Presented in Biosimilars Congress India 2017 (8-9 Aug, Hyerabad, India)

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Helping you find the RIGHT
solution

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Updates on recent FDA guidance on
biosimilar interchangeability
Tamal Raha, Integrated Biopharma and Pharma Consulting

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Disclaimer
These materials have been prepared solely for educational purposes.
The presentation of these materials does not establish any form of
attorney-client relationship with the author or IBPS.
However, the author and IBPS declares their specific interest on this
topic as they work strategic consultant in drug
development/regulatory/Clinical strategy.

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Hatch-Waxman Amendments vs PHSA & BPCI act
• Allowed generic firm to use safety and
efficacy data of innovator drug after
expiration of patents and exclusivities
• A generic must have the same indications,
strength, purity and quality as the original
product.
• It must be prepared in the same
formulation and be bioequivalent Result
84%
12%
• According to the FDA, “drugs” are different from
“biologics”
• Two federal laws for the approval of pharmaceuticals
• Food, Drug, and Cosmetic Act (FDCA)
• New drug application (NDA)
• Abbreviated NDA (ANDA)
• Public Health Service Act (PHSA)
• Biologics license application (BLA)
• Most biologics approved under PHSA
• “Hatch Waxman Act” of 1984 does not apply
• Biologics Price Competition and Innovation Act
(BPCI) of 2009 created an abbreviated FDA
approval pathway for biosimilar.

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Hatch-Waxman Amendments- Federal Food Drug & Cosmetic
Act (FDCA)- 1984
Biologics, Approved
via PHSA
BLA
351(k)
BLA
351(a)
Prove highly similar
to 351(a) reference
Safety & Efficacy
must
More data to claim
interchangeability
Small molecules,
Approved by FDCA
ANDA
505(b)(2)
NDA
505(b)(1)
Bioequivalence
focused
Safety & Efficacy
focused
Can be filed after 4 years of
Ref product listing

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Definition: Interchangeability
• The biological product is biosimilar to the reference product;
• it can be expected to produce the same clinical result as the reference product in
any given patient; and
• for a product that is administered more than once to an individual, the risk in
terms of safety or diminished efficacy of alternating or switching between use of
the product and its reference product is not greater than the risk of using the
reference product without such alternation or switch.
Note: The interchangeable product may be substituted for the reference product
without the intervention of the health care provider who prescribed the reference
product.

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Why is Biosimilar interchangeability important, the
business impact
• Significant rewards await the sponsor who demonstrates interchangeability. The
first interchangeable biological product receives up to one year of exclusivity
over subsequent follow-on biologics.
• A temporary duopoly will preserve high prices, increasing the profitability of the
follow-on biologic.
• The interchangeable biologic also enjoys an advantage over the brand-name
equivalent, because pharmacies will be free to substitute the interchangeable
biologic without consulting the prescribing health care provider.
Ref: 42 USC §262(k)(6) and 42 USC §262(i)(3)

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Why is Biosimilar interchangeability important
• A biosimilar designation means the product is highly similar to the reference product,
meaning it has no clinically meaningful differences from the reference product.
• There are some allowable differences due to the fact that it’s a complex molecule made from a living
organism.
• An interchangeable designation means that in addition to demonstrating biosimilarity,
the product is expected to produce the same clinical results as the reference product.
• Hence, by definition, interchangeable biosimilar is one that “may be substituted for the
reference product without the intervention of the health care provider who prescribed
the reference product”.
• If a biosimilar is deemed interchangeable,
• the biosimilar product can be substituted for the reference product – and that part is really key.
• Even if a health care provider prescribes the reference product for the patient, the patient may actually
receive the biosimilar version if deemed interchangeable.

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What does this actually mean?
• In order to be recognized by the FDA as interchangeable with its reference product, the
biosimilar biological product must meet additional regulatory standards beyond being
“biosimilar” to the reference product
• Longer clinical trial?
• Not necessarily! It depends on the candidate product
• If the biosimilar product is administered more than once, the manufacturer must also conduct a switching
study to demonstrate that the safety and efficacy is the same in patients alternating between biosimilar and
the reference product, as compared to patients receiving the reference product exclusively.
• It depends primarily on how the product is intended to be used: if it’s being used 1 time, an additional trial
may not be needed, but if it’s being used more than once, a switching study will be required.
• It is important to note, however, that biosimilars with additional efficacy studies are not
necessarily “better” or “more interchangeable” than other products. In fact, because
efficacy studies are not required to determine interchangeability as per FDA regulations,
clinicians should not expect these trials to be available for the majority of biosimilars,
regardless of whether they receive interchangeability designation.

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Switching study
• FDA guidance for demonstrating interchangeability would require a “dedicated switching
study” design, in which
• patients start with the reference product and are randomly assigned to switch to the biosimilar or
continue using the reference product.
• The “switching” group would be expected to incorporate at least three switches between the reference
and biosimilar products.
• The agency also suggests using a non-switching proposed product arm through the duration of the
switching studies to serve as a control.
• The FDA states that the primary endpoints of switching studies must be pharmacokinetic and
pharmacodynamic in nature to determine if there are any concerns with immunogenicity.
• Assessment of additional safety and immunogenicity parameters must be incorporated into the study
design.
• In cases in which there are rare but serious safety risks with the reference product — and,
subsequently, the biosimilar — postmarket monitoring may play a role in informing
interchangeability.
• This is because these safety risks largely would go underreported in premarket clinical trials because the sample sizes
within these studies are not large enough to assess rare events.

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Clinical Expectations
• The data required by the FDA to obtain a designation of being “interchangeable” are
different than the data required to demonstrate safety and efficacy.
• Clinicians should expect the studies that demonstrate interchangeability will not utilize
the same endpoints and sample size as one would use to demonstrate clinical utility.
• Dedicated switching studies that evaluate pharmacokinetic/pharmacodynamic endpoints
— and possibly post-market studies for some molecules — are the norm.
• Do not fall in the trap of a large randomized controlled trial of OS or PFS because this study design
is not adequately sensitive enough to detect issues with immunogenicity.
• the “originator” products that will serve as controls may not be sourced from outside of
the United States. Although biosimilar sponsors can use data from non-US sources to
prove biosimilarity, they may NOT use these data to support an interchangeability
designation.
• Commitments to post-marketing pharmacovigilance programs may be mandated as part
of the interchangeability determination, and they will be critical to confirming or
negating the designation.

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Substitution Process
• Within the medication use process — prescribing, dispensing and administration
— the interchangeability designation plays a major role in that many state
pharmacy practice laws allow pharmacists to independently substitute a
biosimilar for the reference if it is designated as interchangeable by the FDA..
• Some differences
• Pharmacists are not able to legally substitute biosimilars for the reference product outside of
obtaining a new prescription.
• If the prescription is written based on the reference product’s name, the patient’s out-of-pocket
costs may be higher based on the patient’s insurance benefit design. Consequently, prescribers
must specify which product should be dispensed to the patient.
• If interchangeable biosimilars are available and the prescriber has no preference about the specific
product given, the prescriber should write the prescription based on the reference product’s name
so the pharmacist can decide which product will be dispensed.
• If a prescriber has a specific product in mind — whether it is a biosimilar or reference product —
the actual product’s name should be stated, with a note that substitution is not permissible.

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FDA had not designated any biosimilars as interchangeable,
and it may be some time before we see any.
Reference or Originator Biosimilar Interchangeable
Biosimilar
Depth of data
submitted to the FDA
“Standard” data package Abbreviated data package Abbreviated data
package, more
information on efficacy
and safety
Compared to
reference?
N/A Yes Yes
Current example in
USA
• Filgrastim/Neupogen®
• Remicade®
• Enbrel®
• Humira®
• Remicade®
• Filgrastim-sndz /Zarxio®, March 2015
• Infliximab-dyyb/Inflectra, Apr 2016
• etanercept-szzs/Erelzi, Aug 2016
• adalimumab-atto/ Amjevita, Sep 2016
• Infliximab-abda/Renflexis, Apr 2017
Not Yet

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Celtrion’s infliximab case
• interchangeability was not proposed nor requested in Celltrion’s biologics license application
(BLA) for Inflectra (called Remsima in Canada and other regions)
• The company did present some preliminary switching data in its BLA. FDA wrote in a briefing on
that data,
• “the single transition from EU-approved Remicade to CT-P13 during the long-term extension studies in
RA and AS did not result in worse safety or immunogenicity profile. This would support the safety of a
clinical scenario where non-treatment naïve patients undergo a single transition to CT-P13.”
• Despite the fact that the agency acknowledged at the time of Inflectra’s review that Celltrion’s
switching data could theoretically support an interchangeability status, it would appear that the
agency has backtracked on this statement
• Moreover, the EU-approved Remicade could not actually be used in switching studies because of
its origin of manufacture.
• More than 30 distinct orthogonal methods were used to evaluate the analytical similarity of
Inflectra to Remicade, so sponsors should expect to present results for numerous types of
analytical tests.
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