By Manfred Weiler and Angel Uriol
In early January 2017, the U.S. FDA finally released the long-awaited draft guidance for interchangeability: “Considerations in Demonstrating Interchangeability With a Reference Product.” Since the introduction of the Biologics Price Competition and Innovation Act (BPCI Act)[1], signed into law on March 23, 2010, interchangeability has been considered the Holy Grail in biosimilar development.
In several states in the U.S., interchangeability will allow pharmacists to substitute a biologic therapy with a biosimilar one. In most states, the pharmacist has to notify the prescriber within a given time frame, but this differs state by state, from one day (North Dakota) up to ten days (Indiana). Of course, interchangeability is seen as a key prerequisite for rapid biosimilar market penetration of biosimilars.
The biggest uncertainty in demonstrating interchangeability has been the requirement that the “biosimilar must be expected to produce the same clinical result in any given patient, and that switching a patient back and forth between the reference product and the proposed interchangeable product does not present a risk to the patient in terms of safety or diminished efficacy when compared to treating them with the reference product continuously.” By nature, demonstrating the same clinical result in any given patient is difficult to prove and there has been much speculation as to how to properly address this concern.
In our recent experience with the FDA, we had already seen the request for a single switch from the originator to the biosimilar. While this addresses the concern of increased immunogenicity after switching from the originator to the biosimilar, it is not sufficient to demonstrate interchangeability.
The new draft biosimilar guidance provides better clarity on how to assess interchangeability. With clinical efficacy endpoints in most cases not being sensitive enough, the agency recommends assessing clinical pharmacokinetics (PK) and pharmacodynamics (PD) as primary endpoints. There is also a request for at least two separate exposure periods to each of the two products, which makes it at least three switches.
PK considerations (inter-subject variability in AUCtau or Cmax) will drive sample size calculation for these studies. While many of the Phase I PK studies for biosimilars have been conducted in healthy volunteers, this might be difficult given the repeated exposure to the study drugs in an interchangeability study design. The exact nature of a biosimilar interchangeability study will depend on the specific biologic, the indication and targeted patient population, treatment intervals and mechanism of action. Both options are possible.
