By Loan Pham and Vien Lai
Being “biosimilar” does not equal being “interchangeable.” As mentioned in yesterday’s blog post, the Food and Drug Administration (FDA) draft guidance Considerations in Demonstrating Interchangeability With a Reference Product was released in January. That guidance provides details on how to ensure that your biosimilar is interchangeable, but some of the recommendations don’t take all aspects of the drug development process into consideration.
To support interchangeability, the primary analysis in such study(ies) should be the demonstration of bioequivalence of pharmacokinetic (PK) parameters such as the total systemic drug exposure at steady state and the maximum concentration of the biologic in plasma at steady state for the test and reference biological product. While the selection of maximum plasma concentration and total systemic exposure seems appropriate to show therapeutic equivalence (and thereby support interchangeability) at steady state of the studied biological protein products, demonstration of equivalence of such parameters would be an unnecessary burden for a biologic that is designed to be used only once over a prolonged period. For example, for the treatment of rheumatoid arthritis, the first two doses of rituximab are administered intravenously separated by two weeks, and subsequent courses are conventionally administered every six months. Therefore, it would take multiple six month periods for the lead-in period to reach therapeutic steady state with the rituximab-reference product, before heading to the switching period. In this case, the practicality of conducting such a lengthy study should be considered. Strikingly, for locally acting or topical protein products that have minimal to no systemic absorption, it may not be ideal to use the steady state PK parameters as primary criteria in the dedicated switching study to demonstrate interchangeability.
Notably in the guidance, pharmacodynamics (PD) endpoints are marked as “when evaluated.” PD data are usually required for biosimilar approval, thus PD assessment may be optional for a product that has been demonstrated to be biosimilar. Clearly, this will be a topic to discuss during preapproval meetings/interactions with FDA.
The draft interchangeability guidance also provides instructions for the design of the “integrated study” where demonstration of biosimilarity and interchangeability between the test and reference protein products can both be evaluated. For this type of study, multiple endpoints will be needed to demonstrate both biosimilarity and interchangeability. Some sponsors may find it is a “too late” opportunity as they have initiated or finalized their studies that only aim for biosimilarity.
The draft guidance for interchangeability is also helpful for the sponsors to determine if they want their products to be interchangeable with the reference but also be distinct, the recognition is possible on the basis of differences in product presentation. If that is the case, additional analysis including comparative use human factor studies will be needed.
In summary, after almost two years since the approval of the first biosimilar product, FDA became clear about what data should be submitted to support the interchangeability of biosimilar protein products by releasing the draft guidance for interchangeability biological products. The draft guidance provides helpful general instructions to the pharmaceutical industry. However, there are certain cases that will require additional discussion. In addition, there are potential biological products, such as those intended for local use, which have not found themselves discussed explicitly in the draft guidance.