practical challenges in the cmc development of biosimilars...nature reviews drug discovery. february...
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Practical challenges in the CMC
development of biosimilars
Simon Hotchin
Executive Director Regulatory Affairs
Amgen Inc.
CASSS Bay Area Discussion Group
12 Nov 2015 2
Overview
• Introduction
• Statistical methodologies in the assessment of analytical
similarity
• Selection of analytical methods for similarity assessment
• Reference product bridging assessments
• Discussion points
Introduction
CASSS Bay Area Discussion Group
12 Nov 2015 4
Analytical similarity remains the
cornerstone of biosimilar development
•Analytical data form the
cornerstone of the similarity
assessment
•Products must be ‘highly similar’
to be eligible for approval as
biosimilars
•Increasing the extent and
discriminatory power of the
analytical assessment may permit
a more targeted and selective
approach to nonclinical and
clinical studies.
Clinical
Clinical Pharmacology
Nonclinical
Analytical
CASSS Bay Area Discussion Group
12 Nov 2015 5
Approval requires a careful assessment
of the totality of evidence
• Biosimilar or Biosimilarity means:
• that the biological product is highly similar to the
reference product notwithstanding minor
differences in clinically inactive components; and
• 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.
Analytical and Functional
Data
Clinical Data
CASSS Bay Area Discussion Group
12 Nov 2015 6
The definition of biosimilarity poses
some practical questions
• How similar is similar and how can a level playing field
be assured?
• How does analytical method capability impact the
assessment of similarity, and what methods should be
used?
• How to conduct efficient global biosimilar development
when the approval pathway has an inherently national
aspect?
Analytical similarity standards:
statistical methodologies
CASSS Bay Area Discussion Group
12 Nov 2015 8
FDA has recommended a tiered attribute
assessment for demonstrating similarity
• Tier 1 is based on a test of
equivalence
– Analytically similar if 90%
confidence interval of the true
mean diff. is within equivalence
margins (δ1, δ2)
– The equivalence margin is
1.5sR where sR is the true
standard deviation of the RP
• Tier 2 is based on majority of
results falling within a quality
range of +/- X SD
(δ1δ2)
90% CI
Fail
Fail
Yi Tsong, FDA, DIA/FDA statistics Forum 2015
CASSS Bay Area Discussion Group
12 Nov 2015 9
There are potentially some practical
challenges with the proposed approach
• Existing knowledge of attribute criticality may not be
sufficient to clearly delineate the appropriate testing tier
• Reliable estimates of the true mean and variance of the
reference product can be difficult to establish during
development, and both can change over the
development time frame
• A statistical approach based on data from to-be-
commercial lots may not be the most effective means to
assure a robust process to deliver similar product
CASSS Bay Area Discussion Group
12 Nov 2015 10
The appropriate tier assignment for an
attribute may be less than obvious
• Product labels and literature may
include information suggesting a
role for e.g. effector function in the
MoA of a product
• However, understanding regarding
the quantitative relationship
between attributes and
safety/efficacy in patients is
typically incomplete
• Scientific judgment on tiering
assignment must be made based
on the available evidence and
application of risk management
principles
• Differing conclusions may be
reached
• FDA vs Sponsor
• Sponsor vs Sponsor
Reproduced from: Jiang et al. Advances in the assessment and control of
the effector functions of therapeutic antibodies. Nature Reviews Drug
Discovery. February 2011.
CASSS Bay Area Discussion Group
12 Nov 2015 11
Cell Line and Process
Development
Nonclinand
Clinical Dev.
Submission and
Approval
Cell Line and Process
DevelopmentNonclinical Clinical
Submission and Approval
Post Approval
Estimating the true mean of the
reference product can be challenging
Reference product
lifecycle
Biosimilar product
lifecycle
Simulated data for illustrative purposes
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Identifying Tier 1 attributes early is
critical to demonstration of similarity
▲Probability to pass Tier 1▲
Adequate power
Means match
Some results slightly outside
RP range
▼Probability to pass Tier 1▼
Inadequate power
Means do not match
All results inside RP range
• Early cell line and process development
focused on matching mean for attribute
• Similarity testing protocol captured sufficient
results for attribute
• Early cell line and process development
targeted matching RP range
• RP variability greater than anticipated
• Similarity testing protocol assumed reduced
testing sufficient
Simulated data for illustrative purposes
CASSS Bay Area Discussion Group
12 Nov 2015 13
Cell Line and Process
Development
Nonclinand
Clinical Dev.
Submission and
Approval
Pre-Approval Post-Approval
Actual shifts in the reference product
may also be apparent
Reference product
lifecycle
Biosimilar product
lifecycle
Simulated data for illustrative purposes
CASSS Bay Area Discussion Group
12 Nov 2015 14
Data from at-scale lots may not be the
sole means to establish similarity
• The Tier 1 statistical approach rewards increasing sample size
– Minimum of 6 lots recommended for equivalence testing
– 10 or more required to achieve power levels that sponsors may deem
appropriate when multiple attributes are included in Tier 1
– May drive sponsors to manufacture additional lots for analytical similarity
purposes
• Is this form of ‘extended process validation’ the most appropriate
means to ensure similarity of future lots?
– Could data from a validated small scale model and/or generated by
mathematical process modelling be included in the statistical analysis?
– Should data from at-scale production be considered as confirmatory
evidence?
Analytical similarity methodology:
selection of analytical procedures
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12 Nov 2015 16
Stability
Primary structure
Biological function
Particles and
aggregates
Process-related
impurities
General properties
and excipients
Higher order
structureProduct-related
substances and
impurities
Attributes related to the amino acid
sequence and all post-translational
modifications, including glycansBiological and functional
activities, including receptor binding
and immunochemical properties
Quantitative levels of
product variants and
their identities
Degradation profiles
denoting stability
Subvisible and submicron particles
and aggregates of various sizes
Integrity of the secondary, tertiary,
and quaternary structure
Properties of the finished
drug product, including
strength and formulation Impurities from host cells
and downstream process
Comprehensive analytical similarity assessment reduces the degree of uncertainty
CASSS Bay Area Discussion Group
12 Nov 2015 17
The choice and performance of analytical
tools matters
Slide from Kozlowski, S (CDER) presentation at 2014 Biomanufacturing Technology Summit, Rockville, MD, June 13, 2014
Reliability - Methods are qualified and fit-for-use for intended purposes
Relevance - Methods provide meaningful information and may predict clinical performance
Resolution - Methods are sensitive and capable of resolving differences which are critical attributes
CASSS Bay Area Discussion Group
12 Nov 2015 18
Different methods provide differing levels of
information relative to criticality and similarity
Critical
glycan
attribute
Glycan
Map
profile
Monosaccharide
analysis
Rel
evan
ce
Reliability
0.0
10.0
20.0
30.0
4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0
min
A2
G0
F
A1
G0
F
M5
A2G
0
A1
G1
F
A2
G1
F(a
)A
2G
1F
(b)
M6
A2
G2
F
M7
Monosaccharide analysis
Glycan mapConfidence in similarity
CASSS Bay Area Discussion Group
12 Nov 2015 19
Rel
evan
ce
Reliability
NK92
ADCC
FcgRIIIa
binding
PBMC
ADCC
Glycan
map
Confidence in manufacturing
Knowing the correlation of orthogonal methods
helps develop a robust control strategy
High resolution and reliable methods suited for process control can guide the process and product development.
Orthogonal assays with increasing biological relevance to discern clinically meaningful differences and confirm functional similarity
Response (LU))
0.0
10.0
20.0
30.0
4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0
min
A2G
0F
A1G
0F
M5
A2G
0
A1G
1F
A2G
1F
(a)
A2G
1F
(b)
M6 A2G
2F
M7
Chung, mAbs, 326-340, May 2012
ADCC vs. Afucosylated glycan
Analytical similarity requirements:
reference product considerations
CASSS Bay Area Discussion Group
12 Nov 2015 21
Background
• Biosimilar regulations continue to roll-out & evolve around the world
• The majority of the regulations necessarily require demonstration of
similarity to a local reference product approved on that market
• Use of analytical, nonclinical and clinical data generated with a
foreign reference product can be negotiated, by providing evidence
to demonstrate the equivalence of the local and foreign reference
products.
• The level of evidence required for bridging varies.
CASSS Bay Area Discussion Group
12 Nov 2015 22
Why bridging?
• Is a foreign comparator truly representative of the local reference product
with respect to quality, safety and efficacy?
• Some regulators may require analytical (± PK) bridging to a locally procured
reference product
• Possible factors causing geographic divergence in originator product quality
attributes
– Supply chain partitioning between geographies (eg, local manufacturing)
– Licensing arrangements without shared manufacturing
– Asynchronous implementation of major process variations
Hypothetical concerns? Consider epoetin alfa, supplied by 3 distinct companies using independent DS and DP sources. Only one originator
product was associated with a specific quality related safety issue (eg, PRCA cluster in Europe, 1998-2002).
Casadevall et al. NEJM 346:469-475 (2002).
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Problem Statement: How to go from
this…
EU US
Pivotal Trials
Analytical Sim
Nonclinical
Analytical Sim
Bridging
Analytical
Bridging PK
CORE
X Originator product lots sourced from country X
Map of comparisons made between product lots(originator to biosimilar or originator sourced in EU to originator sourced in US)
CASSS Bay Area Discussion Group
12 Nov 2015 24
To this…
EU US
JP
Pivotal Trials
Analytical Sim
Nonclinical
Analytical Sim
Bridging
Analytical
Bridging PK
AUS
CN
RSA
TURBRMEX
RUS
KR
CAN
??
?
?
? ? ?
CORE
??
?
X Originator product lots sourced from country X
CASSS Bay Area Discussion Group
12 Nov 2015 25
Various bridging options are possible.
Some may represent a higher challenge.
• Minimal similarity risks and costsNo additional justification
• Minimal similarity risks and costsPaper based justification
• Similarity risks and costsLimited analytical bridge
• Similarity risks and costsComprehensive analytical
bridge
• Significant similarity risks and costs
Analytical plus BE
• High similarity risks and costsStand-alone development
Lacking other evidence of a
harmonized originator product
supply would these approaches
protect patients from geographic
“divergence”?
CASSS Bay Area Discussion Group
12 Nov 2015 26
Conclusions
• High standards will help to build confidence and drive biosimilar adoption.
Statistics can play a role in assessment of similarity, but approaches based
on comparisons of means may be practically challenging to implement.
• Ensuring early transparency to the identity of the highest risk attributes for a
given molecule would increase predictability in biosimilar development.
• The application of methods that have been demonstrated to be capable of
discriminating differences in critical attributes will increase confidence in
similarity.
• Flexibility in the application of regional bridging requirements will ensure
global access to high quality biosimilar medicines
CASSS Bay Area Discussion Group
12 Nov 2015 27
Acknowledgements
• Jennifer Liu
• Margaret Karow
• Rick Burdick
• Gino Grampp
• Richard Markus