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CONFIDENTIAL © 2014 PAREXEL INTERNATIONAL CORP.
BIOSIMILAR
FDA CLINICAL
PHARMACOLOGY
DRAFT GUIDANCE:
INDUSTRY
PERSPECTIVE
Date: November 4, 2014
Sally Choe, Ph.D.
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 2 Bayer Core w EU & Sum 08-OCT-2014.pptx
OUTLINE
• Regulatory Framework and Expectations
• Role and scope of comparative PK, PD and PK/PD data
• Accepted examples of PK and PD in biosimilarity demonstration
• Future applications - Greater acceptability and integration of
PK/PD
• Conclusions
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 3 Bayer Core w EU & Sum 08-OCT-2014.pptx
UNDERLYING REGULATORY FRAMEWORK AND
EXPECTATIONS
• Data requirements for a Biosimilar application will be less than a
full complement of product-specific preclinical and clinical data
required for an original BLA application
• FDA may waive any of these data requirements if it finds the
data are “unnecessary”
• FDA has a “longstanding policy of permitting appropriate reliance
on what is already known about a drug, thereby saving time and
resources…and avoiding ethical concerns associated with
unnecessary duplication of human or animal testing.”
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 4 Bayer Core w EU & Sum 08-OCT-2014.pptx
HIGHLY SIMILAR ANALYTICAL AND PK / PD DATA =
LOWER RISK OF CLINICAL DIFFERENCES
Risk-Based, Stepwise, Totality
of Evidence
Analytical Characterization is
the foundation
PK/PD is a key component of
initial clinical assessment
Comparative Immunogenicity
assessment expected
Clinical
PK/PD
Nonclinical
Analytical
PK/PD
Nonclinical
Analytical
Clinical
Sim
ilarity
Ass
ess
ment
with R
efe
renc
e
Reduc
ing
Unc
ert
ainty
Clinical efficacy and safety
studies
Additional Clinical studies, if
needed
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 5 Bayer Core w EU & Sum 08-OCT-2014.pptx
QUALITY ATTRIBUTES THAT IMPACT PHARMACOKINETICS
AND PHARMACODYNAMICS
Attributes Impact on PK, PD
Primary amino acid sequence, Fc
receptors
Ligand binding impacts distribution and
elimination
FcRn binding Alters elimination rate
Folding, disulfide bridges Misfolding is associated with faster clearance
Oxidation Can impact FcRn binding
Glycosylation Impacts immunogenicity and has the potential
to impact PK
Degradation Degraded products have faster clearance
Adopted from Windisch J. DIA Biosimilars Meeting, Washington DC, 2014
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 6 Bayer Core w EU & Sum 08-OCT-2014.pptx
PK AND/OR PD STUDY CONSIDERATIONS
• Cross-over vs. Parallel
• Healthy volunteers vs. patients
• Dose (s) and routes of administration
• Sensitive and relevant assays
• PK parameters, i.e. Cmax, AUC
• Alternate data analysis strategy to deal with PK variability
• When you do not meet the similarity (80-125%) margin:
Unlikely that PD and/or clinical endpoint can rescue the PK similarity evaluation
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 7 Bayer Core w EU & Sum 08-OCT-2014.pptx
PD AND PK/PD EVALUATION – TOTALITY OF EVIDENCE
Prior knowledge from drug and disease including the reference product and
therapeutic class
Mechanistic basis for drug action
Relevant to disease process related to effectiveness and safety
Sensitivity to detect clinically meaningful differences between the two
products, i.e. dynamic range
Can be assessed after a sufficient period of time after dosing, and with
appropriate precision
Multiple PD parameters generate relevant fingerprinting and reduce residual
uncertainty
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 8 Bayer Core w EU & Sum 08-OCT-2014.pptx
UTILITY OF POPULATION PHARMACOKINETICS AND
PHARMACOMETRIC APPROACHES TOWARDS
BIOSIMILARITY EVALUATION
Population PK alone is not adequate to demonstrate PK similarity; it is
additional supportive data towards a totality of the evidence approach to
achieve an overall demonstration of biosimilarity
M&S tools can be useful when designing a PK and/or PD study
• Selection of an optimally informative dose (s) for evaluating PD similarity
• Evaluating an Exposure (or Dose) – Response relationship
• Developing acceptable limits for PD similarity based on biomarker-clinical endpoint
relationship
Modeling exercise to compare relevant PK parameters, such as clearance
and volume of distribution following multiple routes of administration following
single and multiple-dose administration
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 9 Bayer Core w EU & Sum 08-OCT-2014.pptx
PK, PD, PK/PD ARE KEYS TO EXTRAPOLATION TO
OTHER INDICATIONS NOT STUDIED IN THE PROGRAM
Indication 3 Indication 2
Robust CMC
Data
Keys to Extrapolation
Fewer Indications
All Indications
Pivotal PK/PD/Phase 3 in Core Indication
Agency Negotiation
MOA/PK/PD/Biodistribution
Toxicity
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 10 Bayer Core w EU & Sum 08-OCT-2014.pptx
PK SIMILARITY DEMONSTRATED BETWEEN NEUPOGEN
AND FILGRASTIM BIOSIMILAR (ZARZIO)
PK parameter Day Ratio (90% CI)
Cmax 1 95.91 (88.73 - 103.67)
AUC 1 95.87 (90.31 - 101.78)
Cmax 7 80.05 (70.19 - 91.30)*
AUC 7 86.90 (80.90 - 93.35)
Single-dose conc-time curves
superimposable between 5 mg/kg
IV Neupogen and Zarzio – PK
similarity achieved
Exploration of PK similarity for 5
mg/kg after single and multiple
dose administration between SC
Neupogen and Zarzio
IV route
SC route
* Outside the standard equivalent limits
Ref: McCamish M and Woollett G (2012) Clinical Pharmacology & Therapeutics
Ref: CHMP Assessment for Zarzio, 2008
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 11 Bayer Core w EU & Sum 08-OCT-2014.pptx
PD (ANC AND CD34+) SIMILARITY DEMONSTRATED
BETWEEN NEUPOGEN AND FILGRASTIM BIOSIMILAR
ZARZIO
PD parameter Ratio (90% CI)
AUEC0-216h
(103.h/mL) 99.37 (96.30 – 102.54)
PD parameter Ratio (90% CI)
CD34+ (h/mL) 102.11 (93.53 – 111.47)
McCamish M and Woollett G (2012) Clinical
Pharmacology & Therapeutics
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 12 Bayer Core w EU & Sum 08-OCT-2014.pptx
ANALYTICAL PK PD SIMILARITY
ABBREVIATED CLINICAL PROGRAM
Demonstration of highly similar physicochemical and functional characteristics
between the potential biosimilar and the reference biologic is the foundation
on which biosimilarity stands
Following analytical similarity, step-wise demonstration of PK and PD
similarity based on the 80-125% equivalence margin was sufficient (w.r.t.
efficacy) for approval per CHMP
The sponsor undertook a supportive clinical study designed as a single-arm,
open-label, parallel, safety, tolerability and immunogenicity study in breast
cancer patients treated with myelosuppressive chemotherapy
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 13 Bayer Core w EU & Sum 08-OCT-2014.pptx
TYPICAL GLOBAL CLINICAL PROGRAM :
CAN WE DO BETTER THAN THIS?
Products Phase 1
(3-way PK)
Phase 3
(Equivalence trial)
Estimated Costs
Trastuzumab
(Herceptin)
~100 HVs 600 - 800 pts $40 million
Bevacizumab
(Avastin)
~100 HVs 800 – 1200 pts $60 million
Etanercept
(Enbrel)
~80 HVs 500 – 600 pts $40 million
Rituximab
(Rituxan)
~300 patients 500 – 1000 pts $50 million
Adopted from Nick C. DIA Biosimilars Meeting, Washington DC, 2014
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 14 Bayer Core w EU & Sum 08-OCT-2014.pptx
TRADITIONAL CLINICAL ENDPOINTS ARE BLUNT
INSTRUMENTS TO DETECT ANALYTICAL DIFFERENCES
Adopted from Windisch J. DIA Biosimilars Meeting, Washington DC, 2014
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 15 Bayer Core w EU & Sum 08-OCT-2014.pptx
LOOKING FOR A SENSITIVE PD/SURROGATE
Clinical Endpoint PD Marker /
Clinical Surrogate
Clinical endpoint with which the reference product was approved is
often not sensitive enough to identify clinically meaningful differences
Human PK and PD data may be able to substitute a large Phase 3 study in
order to support a demonstration of biosimilarity in some cases
Adopted from Nick Holford
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 16 Bayer Core w EU & Sum 08-OCT-2014.pptx
PROBABLE PK/PD APPROACHES THAT MAY
ABBREVIATE CLINICAL PROGRAMS FOR
MONOCLONAL ANTIBODIES
Biologics PK/PD metrics Outcome
Omalizumab
(Anti-IgE)
PK – free & total IgE – asthma
exacerbation
Support for the approved BW
and IgE-based dosing table (ref: Xolair USPI 2014)
Tocilizumab
(Anti-IL-6) PK – DAS28 response model
Dosing regimen justified (ref: Clinical Pharmacology review of
BLA125472, 1/29/2013)
Adalimumab
(Anti-TNF)
PK – remission and time to response
in the induction treatment phase in
moderate to severe UC
Support for optimal dosing (ref: FDA Gastrointestinal AdCom
meeting for Adalimumab, FDA Clinical
Pharmacology slide presentation,
08/28/2012)
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 17 Bayer Core w EU & Sum 08-OCT-2014.pptx
CONCLUSIONS
• Clinical Pharmacology data is a critical part of the totality of evidence to
support a demonstration of biosimilarity to a Reference product
• PK and PD data has been utilized as pivotal clinical data to support
clinical similarity between the biosimilar product and the reference
product
• Exposure-Response evaluation has the potential to substantially
abbreviate a biosimilar clinical development
• Can PK/PD ever replace a Phase 3 therapeutic equivalence study for
biosimilars?
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 18 Bayer Core w EU & Sum 08-OCT-2014.pptx
ACKNOWLEDGEMENT
• Partha Roy, Ph.D.
Principal Consultant, PAREXEL
• Biosimilar Experts at PAREXEL
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 19 Bayer Core w EU & Sum 08-OCT-2014.pptx
THANK YOU
© 2014 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL 19
For more information, please contact:
Sally Choe, Ph.D.
Senior Director
PAREXEL Consulting