The issue of the use of biosimilars and their uptake in the market has been a discussion point since the first biosimilar was approved in 2015.  Today, the FDA issued a long-awaited guidance on how a firm can demonstrate interchangeability of a biosimilar to its reference licensed product. The guidance is titled Considerations in Demonstrating Interchangeability With a Reference Product (which is a bit confusing as it applies only to biosimilars) and can be found here.

The Agency notes that it “will determine the biological product to be interchangeable with the reference product if FDA determines that the information submitted in the application or the supplement is sufficient to show that the biological product “is biosimilar to the reference product” and “can be expected to produce the same clinical result as the reference product in any given patient” and that “for a biological product that is administered more than once to 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.””

Such an interchangeability finding will mean that the biosimilar product can be freely substituted without the intervention of a health care practitioner that wrote the prescription for the reference product.  This finding would be similar to a finding of therapeutic equivalence for a generic drug.

FDA lists the scientific consideration for such a finding once a product has been found to be biosimilar as follows:

  • 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 23-page guidance discusses the parameters to be measured some of which will depend on the complexity of the biosimilar, the indications proposed for the biosimilar, repeat dosing considerations, product-specific immunogenicity risk, use of switch studies, impact of post marketing data for a biosimilar that was approved without a finding of interchangeability, among others.

The guidance is very comprehensive in regard to the discussion of design of the various studies that will likely be required to support a finding of interchangeability, but the Agency notes that the data necessary to support a finding of interchangeability will be evaluated and established on a case by case basis.

Much attention is devoted to describing how PK and PD (if available) data should be used, as well as the actual design elements of the switching study, the number of subjects, target population, as well as study analysis. The document also discusses the use of non-US based reference products and the need for a bridge between the US product and the non-US based product. The FDA also points out the potential problems associated with a decision to use a non-US licensed product and what additional considerations should be evaluated if a non-US licensed product is used as the reference.

The guidance is out, and the ground rules are laid down. It looks like a lot of work and it will be interesting to see if biosimilar manufacturers want to go through the required effort, given the fairly low uptake of approved biosimilars in the market.  Will an FDA finding of interchangeability spur the confidence and acceptance of these products in the medical community? Only time will tell. Let’s see how long it takes before a company jumps into the interchangeability pool!