Reducing risk of Biosimilar product development requires early attention to evidence development and effective communication to multiple stakeholders. Skill set for effective leadership and management, in the US market context, includes ability to: (1) Overcome the ‘blind spots’, (2) Analysis of knowledge, and (3) Evidence logic & communication. This presentation makes these points while comparing the EU and the USA regulatory context and the challenges of integration across multiple scientific and clinical disciplines.

1. Presented at DCAT Week 2014
March 10-14, 2014
New York, NY
Reducing Technical &
Regulatory Uncertainty in
Biosimilar Development
1

2. Background
Previous speakers have
covered
• Market overview,
manufacturing
technologies, and
recent developments
in this area
• The current status of
US regulatory pathway
for biosimilars and
related issues on a
state level
In this presentation we will
review
• Similarity and
differences in the US
and EU regulatory
framework
• With the objective to
understand how to
reduce technical and
regulatory uncertainty
in the US market
context
2

3. Reduce technical and regulatory
uncertainty in Biosimilar Development
• Reduce cost and time of biosimilar development and enhance
market penetration
Why
• Understanding the basis of approvals of selected products and
established and emerging guidelines and open issues
How
• Technical and organizational considerations; analytical
characterization, PK/PD studies, and clinical trial designs to
address residual uncertainty
What
3

4. Determinants of success
Cost and time of
development
Analytical
characterization of
reference product
Clone selection and
design of upstream
and downstream
process
Comparability &
similarity; residual
uncertainty
PK/PD, Clinical trial
design, human factor
analysis
Market
penetration
• Indications & evidence
• Clinical data vs.
extrapolation across
indications
• Interchangeability (USA)
4

5. Basis of approvals of selected products
US FDA
• Omnitrope® (Sandoz)
• Tbo-filgrastim® (Teva)
• Generic Enoxaparin (Sandoz-
Momenta and Watson-
Amphastar)
Products
• Process & Analytical
• Clinical
Evidence
EMA
• Omnitrope® (Sandoz)
• Tbo-filgrastim® (Teva)
• Biosimilar Enoxaparin (none-
approved yet)
• Other products
Products
• Process & Analytical
• Clinical
Evidence
5

6. Established and emerging guidelines
US FDA
• General (e.g., ICH)
• Biosimilar (Emerging)
• Product specific (??)
Guidelines
• Process & Analytical
• Clinical
Review process
EMA
• General (e.g., ICH)
• Biosimilar (Established)
• Product specific (Yes)
Guidelines
• Process & Analytical
• Clinical
Review process
6

7. TPP & QTPP
•Why add TPP?
What is the specific purpose of TPP &
QTPP in biosimilar development?
•How many lots; when to characterize?
How to leverage lot to lot variability in the
reference medicinal product?
•Understanding clinical relevance
Which differences are acceptable while
ensuring ability to demonstrate similarity?
7

8. QTTP
• Define the targets for
biosimilar development
– Prior-knowledge (structure
function, clinical,..) & RLD
• Define ‘similar’ -
acceptance criteria
– Clinical endpoints &
variability in reference
product
• QTPP should identify
attributes most relevant
– Facilitates development of
meaningful target &
acceptance criteria
8
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Expiry Date
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[% of glycans]
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120
140
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Expiry Date
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[% of reference] Post-
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Post-
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Schiestl, M., et al.: Acceptable Changes in Quality Attributes of Glycosylated
Biopharmaceuticals. Nature Biotechnology, 29: 310-312, 2011
“This [enoxaparin] approval represents a major development
in US regulatory science and policy that will likely affect
several other complex drug products...the extensive
analytical characterization, as carried out for enoxaparin,
will be important in the evaluation of protein products and
may help to reduce the scope and extent of animal and
clinical studies for biosimilars.”
Sau Lee, et. al., Scientific Considerations in the Review and
Approval of Generic Enoxaparin in the United States.
Nature Biotechnology. Volume 3, 220-226 (2013)

9. Stepwise approach
Analytic
characterization
before in-vivo
non-clinical and
then clinical
studies
In EU adequacy
of analytic
characterization
evaluated
during MAA
In US a step
wise review
approach has
been
established
Companies
with internal
systems such
as ‘QbD
development’
can benefit
9
External review should be leveraged
but need internal review

10. Common pitfalls and symptoms
Inadequate focus on TPP, QTPP (analytics) & market
research
Functional check-box
Cut-paste approach to clinical trials
Rush to clinical
10

11. Clinical Trials (WHO): Biosimilar
11
96

12. Clinical Trails (US): Biosimilar
12
28

13. ClinicalTrail.Gov: Biosimilar
13

14. ‘Biosimilar rituximab development a
rocky road’
Roche does not see a threat from biosimilar
(rituximab) until 2015
“Samsung
and Teva
both
suspended
their Phase
III programs
in October
2012 within
months of
starting
them”
One reason for the delay – clinical
considerations; challenge of extrapolation
across indications
“Totality of evidence”
Sandoz and Boehringer are
both already running Phase III
trials, placing them ahead of
Celltrion in the race”
14
http://www.ft.com/cms/s/2/dcad130c-a8fb-11e2-a096-00144feabdc0.html#axzz2TqDBcYlB
http://www.biosimilarnews.com/roche-doesnt-see-a-threat-from-biosimilars-till-2015

15. Sandoz Trials: Biosimilar rituximab
• A Randomized, Double-blind, Controlled Study to Evaluate PK, PD, Safety and
Efficacy of GP2013 and Rituximab in Patients With Rheumatoid Arthritis
Refractory or Intolerant to Standard DMARDs and One or Two Anti-TNF
Therapies. (ClinicalTrials.gov Identifier: NCT01274182)
• 164 subjects estimated completion date April 2012
Phase I/II
• A Randomized, Controlled, Double-Blind Phase III Trial to Compare the
Efficacy, Safety and Pharmacokinetics of GP2013 vs. MabThera® in Patients
With Previously Untreated, Advanced Stage Follicular Lymphoma
(ClinicalTrials.gov Identifier: NCT01419665)
• 618 subjects; estimated completion date March 2014
Phase III
15

16. Boehringer Ingelheim Trials: Biosimilar
rituximab
•A Randomized, Double-blind, Parallel-arm, Phase I Study to Evaluate the Pharmacokinetics and
Pharmacodynamics of BI 695500 vs. Rituximab (MabThera) Induction Immunotherapy as a
First-line Treatment in Patients With Low Tumor Burden Follicular Lymphoma (ClinicalTrials.gov
Identifier: NCT01950273)
•90 subjects; Estimated completion date January 2015
Phase I
•Efficacy, Pharmacokinetics, and Safety of BI 695500 Versus Rituximab in Patients With
Moderately to Severely Active Rheumatoid Arthritis: a Randomized, Double-blind, Parallel
Arm, Multiple Dose, Active Comparator Trial (ClinicalTrials.gov Identifier: NCT01682512)
•360 subjects; Estimated completion date January 2016
•Safety and Efficacy of BI 695500 in Patients With Moderately to Severely Active Rheumatoid
Arthritis: an Open-label Extension Trial (ClinicalTrials.gov Identifier: NCT01955733)
•250 subjects; Estimated completion date December 2016
Phase III
16

17. Celltrion Trials: Biosimilar rituximab
• A Phase 1, Multicenter, Open-Label, Single-Arm Study to Evaluate the Initial Safety, Pharmacokinetics,
Pharmacodynamics, and Efficacy of CT-P10 Given in Combination With Dexamethasone, Cytosine Arabinoside,
and Cisplatin (DHAP) in Patients With Diffuse Large B-Cell Lymphoma as Second-Line Chemotherapy
(ClinicalTrials.gov Identifier: NCT01534949)
• 10 Subjects; currently recruiting
• Phase 1, Randomized, Controlled, Multicenter, 2-Arm, Parallel-Group, Double-Blind Study to Demonstrate the
Equivalence of CT-P10 to MabThera With Respect to the Pharmacokinetic Profile in Patients With Rheumatoid
Arthritis
• 147 subjects; Estimated primary completion date August 2013
• An Open-Label, Single-Arm, Maintenance Study to Demonstrate Long-Term Efficacy and Safety of CT-P10 in
Patients With Rheumatoid Arthritis Who Were Treated With Rituximab (MabThera or CT-P10) in Study CT-
P10 1.1 (ClinicalTrials.gov Identifier: NCT01873443)
• 102 subjects; Estimated primary completion date September 2014
Phase I
• A Phase 3, Randomized, Parallel-Group, Active-Controlled, Double-Blind Study to Compare the Efficacy and
Safety of CT-P10 With MabThera, Each Administered in Combination With Cyclophosphamide, Vinc...
(EudraCT Number: 2011-002813-12)
• Study terminated
Phase III
17

18. The totality of evidence
Proven comparability in the
most sensitive indication are the
key to secure (extrapolation of)
indications (achieve TPP)
A greater degree of analytical
comparability & RLD variability
informing on remining
uncertinty
Design of manufacturing process
and controls to deliver a product
conforming to QTTP
18

19. Key areas for consideration
Overcoming the
‘blind spots’
• Sampling and
statistical criteria
(starting with RLD
samples)
Analysis of
knowledge
• Pertaining to
analytical
characterization
and comparability
acceptance criteria
Evidence logic &
communication
• Argumentation is a
central means by
which the
community
assesses the
promise of
conjectures and
the validity of
claims
19
Multiple
disciplines &
stakeholders

20. Organizing for success
Early investment in analytics and understanding
variability in RLD
TPP & QTPP in the context of residual uncertainty
Review/challenge/integration system that does not
impede development
Design of clinical trials to address scientific and
clinical (market) uncertainty
20

21. Thank You!
Insight Advice & Solutions LLC
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Ajaz@ajazhussain.com
Ajaz S. Hussain, Ph.D.