The documents include a Q&A regarding “Implementation of the Biologics Price Competition and Innovation Act of 2009,” final guidance on “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product,” and other final guidance on “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.”
The Q&A lays out the provisions included in the BPCI (Biologics Price Competition and Innovation) Act of 2009 and notes certain cases when a biosimilar may have a different formulation than the reference product and when a proposed biosimilar can have a delivery device or container closure system that is different from its reference product.
More generally, the FDA calls on developers to demonstrate that there are no clinically meaningful differences between the proposed biosimilar product and the reference product in terms of safety, purity, and potency, though in a limited number of circumstances, “this may include providing information from one or more studies using a route of administration for which licensure is not requested.”
In addition, biosimilar applicants are not required to obtain licensure for all presentations for which the reference product is licensed, and they also may obtain licensure for fewer than all conditions of use for which the reference product is licensed.
The agency gives the example of an applicant obtaining licensure of a proposed biosimilar in a pre-filled syringe or in an auto-injector device even if the reference product is licensed in a vial presentation as long as the proposed biosimilar “meets the statutory standard for biosimilarity and adequate performance data for the delivery device or container closure system are provided.”
Still, the agency says it expects injectable biologics to have both the same total content of drug substance (in mass or units of activity in a container closure) and the same concentration of drug substance (in mass or units of activity per unit volume) as the reference product.
Quality Considerations
The guidance document on quality considerations for biosimilars offers an in-depth view on the analytical studies relevant to assessing whether the proposed biosimilar and reference product are highly similar.
“Under certain circumstances, a sponsor may use a non-U.S.-licensed comparator product in certain studies to support a demonstration that the proposed product is biosimilar to the U.S.-licensed reference product. However, as a scientific matter, analytical studies and at least one clinical PK study and, if appropriate, at least one PD study intended to support a demonstration of biosimilarity must include an adequate comparison of the proposed product directly with the U.S.-licensed reference product unless it can be scientifically justified that such a study is not needed,” the agency says.
Manufacturing
Both of the guidance documents also reflect on the manufacturing of biosimilars and the way that sponsors should consider manufacturing changes after completing the initial analytical similarity assessment or after completing clinical studies intended to support a 351(k) application as they “will need to demonstrate comparability between the pre- and post-change proposed product and may need to conduct additional analytical studies.”
The agency adds that analytical similarity studies should include a sufficient number of lots of the proposed biosimilar used in clinical trials, as well as from the proposed commercial process if the process is different from what’s used to make trial products.
“Demonstrating that a proposed product is biosimilar to a reference product typically will be more complex than assessing the comparability of a product before and after manufacturing changes made by the same manufacturer,” the FDA says, noting that the manufacturer of a proposed biosimilar is likely to have a different manufacturing process, such as a different cell line, raw materials, equipment, processes, process controls, and acceptance criteria, as well as no direct knowledge of the manufacturing process for the reference product.
“FDA anticipates that more data and information will be needed to establish biosimilarity than would be needed to establish that a manufacturer’s post-manufacturing change product is comparable to the pre-manufacturing change product,” the agency notes.