I think the question of whether a biosimilar is
“interchangeable” to a reference or innovator product can be answered with a
mixture of science and faith. That may sound like a classic contradiction, but
hear me out on this. The nature of biologic agents prohibits FDA from applying
the AB-type ratings to biosimilars that it uses to describe bioequivalent
generic drugs. However, from a practical standpoint, does it really matter?
Let’s look at this 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. That said, what the FDA is basically saying in their
definition, is 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 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 limited to rheumatoid arthritis and inflammatory bowel disease
(not 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. That last bit is still a
work in progress, as states grapple with passing 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 drug is
interchangeable? This is merely semantics.
For all practical purposes, the answer is yes. Celltrion’s
product has been used in Europe and elsewhere for many years in doctor’s
offices for all of these indications, without untowards differences in
outcomes.
Whereas the approving a drug to be biosimilar to another is
extremely complicated, but I don’t think the interchangeability question is.
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.
As we continue to await FDA’s long-delayed guidance on how
it will designate the interchangeability of biosimilars, there seems to be
little practical difference between expected equivalent outcomes in untested
indications and the anticipated benefits of interchangeability.
