, PhD, Associate Director, Biosimilars and Biologics Policy, Office of Biological Products, CDER, FDA, at the PDA/FDA Joint Regulatory Conference in Washington, DC.
A product is considered “interchangeable” when the biological product is biosimilar to the reference product; can be expected to produce the same clinical result as the reference product in any given patient; and when a product is administered more than once to an individual, the safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without alternating or switching.
An interchangeable product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.
On March 23rd, 2010, President Obama signed the Affordable Care Act into law and the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed. The BPCI Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product.
This abbreviated licensure pathway allows a biosimilar biological product to be licensed under 351(k) of the Public Health Service Act (PHS Act) based on less than a full complement of product-specific preclinical and clinical data. If the biological is demonstrated to be “highly similar” to an FDA-licensed biological product (the reference product), it may apply for licensure on comparative clinical data and publicly available information regarding PDA’s previous determination that the reference product is safe, pure, and potent. This reduces the time to market for many essential products.
The 351(k) application must include information that demonstrates the biological product:
Is biosimilar to the reference product
Utilizes the same mechanisms of action for the proposed condition(s) of use
Condition(s) of use proposed in labeling have been previously approved for the reference product
Has the same route of administration, dosage form, and strength as the reference product
Is manufactured, processed, packed, or held in a facility that meets standards designed to assure that the biological product continues to be safe, pure, and potent
The PHS Act requires information demonstrating biosimilarity based on data from analytical studies, animal studies and a clinical study or studies.
Analytical studies are studies that characterize reference product quality characteristics and product variability. The manufacturing process for the proposed biosimilar product should be designed to produce a product with little to no difference in product quality characteristics compared to the reference product. Comparative assessment of attributes include: amino acid sequence and modifications, higher order structures, impurities, and biological activity, among other things. Statistical analyses are conducted to support a determination of “highly similar”, with quality attributes ranked based on risk.
A test for animal toxicity data is useful when uncertainties remain about the safety of the proposed products prior to initiating the clinical studies. The scope and extent of the animal studies depends on publicly available information and/or data submitted in the biosimilar application regarding the reference product and the proposed biosimilar product, and the extent of known similarities or differences between the two.
FDA does not think in “Phased Development” terms (Phase 1, 2, and 3 studies) for clinical studies for biosimilar development programs. The goal of the clinical studies is not to select a dose or to independently establish safety and effectiveness of the proposed product. The nature and scope of the clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting structural and functional characterization and, where relevant, animal studies.
There is no one study that demonstrates biosimilarity. They ask, “What differences have been observed and what is the potential impact?” And, “What is the residual uncertainty and what study or studies will address it?”
Ultimately, FDA uses a “totality-of-the-evidence” approach and evaluates residual uncertainty at each step.