Utilization of Clinical Pharmacology Data to Support a Demonstration of Biosimilarity by Partha Roy, Ph.D.

1. UTILIZATION OF
CLINICAL
PHARMACOLOGY
DATA TO SUPPORT A
DEMONSTRATION OF
BIOSIMILARITY
Date: Feb 24, 2014
Partha Roy, Ph.D.

2. 2
OUTLINE
Regulatory Framework and Guidance
Role and scope of comparative Clinical Pharmacology data
Filgrastim’s Clinical PK and PD Story
Future applications - acceptability of PK/PD
Conclusions

3. 3
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.”

4. 4
FDA’S DRAFT CLINICAL PHARMACOLOGY GUIDANCE
FOR BIOSIMILARS
• Draft Guidance published on May, 2014
• Clinical pharmacology roadmap in the context of assessing clinically
meaningful differences and supporting a demonstration of
biosimilarity
• Categories of analytical characterization
 Not similar – 351K path not appropriate
 Similar – significant differences noted and therefore additional analytical and/or
PK/PD data needed to resolve differences
 Highly Similar – just meeting the statutory standard for similarity and candidate
for a targeted and selective program to resolve residual uncertainty
 Highly Similar with Fingerprint-like similarity – highest level of similarity and
comfortably meeting the statutory standard for similarity and candidate for a
even more targeted and selective program

5. 5
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
SimilarityAssessmentwithReference
ReducingUncertainty
• Additional Clinical studies, if
needed

6. 6
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

7. 7
PK AND/OR PD STUDY DESIGN CONSIDERATIONS
Cross-over vs. Parallel
Healthy subjects vs.
patients
Dose(s) and routes of
administration
Availability of validated
assays
Sensitive and clinically
relevant PD markers
Impact of PK on PD
response
Alternate data analysis
strategy to deal with
PK and PD variability

8. 8
UTILITY OF PHARMACOMETRIC APPROACHES
TOWARDS BIOSIMILARITY EVALUATION
Population PK alone is not adequate to demonstrate PK similarity; it is additional
supportive data towards 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 PD-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

9. 9
PK, PD, PK/PD ARE KEYS TO EXTRAPOLATION TO
OTHER INDICATIONS NOT STUDIED IN THE PROGRAM
Indication 3Indication 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

10. 10
PK SIMILARITY DEMONSTRATED BETWEEN NEUPOGEN
AND SANDOZ FILGRASTIM BIOSIMILAR
• Single-dose conc-time curves
superimposable between 5 mg/kg
IV Neupogen and Sandoz
Biosimilar – PK similarity met
• Met the predefined similarity limits
for PK (90% CI within 80‐125%)
following 10 mcg/kg dose
IV route
Adapted from McCamish M and Woollett G (2012) Clinical
Pharmacology & Therapeutics
Adapted from Sandoz Briefing Book from ODAC
Advisory Committee Meeting, Jan 7, 2015
SC route

11. 11
PD (ANC AND CD34+) SIMILARITY DEMONSTRATED
FOLLOWING SINGLE DOSE ADMINISTRATION
PD parameter
(ANC)
Ratio (95% CI)
AUEC0-120h 103 (100 – 106)
Emax 100 (96 – 105)
Adapted from Sandoz Briefing Book from ODAC meeting,
Jan 7, 2015
PD parameter
(CD34+)
Ratio (95% CI)
AUEC0-120h 102 (94 – 112)
Emax 105 (92 – 120)

12. 12
PD (ANC AND CD34+) SIMILARITY DEMONSTRATED
FOLLOWING MULTIPLE DOSE ADMINISTRATION
Adapted from Sandoz Briefing
Book from ODAC meeting,
Jan 7, 2015
ANC
CD34+

13. 13
PD ATTRIBUTES FOR BIOSIMILARITY DEMONSTRATION
• Prior knowledge from drug and disease
• Mechanistic basis for drug action (both ANC and CD34+)
• Relevant to disease process related to effectiveness and safety (ANC
is correlated with Duration of Severe Neutropenia)
• Sensitivity to detect clinically meaningful differences between the two
products (CD34+ cell counts correlated with CFU-GM cell level)
• Can be assessed after a sufficient period of time after dosing, and
with appropriate precision (Day 1 and Day 7)
• Multiple PD parameters generate relevant fingerprinting and reduce
residual uncertainty

14. 14
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 gaining ODAC’s
recommendation for approval
• The sponsor undertook a supportive clinical study designed as an active-controlled,
double-bind, parallel, safety, tolerability and immunogenicity study in breast cancer
patients treated with myelosuppressive chemotherapy

15. 15
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
Adapted from Nick C. DIA Biosimilars Meeting, Washington DC, 2014

16. 16
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 select cases
Adapted from Nick Holford

17. 17
TRADITIONAL CLINICAL ENDPOINTS ARE BLUNT
INSTRUMENTS TO DETECT ANALYTICAL DIFFERENCES
Adapted from Windisch J. DIA Biosimilars Meeting, Washington DC, 2014

18. 18
EXPLORATORY PK/PD EVALUATION THAT MAY
ABBREVIATE CLINICAL PROGRAMS
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)

19. 19
CONCLUSIONS
• Based on the draft FDA Guidance, comparative clinical safety and
effectiveness data will be necessary if there are residual uncertainties
about the biosimilarity of the two products.
• 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 for Filgrastim
• Exposure-Response evaluation has the potential to substantially
abbreviate a biosimilar clinical development
• PK/PD can eventually replace a Phase 3 therapeutic equivalence study
for biosimilars, at least for some biological products

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CONTACT INFORMATION
Partha Roy, Ph.D.
Director
PAREXEL Consulting
Partha.Roy@PAREXEL.com
www.PAREXEL.com