Covance Comparability Studies: The Key to a Biosimilar's Success
-
Upload
covance -
Category
Health & Medicine
-
view
2.525 -
download
0
Transcript of Covance Comparability Studies: The Key to a Biosimilar's Success
Comparability Studies:The Key to a Biosimilar's Success
Raymond Kaiser, PhD
Global Vice President
BioPharmaceutical CMC Solutions
Covance
2
Presentation Outline
What is “Biosimilarity”
Global Regulatory CMC Expectations
Comparability Expectations
Analytical Approaches to Comparability
“Real World” Observations
Q&A
33
What is a Biosimilar?
Biosimilars are follow-on biologics New versions of innovator
biopharmaceutical products,
following patent expiry
The very nature of a biologic means It is practically impossible for two different
manufacturers to produce two identical biopharmaceuticals if identical host expression systems, processes and equivalent technologies are not used
This has to be demonstrated in an extensive comparability program
4
Biosimilar or Biosimilarity means:
The biological product is highly similar
to the reference product notwithstanding minor differences in clinically inactive components
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
5
Global Regulatory LandscapeEMA (The European Medicines Agency)
Established EMA approval pathway: 14 biosimilars approved* within the product classes of:
human growth hormone granulocyte colony-stimulating factor (G-CSF) erythropoietin
US FDA Biologics Price and Innovation Act passed in 2010
Empowers FDA to develop standards to evaluate and approve biosimilarsFDA February 2012 draft guidance documents
Risk-based “totality-of-the-evidence” approach
Health CanadaGuidance came out in 2010
JapanGuideline came out in 2009
WHOGuideline document came out in 2009
ROWArgentina, Australia (amending), Brazil, Jordan, Korea, Malaysia, Saudi Arabia, Singapore, Taiwan,
Turkey, Venezuela – Guidelines availableColombia, Cuba, India, Mexico, South Africa, and Thailand – Draft Guidelines available
Biosimilar Regulatory Guidance documents and discussions are on-going and expanding globally.
6
Regulatory Environment - EU
Established EMA approval pathway 14 biosimilars approved within the product classes of:
Human growth hormone
Granulocyte colony-stimulating factor (G-CSF)
Erythropoietin
Key EMA guidance documents “Overarching” guideline on similar biological medicinal products
From 2005, currently being updated
Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: quality issues
From 2005
Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: nonclinical and clinical issues
From 2005, currently being updated to incorporate risk-related approaches
7
Regulatory Environment – US
FDA approval pathway established
Biologics Price and Innovation Act passed in 2010 empowers FDA to develop standards to evaluate and approve biosimilars
FDA February 2012 draft guidance documents Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
- Risk-based “totality-of-the-evidence” approach
Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product- Overview of analytical factors to consider, includes analytical, physico-
chemical and biological characterization
Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 - Provides answers to common questions that may arise in the early stages
of product development
8
General Requirements of FDA Guidance
A 351(k) application must include information demonstrating biosimilarity based on data derived from:
Analytical studies demonstrating that the biological product is “highly similar” to the reference product notwithstanding minor differences in clinically inactive components
Animal studies (including the assessment of toxicity) A clinical study or studies (including the assessment of
immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD)) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed
FDA may determine, at its discretion, that an element described above is unnecessary in a 351(k) application
9
Regulatory Environment - ICH Regions
How do the requirements compare?
US, EU and Japan all require comparability with reference product
Reference product must be registered under the Regulatory jurisdiction In EU this is law FDA will consider non-US registered reference product with studies to bridge to US reference Japan requires Japanese registered product
Early engagement with Regulatory Authority is vital
Extrapolation of indications will be considered
At least one Phase III comparable efficacy study (usually with equivalence design) is required for licence
10
Regulatory Comparability PackageExtensive Analytical & In Vitro
Extensive analytical characterization versus reference product(s) If mAb
specificity & affinity to epitope potency using CDC, ADCC &/or functional in vitro cell-based assays
Limited in vivo Nonclinical PK/PD studies, Toxicology (SD/MD), and Immunogenicity studies
(requirement for nonhuman primates?)
Limited Clinical Phase I
comparability of PK/PD & Immunogenicity in volunteers or patients at reference dose and regimen for targeted indications
Phase III comparability for safety and efficacy (single pivotal) based on PK/PD,
surrogate endpoints and clinical outcomes
Extensive Post-Approval REMS and pharmacovigilance planning including patient registry(ies) for
assessment of incidence of specific safety issues
11
Development Challenges
Regulatory, manufacturing and marketing complexities
Biosimilar must be highly similar to innovator biologic, which can be difficult to demonstrate as all data for innovator will be lacking
A comparability exercise has to be followed with the innovator product at all levels of product development
Physico-chemical characterization
Biological activity
Preclinical in vivo comparability
Phase I PK and safety
Phase III efficacy and safety
It’s all about comparability
12
Biosimilarity?
How close do the proposed biosimilar products (figures B-E) compare to the reference product (figure A)?
Advances in current state-of-the-art analytical methods enhance the likelihood that a product will be highly similar to another product by better targeting the original product's physicochemical and functional properties
‘Biosimilar Biological Product’ Webinar, Rachel Sherman, FDA, 15FEB2012
14
Biosimilars must be Systematically Engineered to Match the Reference Product
Mark McCamish, Novartis, International Conference on Drug Development, Austin TX, 29FEB2012
15
Characterization
Comprehensive Characterization Physicochemical as well as biological
Multiple batches from innovator spanning a number of years
Understand innovator variability Specification changes over life of product
No label change
1616
Biosimilars at CovanceYear on year doubling of analytical demand for Biosimilars since 2008
Upgraded Protein Chemistry techniques
with additional characterization to demonstrate comparability or understand differences
Moved toward higher defining analytics (e.g. UPLC, LC/MS)
Compounds 1000 500 250 100 20 1
IND/CTA NDA /BLA Approval
DISCOVERY
PreclinicalResearch Phase I Phase II Ph. IIIa IIb Phase IV
DRUG DEVELOPMENT COMMERCIALIZATION
Biosimilar
NBE
Am
ou
nt
of
Ch
ara
cte
ris
atio
n
1717
Why More Characterization for Biosimilars?
Client has to show high ‘similarity’ to Innovator
“Proving ‘highly similar’ to the reference product often required multiple iterations of process change and physiochemical characterization”
Characterization of the Innovator (beware literature!) Characterization of the Biosimilar Monitor Manufacture
‘Process is the product’ Monitor changes in Innovator
Analytical tools for characterizing biopharmaceuticals and the implications for Biosimilars. S Berkowitz, J Mazzeo, G Jones, Nature review Vol 11, Jul 2012
19
Protein Heterogeneity Amino Acid Substitution AA Misincorporation (e.g.
METNLE) N- and C-terminal mods Mismatched S-S bonds Folding Truncation Aggregation Multimer Dissociation Denaturation Acetylation Fatty acid acylation Deamidation
Oxidation Carbamylation Carboxylation Formylation -Carboxyglutamylation O-linked Glycosylation N-linked Glycosylation Methylation Phosporylation Sulphation PEGylation etc.
20
Analytical Tools to Evaluate Protein Structure (subset)
Protein Functionality Analytical Technique
AA Sequence and Modifications
Mass Spectrometry (MS), peptide mapping, Edman Sequence analysis, chromatographic separations
FoldingS-S bonding, calorimetry, HDX and Ion mobility MS, NMR, CD, FT & Raman spectroscopy, fluorescence, chromatography
Subunit Interactions Chromatography, ion mobility MS
Heterogeneity of size, charge, hydrophobicity
Chromatography, gel & capillary electrophoresis, light scatter
Glycosylation Anion exchange, enzymatic digestion, peptide mapping, CE, MS
PEGylation & isomers Chromatography, peptide mapping
Bioactivity, cellular and animal bioassays
Ligand & receptor binding (ELISA, SPR), signal transduction
AggregationAnalytical ultracentrifugation, size-exclusion chromatography, field flow fractionation, light scatter, microscopy
Proteolysis Electrophoresis, chromatography, MS
Impurities Chromatography, proteomics, immunoassays, PCR
2121
Mass Spectrometry
Intact mass, comparison of Glycan variants. The difference in 56Da attributed to incorrect amino acid sequence
2222
Hormone Receptor Binding by Biacore
-10
0
10
20
30
40
50
60
70
80
0 50 100 150 200 250 300 350
Time s
Re
sp
. D
iff.
RU
-10
0
10
20
30
40
50
60
70
80
0 50 100 150 200 250 300 350
Time s
Re
sp
. D
iff.
RU
-10
10
30
50
70
90
0 50 100 150 200 250 300 350
Time s
Re
sp
. D
iff.
RU
DS BiosimilarDP Biosimilar
Innovator
Sample Lot No. KD (nM) % Difference1 3012 3993 4121 4152 3503 397
Drug Substance
4.40
Innovator
Biosimilar
Sample Lot No. KD (nM) % Difference1 2022 1723 1181 1382 1883 158
Drug Product
-1.64
Biosimilar
Innovator
2323
Finding the Differences by C-IEF
7.41
9
7.52
4
Mai
n -
7.61
3
7.80
8
7.99
1
8.14
5
Abs
orba
nce
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
Minutes
6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40
Blue - BiosimilarBlack - Innovator
2424
Carboxypeptidase Treatment
7.15
9
7.24
9
7.33
3
7.43
0
Mai
n -
7.53
3
7.65
9
7.73
1
Abs
orba
nce
-0.02
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
0.26
0.28
Minutes
6.40 6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40 9.60
Blue - InnovatorBlack - Biosimilar
2525
Forced Degradation
6.79
8
6.92
76.
996
7.13
8
7.26
5
7.38
2
7.48
1M
ain
- 7.
531
7.60
3
7.70
9
7.80
5
7.90
6
8.04
1
Abs
orba
nce
-0.010
0.000
0.010
0.020
0.030
0.040
0.050
0.060
0.070
0.080
0.090
0.100
0.110
0.120
0.130
Minutes
6.00 6.20 6.40 6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40 9.60 9.80
Black - InnovatorBlue - Biosimilar
2727
Simplify by De-sialylation?A
bsorb
ance
-0.02
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
0.26
0.28
0.30
Minutes
3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50 8.00 8.50 9.00 9.50
Blue- InnovatorBlack- Biosimilar
2828
N-Glycan SimilarityE
nerg
y
0.00
200.00
400.00
600.00
800.00
1000.00
1200.00
1400.00
1600.00
1800.00
2000.00
2200.00
Minutes
8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00
G0F
G1F
G1F’
G0 G1G1’
Man5
G2F Blue- InnovatorBlack- Biosimilar
31
NOTE: Originators make ‘biosimilars’ every time there is a manufacturing process change
Aranesp ® (Darbepoetin-alfa)
MabThera®/Rituxan® (Rituximab)
Enbrel ® (Etanercept)
Ref: Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312 (Sandoz)
32
Characterization of Commercial Batches of Darbepoetin alfa from the EU
Change in isoform distribution between two sets of batches (expiry date April 2010 and September 2010)
Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312
33
Characterization of Commercial Batches Mabthera®/Rituxan® (rituximab)
•Shift in Glycosylation Profile and ADCC Potency
• Differences/shift in glycosylation pattern results in different potency in cell-based assays• Product label remained unchanged –indicating comparable quality
Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312
34
Characterization of Commercial Batches of Enbrel
• Shift in Glycosylation Profile
• Differences/shift in glycosylation pattern• Product label remained unchanged –indicating comparable quality
Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312
3535
Demonstrating Comparability in an Ideal World?
Product heterogeneity is clearly understood, variants are easily isolated and characterized Product variants and related impurities Process related impurities
Smooth manufacturing scale up, no process changes
Methods ready to demonstrate comparability without development. “One size fits all”
Enough time and a ‘crystal ball’ to know what to look for
3636
What does This Look Like in the ‘Real World’?
Biosimilars are “snowflakes”. No two are the same
Incomplete comparability characterization
Experience rapid time pressures
Final formulation often undecided
Manufacturing difficulties with scale up
Fast turn around in-process sample analysis
Rapid development and validation for ‘discriminating’ assays
Need justification and risk assessment for observed differences
37
Other ‘Real World’ Observations II
Stress stability studies (w/ multiple time points) needed
Multiple lots of reference product often used. Understand impact of ref. product ‘shelf-life’ on results. Justify use
Reference product isolation procedure can impact results
Comparability continues even after release
GMPs apply for biosimilar product development
Meet with BOHs as early as possible to discuss your analytical control strategy
38
Other ‘Real World’ Observations IIIProtein analysis requires an ‘integrated’ set of analytical
methodsEvaluate all domains and protein modifications
Use orthogonal analytical methods to confirm observations and expectations.
State-of-the-art techniques are expected
Realize each analytical method has strengths and weaknesses:Spectral methods measure averages
Qualitative vs. quantitative?
Variable sensitivity
etc.
3939
Summary
Biosimilar regulatory guidelines continue to evolve
Demand for biosimilar CMC development continues to grow
Demonstrating comparability requires extensive analysis pre- and post-clinically. Must completely characterize innovator product
We are making progress linking some, but not all, biological properties to critical quality attributes; therefore, Given a gradation of a biologics complexity, a one size fits all
strategy for biosimilars will not be possible
40
Let us know how we can help you!
Reimbursement
Post-Marketing Commitments
Health Economics Assessment
Clinical Development: Special Populations
Outcomes/PE Studies
Clinical Development: Target Population
Central Labs Data: Safety and Genotyping
Phase I to Phase III Clinical Trials
Serum Production
Clinical Feasibility
DEVELOPMENTDEVELOPMENT COMMERCIALIZATIONCOMMERCIALIZATIONDISCOVERYDISCOVERY
PHASE IVPHASE IVRESEARCHRESEARCH PRECLINICALPRECLINICAL PHASE IPHASE I PHASE IIIPHASE III
Molecular Development (Program Management & Clinical)
Efficacy Model Development/Biomarker Development
Regulatory Strategy, EMA/FDA Documentation Prep & Meeting Attendance, CTA/IND/BLA Support and Submission
Viral Clearance
Immunogenicity, PK, TK
Process Development Support, Biomanufacturing Support, Biosafety Testing
Pharmacokinetics/Toxicity
Tissue Cross Reactivity
In vivo/In vitro Biopotency
Immunotoxicity: CDC & ADCC
Physicochem & Biological Characterization
Stability and Release