The question of biosimilar interchangeability can be answered with a mixture of science and faith. That may sound like a classic contradiction, but hear me out. The nature of biologic agents prohibits applying the AB-type ratings to biosimilars that the Food and Drug Administration (FDA) uses to designate bioequivalent generic drugs. However, from a practical standpoint, does it really matter? Let’s look at this interchangeable designation issue from the perspective of the FDA and that of the clinician.
The FDA defines interchangeable products as being:
“biosimilar to an FDA-approved reference product, and can be expected to produce the same clinical result as the reference product in any given patient. An interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.
“In addition, for a biological product that is administered more than once to an individual, the risk in terms of safety or efficacy of alternating or switching between the biological product and the reference product will not be greater than the risk of using the reference product without alternating or switching.
“An application for an interchangeable biological product also must include data or information to show that the proposed interchangeable biological product is expected to produce the same clinical result as the reference product in any given patient. In addition, for a product that will be administered more than once to an individual (as many biological products are), the application must include information that demonstrates that the risk in terms of safety or diminished effectiveness of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without alternating or switching.”
The need for scientific studies characterizing the pharmacokinetic and pharmacodynamic profiles of the new agent and clinical studies to determine the biosimilarity of the product to the reference product is unquestioned. In its definition, the FDA is saying that the manufacturer must conduct additional “switching” studies to prove that patient outcomes will be roughly the same after the patient is taken off a reference product and given the biosimilar and vice versa, and this must apply to any patient, not just a patient with an isolated indication. That’s the science.
Here’s the faith: If the FDA grants extrapolation to the biosimilar for the full set of indications, as it did for Pfizer/Celltrion’s Inflectra® version of infliximab, then it believes that patient outcomes will be roughly the same for any of these patients (despite the absence of large-scale clinical studies in some extrapolated indications). Interchangeability is then further defined by whether the switching studies have been done in all possible indications. Celltrion’s switching studies were focused on rheumatoid arthritis and inflammatory bowel disease (rather than psoriasis, psoriatic arthritis).
FDA takes it one step further, to define an interchangeable product as one not needing permission by a clinician in order for it to be substituted for the reference product by the pharmacy. The majority of states have signed and warehoused legislation that allow pharmacists (community or specialty pharmacy–based) the authority to substitute biosimilars without needing a clinician’s permission.
From the physician’s standpoint, must prescribers have faith that Inflectra is interchangeable at the point of prescribing, based on FDA’s ruling? It certainly can be prescribed for any new patient for whom Remicade® can be prescribed, assuming the health plan or insurer covers the medication in the first place. If a patient is already receiving Remicade therapy, can it be switched for the biosimilar if the clinician and patient care to do that (i.e., for cost reasons)? There is no stipulation that it cannot. If the switch is made, does that mean that this particular physician believes that the biosimilar drug is interchangeable? This is merely semantics.
For all practical purposes, the only difference between a basic biosimilar approval and biosimilar interchangeability may be administrative. After years of use, clinical evidence supports that the clinical outcomes between either biosimilar and reference infliximab is not differentiated.
Whereas the biosimilar drug approval process is complicated, the biosimilar interchangeability question is less so. The FDA feels the need to justify a level of certainty reflected by an AB-type rating given to conventional generic drugs, but this cannot be achieved in biologics. It then seems like a matter of faith: If FDA is willing to extrapolate the indications, they believe the therapeutic outcomes will be equivalent, even for diseases for which the biosimilar was not directly tested.
There seems to be little practical difference between expected equivalent outcomes in untested indications and the anticipated benefits of biosimilar interchangeability.