This month the FDA published its Guidance for Industry titled “Considerations in Demonstrating Interchangeability With a Reference Product”. The guidance is “intended to assist sponsors in demonstrating that a proposed therapeutic protein product is interchangeable with a reference product for the purposes of submitting a marketing application or supplement under section 351(k) of the Public Health Service Act” (“PHS Act”). Thus, the guidance “focuses on therapeutic protein products” instead of all biologic products.
The guidance provides an overview of important scientific considerations in demonstrating interchangeability with a reference product, including the following:
- Data and information needed to support a demonstration of interchangeability
- Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability
- Considerations regarding the comparator product in a switching study or studies
- Abbreviated considerations for developing presentations, container closure systems, and delivery device constituent parts for proposed interchangeable products
The guidance states that the FDA “intends to consider the totality of the evidence provided by a sponsor when” evaluating interchangeability. The “switching” study referenced above is a study undertaken to address section 351(k)(4)(B) of the PHS Act. This section requires, inter alia, the FDA to determine the following when evaluating the interchangeability of a proposed biosimilar: (1) whether the proposed biologic product is “biosimilar to the referenced product;” (2) whether the proposed biologic product “can be expected to produce the same clinical result as the reference product in any given patient;” and (3) “for a biological product that is administered more than once in an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” The guidance states that a study to satisfy the last consideration (a “switching study”), “should generally evaluate whether switching between the reference product and the proposed interchangeable product will affect clinical response in terms of safety or diminished efficacy reflected, in part, through an assessment of whether switching results in differences in immunogenicity and PK and/or PD (if available), as compared to not switching. Hence, rather than being used only as a control, the comparator product is used in a switching study in both the active switching arm and the control non-switching arm.” The guidance states that sponsors are encouraged to contact FDA early in the product development process to discuss the design of a switching study, including any proposal to provide adequate scientific justification to support the use of data generated in a switching study using a non-U.S.-licensed comparator product to support a demonstration of interchangeability.
In a press release regarding the guidance, Acting Commissioner of Food and Drugs at the FDA, Dr. Norman Sharpless, stated that the guidance “will help promote competition in the biologic market by providing final guidance on the pathway for ‘interchangeable’ biologics, which may be substituted without the involvement of the prescriber, similar to how generic drugs are routinely substituted for brand name drugs when they are prescribed for patients.” Acting Commissioner Sharpless also discussed how this guidance will apply to insulin biosimilars in the future, stating that:
Separately, and of particular importance to the millions of Americans with diabetes, the final interchangeability guidance will help enable biosimilar or interchangeable insulin products to come to market in the future. There are currently no approved insulin products that can be substituted at the pharmacy level. But, under the BPCI Act, on March 23, 2020, insulin and other biological products that were approved as drugs under the Federal Food, Drug, and Cosmetic Act will be deemed biological products licensed and regulated under the PHS Act. After this transition, the FDA will be able to license biosimilar and interchangeable insulin products that meet the requirements of the PHS Act, and today’s guidance will, among other things, help developers seek licensure for such products.