Check out this presentation from PAREXEL Consulting experts to learn about key regulatory processes affecting biosimilars development including an an overview of the 351(k) Pathway, FDA approvals and managing post-approval challenges.

1. © 2018 PAREXEL INTERNATIONAL CORP.
LIFE OF A
BIOSIMILAR
PARTHA ROY, Ph.D.
Vice President, Technical
PAREXEL International
2018

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WELCOME
• Overview of the 351(k) Pathway and FDA
Approvals
• Managing Post-Approval Challenges
− Manufacturing Changes
− Interchangeability
− Introducing innovation to Biosimilar
Product
− A recent example of Biosimilar Label
Curve-Outs
• Conclusions
AGENDA

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OVERVIEW OF THE BIOSIMILAR PATHWAY
Clinical studies as needed
SimilarityAssessmentwithReference
ReducingUncertainty
Discipline Originator Biosimilar
Integrated Similarity Exercise
Product-specific Quality, Safety
(Immunogenicity) and Efficacy
Cross
Reference
Ehmann F. (2011), “EU Biosimilar Regulatory Framework II”, Presentation at GCC Workshop on Similar
Biological Medicinal Products (Biosimilars)
Analytical
Nonclinical
Clinical

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BIOSIMILARS OBTAIN THE FULL COMPLEMENT OF
INDICATIONS WITHOUT RUNNING CLINICAL TRIALS IN
EACH INDICATION
PK/PD in indication 2
Ph3 in indication 2
Mechanism of Action
PK/PD/Biodistribution
Toxicity
CMC / PK
Comparability
Data
Fewer Indications
All Indications
Clinical Comparability Phase 3 Study in Core (Sensitive) Indication
Agency Decision
Scientific
justification and
totality of data Not a mustJustification

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FDA APPROVED BIOSIMILARS SO FAR
Drug Name Approval Date
Zarxio
(Filgrastim-sndz)
March 2015
Inflectra
(Infliximab-dyyb)
April 2016
Erelzi
(Etanercept-szzs)
August 2016
Amjevita
(Adalimumab -atta)
September 2016
Renflexis
(Infliximab-abda)
May 2017
Cyltezo
(Adalimumab-adbm)
August 2017
Mvasi
(Bevacizumab-awwb)
September 2017
Ogivri
(trastuzumab-dkst)
December 2017

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TAIPEI, TAIWAN
POST APPROVAL
CHALLENGES
MANUFACTURING
CHANGES

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POST-APPROVAL COMPARABILITY EXPECTATIONS
ACROSS JURISDICTIONS
Once approved, the biosimilar will have its own
lifecycle following ICHQ5E for comparability exercise
for any changes to manufacturing process. There is
no regulatory requirement for re-demonstration of
biosimilarity.
Once a Notice of Compliance (NOC) is issued for a
Subsequent Entry Biologic (SEB), it is considered to
be a stand-alone product and regulated accordingly. It
is not required to re-establish its similarity to its
reference biologic drug product.
No specific reference to biosimilar post-approval
comparability expectations in the guidance
documents.

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CHALLENGES AND
UNCERTAINTIES REMAIN
WITH POST-APPROVAL
CHANGES OF A
BIOSIMILAR
• Reference product profile will
continue to change over time
even after biosimilar product
is approved
• Biosimilar process change
post-approval is inevitable
• Hence biosimilar process
can not be locked into a
particular process at the time
of approval, however, the
questions is:
How will you manage a process drift?

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CHALLENGES AND UNCERTAINTIES REMAIN WITH
POST-APPROVAL CHANGES OF A BIOSIMILAR
• Comparability protocol supports post-approval manufacturing changes to ensure
that the quality attribute ranges remain consistent with those of the biosimilar’s
non-clinical and clinical experience including the analytical similarity that
supported approval in the first place
• Hallmark of a biosimilar development is paucity of nonclinical and clinical assessment
with heavy anchoring to the reference product
• Therefore, the reality is that biosimilar product is restricted to the reference product
quality range, manufacturing experience and clinical relevance.
• The need for and the extent of a comparability exercise depends on the potential
impact of the change(s) on the quality, safety and efficacy of the product, i.e. risk
assessment
• Categorization of change? Is there any need for further clinical assessment?
• Potential for quality drift in terms of impurity profile and/or better delivery /
presentation – can lead to a different, unintended target product profile
• How to deal with post-approval process changes for interchangeable biosimilars:
FDA Guidances are silent on this.

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DUBLIN, IRELAND
POST-APPROVAL
CHALLENGES
INTERCHANGEABILITY

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DEFINITIONS: SWITCHING, INTERCHANGEABILITY AND
AUTOMATIC SUBSTITUTION
Switching
− Decision to change therapy (when motivated by economic concerns, may be deemed
“non-medical switching”)
Interchangeability (note: definition may depend on jurisdiction)
− Health or regulatory authority designation that products are equivalent
− Primarily a US standard
− The EMA’s evaluation does not include recommendations on interchangeability
Substitution – Pharmacist Action
− When a pharmacist substitutes a certain prescribed product by another
equivalent product
− Qualified as “automatic” or “involuntary” substitution without prescribing physician’s
involvement

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REGULATORS GENERALLY RECOGNIZE UNIQUE IMPACT THAT ALTERNATING
BIOLOGIC THERAPIES CAN HAVE ON PATIENTS
12©2015 NIBRT AbbVie | Biosimilars are not generics: Important considerations fueling the regulatory debate
US3
“Prior exposure to a therapeutic protein product or to
a structurally similar protein may lead to pre-existing
antibodies at baseline.
Canada1
“Repeated switches between
biosimilars and originator products may
increase immunogenicity with
potentially negative effects.”
WHO5
Generics “can be shown to be bioequivalent and may often be substituted for one another at the
point of dispensing. Because of their structural complexity, the complexity of their manufacturing
processes using living organisms, the greater difficulties in achieving consistency of manufactured
batches and the often complex long-term effects of their administration to a patient,
bioequivalence cannot be easily established for a product containing a biological substance. For
those reasons, many regulatory systems take a different approach between similar
biotherapeutics and generic chemical medicines.”
Japan4
“It is vital to assure the traceability
of adverse events during the
respective surveillance period,. . .
their substitution or combined
application should in principle be
avoided throughout the treatment
period.”
EMA2
“Patient-related factors, which might influence the
immune response to a therapeutic protein, include . . .
pre-existing antibodies (protein therapeutic -reactive
antibodies) due to previous exposure to the product or
products containing substances with structural
similarity”

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SPECIFIC GUIDANCE ON INTERCHANGEABILITY OF
BIOSIMILARS VARIES
• U.S. remains sole regulatory agency that has explicitly additional standard for
interchangeability
• Biosimilar will be deemed interchangeable (and therefore eligible for automatic
substitution at the pharmacy) if the product:
- Is biosimilar to the reference product; and
- Can be expected to produce the same clinical result as the reference
product in any given patient; and
- For a biological 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 biological product and the reference product is not greater
than the risk of using the reference product without such alternation or switch.
• No interchangeability guidance or determinations to date

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IN EUROPE, DECISIONS REGARDING INTERCHANGEABILITY AND SWITCHING
ARE LEFT TO MEMBER STATES AND APPROACHES VARY
14©2015 NIBRT AbbVie | Biosimilars are not generics: Important considerations fueling the regulatory debate
UK
Recommends that biologic
prescriptions be written by
brand name in order to
“ensure that automatic
substitution of a biosimilar
product does not occur
when the medicine is
dispensed by the
pharmacist.”2
Germany
“[A]ny decision needs to be based on
scientific data, in particular data supporting a
high degree of comparability of the biosimilar
and its originator product and the scientific
plausibility of all data referred to in the
discussion process.”3
Norway
Automatic substitution currently
not allowed; government
sponsored “NOR-SWITCH” study
is ongoing; may be used to
support automatic substitution in
the future.
Ireland
“It is not recommended that
patients switch back and
forth between a biosimilar
and reference medicine, as
at the current time the
availability of data on the
impact of this are limited.”1
1. Ireland Health Products Regulatory Agency, Guide to Biosimilars for Healthcare Professionals and Patients, 14 October 2015. , 2. MHRA, Drug Safety Update:
Biosimilar products (February 2008), https://www.gov.uk/drug-safety-update/biosimilar-products. , 3. Paul Ehrlich Institute's position on the interchangeability of
biosimilars.

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AUSTRALIA BECAME FIRST MAJOR REGULATORY JURISDICTION TO
CONSIDER AUTOMATIC SUBSTITUTION FOR BIOSIMILARS
15©2015 NIBRT AbbVie | Biosimilars are not generics: Important considerations fueling the regulatory debate
• Australia’s Reimbursement Authority, Pharmaceutical Benefits Advisory
Committee (PBAC) has recommended that biosimilars are suitable for
substitution at the pharmacy level, otherwise known as “A flagging”.
• However, physicians would retain ability to keep patient on current therapy
(by indicating that substitution is not authorized), hence not a case of
automatic substitution but a pharmacy-level substitution by default
• PBAC will only consider “a-flagging if there is:
− Absence of data to suggest significant differences in clinical effectiveness or safety
compared with the originator
− Absence of identified populations where the risks of using the biosimilar are
disproportionately high
− Availability of data to support switching between the originator and the biosimilar
(one-way transitioning)
− Availability of data for treatment-naïve patients initiating on the biosimilar
− Whether the Therapeutic Goods Administration (TGA) has deemed a product to be
biosimilar with the originator biological.

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TOKYO, JAPAN
POST-APPROVAL
CHALLENGES
INTRODUCING INNOVATION
TO BIOSIMILARS

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BIOSIMILAR PRODUCT
INNOVATION POST-
APPROVAL:
INTRODUCTION OF A NEW
AUTOINJECTOR
• Will be reviewed under a
supplement for the approved
351(k) BLA application
• CDRH evaluation of the device
• Human Factors Study – use-related
hazards evaluation
• Design verification, controls and
performance
• PK bridging study in a range
of BWs
• In-use study in target
population may be needed

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BIOSIMILAR PRODUCT INNOVATION POST-APPROVAL:
INTRODUCTION OF A NEW ROUTE OF ADMINISTRATION
As an example, seeking approval of a SC formulation (new route) when
the reference and the biosimilar are both IV products
• Development under BLA 351(a) pathway and not under a supplement to the
existing Biosimilar, 351(k) BLA
- Stand-alone application and must contain all required data and information necessary to
demonstrate the safety, purity, and potency of the proposed biological product for each of
its proposed indications.
- Expected to include full reports of investigations of safety, purity, and potency, and may
not rely on FDA’s finding of safety, purity, and potency for another approved biological
product or literature-based summaries to fulfill a requirement for licensure
• Need separate INDs for separate indications for which licensure is sought
• Cross-referencing clinical comparability data that supported a demonstration of
biosimilarity to the reference product from the existing 351(k) BLA would only be
considered, if adequately justified, as a comparison to an active control

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BIOSIMILAR PRODUCT
INNOVATION POST-
APPROVAL:
INTRODUCTION OF A
NEW ROUTE OF
ADMINISTRATION
• A single Phase 3 may be justified based
on how much safety and efficacy data
from IV can be relied upon
• Strategically, better to target the
indication for which the core comparability
study was conducted as part of Biosimilar
approval
Get the dose and regimen right
• Phase 2 (PK/PD) study to explore
dose, safety and efficacy
• Study design considerations – non-
inferiority, cross-over, dose cohorts?
• Flat vs. BW (or BSA) - based dosing
• PK/PD modeling
• Safety/Tolerability: Hypersensitivity,
local cutaneous reactions and AESI

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BOSTON, MASSACHUSETTS
POST-APPROVAL
CHALLENGES
BIOSIMILAR LABELS

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FDA’S NEW NON-PROPRIETARY NAMING GUIDANCE
• Draft Guidance finalized on January 2017
• Both newly licensed as well as previously
licensed biological products
• Use of proper name: core name plus a
‘four lower case letter’ suffix
e.g. infliximab-dyyb
• Open questions:
- Random, meaningless suffix?
- Interchangeable products will share
same suffix as reference product?
• Two main justifications for distinguishable
non-proprietary names:
1. Prevent inadvertent substitution
2. Facilitating pharmacovigilance

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BIOSIMILAR LABELLING CAN BE DIFFERENT FROM REFERENCE: AN
EXAMPLE OF LABEL CURVE-OUT
• FDA deleted two indications based on sponsor request driven by patent issues
• FDA felt that it is necessary to retain some safety data related to the deleted indications
• Deleted indication(s) referred to as “another indication” in the label
• Similar approach taken for Inflectra labeling w.r.t. orphan-protected pediatric UC

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CONCLUDING
REMARKS • Many post-approval challenges
remain and need multi-disciplinary
collaborative solution
• Biosimilars product quality mimics
reference product for approval,
however, they become a stand-
alone product after approval
• FDA Guidance largely silent on
product quality expectations for an
interchangeable biosimilar through
its lifecycle
• The regulatory burden of post-
approval innovation for a biosimilar
is yet to be well defined

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THANK YOU
© 2017 PAREXEL INTERNATIONAL CORP. / 24