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for ABP 501 for adalimumab with the approval in September2016, pending addi-
tional studies demonstrating their interchangeability [ 44 ].
Interchangeability allows substitution of the biosimilar to the reference drug
without the intervention of the prescriber, thereby allowing insurance companies to
refuse to pay for the originator drug. The FDA requires the approach to begin with
the demonstration of biosimilarity for the product with proposed interchangeability.
Post-marketing data for the biosimilar in addition to appropriately designed studies-
may be used to support interchangeability, but would generally be inadequate to
prove interchangeability in the absence of prospective switching studies, since post-
marketing data would be unlikely to provide adequate PK and PD data.
The FDA recognizes that if patients experience an immune response or adverse
event duringa switching study, it may be difficult to discern whether the event was
the result of the reference product or the interchangeable drug. In their consider-
ation of switching studies, the FDA outlines issues in determination of sample size,
number, and duration of switches, dosing, and duration of the exposure interval that
may be of the greatest concernin terms of generating immune responses with its
potentialconsequent effects on safety and efficacy [ 45 ]. The design of the study
should include a lead-in period of adequate duration to ensure that an adequate
steady state of pharmacokinetics has been achieved prior to the randomization to the
switching period of the study. The FDA guidance expects that the switching arm
incorporates at least two separate exposure periods to each of the two products. In
addition, the study should be designed in that the last switching interval is from the
referenceproduct to the proposed interchangeable product. An integrated studymay
be designed whereby the first phase is designed to demonstrate biosimilarity and the
subsequent phase is designed to demonstrate interchangeability. Furthermore the
studies may be designed to allow for extrapolation for unstudied indications for
which the reference product has been previously approved [ 45 ].
In demonstrating interchangeability, several different clinical study designs can
be applied such as including a single switch from the reference drug to a biosimilar
and monitoring for safety, efficacy, and immunogenicity. An alternative design can
entail a switch from reference drug to biosimilar and then back to the reference drug
or a switch from the initial use of a biosimilar to the reference drug. An additional
issue in designing a crossover study would be to determine the length of the study
after the crossover to the biosimilar, considering that a substantial percentage of
patients may remain in remission after withdrawal of infliximab in the absence of a
follow on biosimilar anti-TNF. In CD, the median time to relapse in patients with a
sustained response was 16.4 months after withdrawing infliximab, and 44% of
patients relapsed within 1 year. Furthermore, a crossover substitution study would
have to control for concomitant immunomodulator therapy and preexisting patient
risk factors for early recurrence after anti-TNF withdrawal [ 47 ].
Ideally anti-drug antibodies (ADAs) and trough drug levels will need to be deter-
mined at the time of the switch, and over time after the switch. Ben Horin reported
that ADAs (measured by an ELISA that could detect antibodies in the presence of
drug) to reference infliximab recognized and cross-reacted with CT-P13, and these
antibodies could similarly interfere with TNF neutralization by either reference
C.Y. Ha and A. Kornbluth