Navigating Regulatory Complexities of Biosimilar Development by Dr. Ted Carver

1. © 2017 PAREXEL INTERNATIONAL CORP. / 1
© 2017 PAREXEL INTERNATIONAL CORP.
NAVIGATING REGULATORY
COMPLEXITIES OF
BIOSIMILAR DEVELOPMENT
Dr. Ted Carver
Principal Consultant, Integrated Product
Development, PAREXEL Consulting
February 17th, 2017
PAREXEL India Symposium 2017

2. © 2017 PAREXEL INTERNATIONAL CORP. / 2
NAVIGATING REGULATORY
COMPLEXITIES OF
BIOSIMILAR
DEVELOPMENT
EVOLUTION OF BIOSIMILAR PATHWAYS
• U.S and EU Pathways
• Key considerations in evaluating
differences
• First generation Biosimilars: Lessons
learned
• Next generation Biosimilars and
beyond
AGENDA

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U.S VS. EU (AND OTHER REGIONS): COMMON ELEMENTS
• Analytical comparison is foundational and is divided by physicochemical
properties and biological activity
• Arguments based on “orthogonal approaches” e.g. afucosylation vs. ADCC
• Tests for similarity/comparability are largely the same – details, emphasis may
vary
• General “stepwise approach” is recommended
• General principles regarding the role of nonclinical and clinical studies are similar
(resolution of differences deemed to have minor clinical impact)
• Monoclonal antibodies as biosimilars are still relatively new
• Other similarities

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U.S. VS. EU: SOME DISTINCTIONS
• EU experience is still more extensive. Areas of uncertainty in U.S. are being resolved for 1st generation
biosimilars (e.g. statistical approach).
• A large group of protein products regulated as biosimilar in the EU are not in U.S. pathway in the U.S.
until 2020 (growth hormones, insulins, follitropins). 505(b)(2) is not a substitute but will transition.
• Differences in nonclinical requirements for some products. EU open to waiving more nonclinical
requirements in theory, based on guidance.
• Significant differences in clinical strategy across indications, acceptable endpoints, statistical analysis,
most sensitive populations
• Although general CQAs are similar, approaches to tiering and statistical analysis in U.S. are unique
to U.S.
• Pediatric study plan requirements
• Interchangeability

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US: CRITICALITY ASSESSMENT: KEY ELEMENTS
Tier 1
• 2/3 representative CQAs that directly
impact safety/potency
• e.g. Rituximab = ADCC & CDC; Infliximab
= anti-TNF binding & reverse signalling
Tier 2
• Other CQAs that impact safety/ potency
• e.g. glycoprofile, some receptor-binding
assays
Tier 3
• Can be critical or less critical but not
amenable to statistical analysis
These required to fall within +/- 1.5 SD
for results from multiple reference
product batches. It may be possible to
justify broader limits.
These required to fall within +/- 1.5 SD
for results from multiple reference
product batches. It may be possible to
justify broader limits.
Quality range approach generally ±QR
for RMP batches. QR defaults to 3SD but
justified.
Quality range approach generally ±QR
for RMP batches. QR defaults to 3SD but
justified.
Descriptive
Graphical display
Descriptive
Graphical display
Note: ADCC: Antibody-Dependent Cell-Mediated Cytotoxicity
CDC: Complement Dependent Cytotoxicity

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BIOSIMILARITY: DIFFERENCES AT MOLECULAR LEVEL?
• Differences in the active substance
can be permissible, e.g. differences in
terminal sequence, glycosylation,
other posttranslational modifications.
• Expression system need not be the
same; however, use of alternative
expression systems is discouraged in
the guidance.
There are no clinically
meaningful
differences between
the biological product
and the reference
product in terms of
the safety, purity, and
potency of the
product.
“The acceptability of the type, nature, and extent of any differences between the
proposed finished biosimilar product and the finished reference product should
be evaluated and supported by appropriate data and rationale.”
Source: U.S. FDA, “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein to a Reference Product”, April, 2015

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BIOSIMILARITY: DIFFERENCES IN DRUG PRODUCT?
Source: U.S. FDA, “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein to a Reference Product”, April, 2015
•“A risk-based assessment should be performed on any differences in process-related
impurities identified between the proposed product and the reference product.”
•Differences in formulation and primary packaging between the proposed product and the
reference product are among the factors that may affect whether or how subsequent clinical
studies may take a selective and targeted approach”
• Differences in impurity profiles may be
permissible.
• Differences in excipients and formulation of
the finished product may be permissible
• Differences in container/closure and delivery
system may be permissible
The biological
product is highly
similar to the
reference product
notwithstanding
minor differences in
clinically inactive
components.

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A THEORETICAL STEPWISE APPROACH
Extensive analytical and CMC development work must
occur early in the program, prior to clinical studies.
Acquisition of robust data and continued development of
methods for analytical, structural and functional
characterization.
Parallel development of clinical program. Extent of
residual uncertainty can influence clinical designs, but in
practice uncertainties may not be known at that stage. (not
very targeted)
Comparison of critical
quality attributes to the
U.S. reference product
Comparison of critical
quality attributes to the
U.S. reference product
Nonclinical/Clinical program
designed to address residual
uncertainty
(“selective and targeted”)
Nonclinical/Clinical program
designed to address residual
uncertainty
(“selective and targeted”)
IN PRACTICE, APPROACH MAY BE PARALLEL:

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DIFFERENCES: WHEN DO THEY MATTER IN THEORY
Source: Schiestl, M et al (2011): Nature 29(4), 310 – 312.
RITUXIMAB/MABTHERA
CEX chromatograms Difference in basic variants
Difference in ADCC activity

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HEALTH AUTHORITIES MAY HAVE DIFFERING VIEWS ON THE
MECHANISM OF ACTION
FDA VIEW OF THE ROLE OF Fc IN THE MECHANISM OF ACTION FOR ANTI-TNF-a CLASS
Source: FDA summary of existing literature on the topic of Fc functions of TNF- blockers. 15
Murine
Fv
Human
Fc
Human
Fc
Human
Fc
Human
Fc
TNFR2
FvFv
PEG
Fv
Fab’
.

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EXAMPLE: AFUCOSYLATION VS. ADCC FOR INFLIXIMAB
From Celltrion AdCom
Briefing, 2/2016
From FDA AdCom
Briefing, 2/2016
Source: FDA Arthritis Advisory
Committee Meeting Materials,
2/9/2016
ADCC of CT-P13, US-licensed Remicade, and EU-approved Remicade
Using NK Cells as Effector Cells
Scatter Plots Showing Relationship of % Afucosylated Glycan Species (G0+Man5) with
FcyRIIIa Binding Affinity and ADCC Activity

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LESSONS LEARNED FOR 1st GENERATION
 Key potency assays should meet equivalence criteria for a biosimilar
candidate
 For other CQAs, scientifically sound justifications carry weight, but getting
early feedback on differences is critical
 In some cases, functional biological comparisons can be used to justify
modest differences in physicochemical attributes.
 Planning ahead for U.S. and EU will reap benefits for analytical similarity. For
example:
- A more rigorous analytical similarity assessment initially and statistical plan
- adding capabilities for further resolving variants (e.g. mass spectrometry)
- Agency interactions when appropriate

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LESSONS LEARNED (CONTINUED)
• Meeting statistical criteria may require more batches than expected
• If different MOAs are possible, an understanding of the agency position on
CQAs with respect to these is valuable
• Regulatory agencies are open to novel approaches to scientific
justifications and to engineering molecules to having the right properties.

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• New activities engineered into existing
antibodies
- Challenge: how to engineer required activity
vs. RMP?
• Novel biologics and conjugates
• Platform technologies
- For modifying CQAs, “tweaking” activities
- For in depth analysis of new properties,
activities
“NEXT GENERATION”
BIOSIMILARS

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EXTENSION OF TECHNOLOGY PLATFORMS FOR BIOSIMILAR ADCS
Kadcyla® vs. biosimilar,
comparing sites of
attachment
Source: Chen, L. et al (2016) mAbs 8(7),
1210-1223

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