The Interchangeables Are A-Changin’: New FDA Guidance Proposes Eliminating Switching Studies Requirements

In a short but sweet Guidance issued last week, FDA proposed a dramatic change to the way it evaluates interchangeable biosimilars.  For the last 14 years, an applicant could get approval of a biosimilar as a standard biosimilar or an interchangeable biosimilar, but the interchangeable biosimilar presented a higher hurdle to approval: Applicants needed to show that a patient could be switched from the Reference Product to the biosimilar and back without issue.  But, as time has marched on and FDA’s experience with interchangeable biosimilars grown, the Agency’s “experience has shown that . . . the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product.”  Indeed, 9 of the 13 interchangeable products FDA has approved thus far have not included switching studies.  Accordingly, FDA issued this new draft guidance that, when finalized, will revise certain sections of another guidance document, Considerations in Demonstrating Interchangeability With a Reference Product, which was written before FDA had received and reviewed any interchangeable biosimilar applications.

Interchangeable biosimilars differ from standard biosimilars as they may be substituted for the reference product without the intervention of a healthcare provider.  The switching study was intended to provide assurances that such a switch can be done safely by examining any immunogenicity risks.  Based on experience to date, along with currently available analytical technologies that can structurally characterize highly purified therapeutic proteins and model in vivo functional effects, FDA has decided to revise the Interchangeability Guidance such that switching studies are no longer required.  Instead, applicants may choose to provide an assessment of why the comparative analytical and clinical data provided in the application or supplement support a showing that the switching standard has been met.  This new policy applies retroactively to pending biosimilar applications, to which an applicant may submit an amendment, including such an assessment in lieu of switching studies.

FDA, in abrogating the requirement for switching studies, has removed the only significant barrier to interchangeability.  Rather than conducting studies, applicants can use modeling to support interchangeability, drastically decreasing the investment necessary to obtain approval of a biosimilar as interchangeable.  Lowering this standard should increase access to interchangeable drug products, but it raises questions as to whether any differences ultimately remain between biosimilars and interchangeable biosimilars.  And interchangeable exclusivity becomes an extraneous incentive, as there are no additional studies performed for which the reward serves as an incentive.  Effectively, all biosimilars could be interchangeable with the right explanation, which leaves questions of whether the distinction between a regular biosimilar and an interchangeable biosimilar is necessary at all.  Given that FDA asked Congress specifically to do away with the line between interchangeable biosimilars and other biosimilars in its recent Budget Request, this Guidance should not come as much of a surprise.