regulatory analysis & approval of biosimilars
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Regulatory Analysis & Approval of Biosimilars
Dr. Bhaswat S. Chakraborty20.07.2012
Plenary Lecture at Ganpat University
Mehsana, Gujarat, July 20, 2012
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Contents Differences of Biosimilars from Generics of small mol
drugs Guiding Principles for Overall Biosimilars Brief Description of Biosimilar Mfg. PK/TK Assays
Examples Immunogenicity Assays
Antidrug Antibody Assays (ADA) Neutralizing Antidrug Antibody Assays (NAbA) Examples
Risk Management Conclusions
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What are Biosimilars? Biosimilars are often called follow-on biologics,
generic biologics or follow-on proteins Biosimilars are new versions of existing trade-name
biological products whose patents have expired Highly similar biosimilars are not “identical” to the
reference product They do not utilize the same living cell line,
production process, or raw material as the innovator drug
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Size & Complexity
Big Guys
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How are Biopharmaceuticals Made?
Upstream & Downstream
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Overview of EMEA Guidelines for Biosimilars
Mellstedt H et al. Ann Oncol 2007;19:411-419
© The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please e-mail: [email protected]
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Overview of USFDA Guidelines for Biosimilars
Integration of Information to Biosimilarity
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General Regulatory Approach for Assessment A risk-based, totality-of-the-evidence approach to evaluate all
data and information provided by a sponsor to support a demonstration of biosimilarity
Sponsors must use a stepwise approach in their development of biosimilar products
The type and amount of analyses and testing required to demonstrate biosimilarity will be on a product-specific basis
General scientific principles in conducting comparative analyses will be followed
US FDA
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Recombinant protein production: sources of variation between manufacturers.
Mellstedt H et al. Ann Oncol 2007;19:411-419
© The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please e-mail: [email protected]
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Reasons of Biosimilars’ Heterogeneity
Reasons of Biosimilars’ heterogeneity (~ potential differences between the biosimilar and the innovator drug): Biological therapeutics are a complex mixture consisting of the
parent drug, multimers, truncated fragments The components may or may not exhibit biological activity,
post-translational modifications of the parent and/or truncated fragments, host cell proteins as well as process related impurities
Any one of these can cause differences in the way these drugs behave in the immunoassay, bioassay and electrophoresis
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The General Requirements are: Analytical studies demonstrating that the biological product is
“highly similar” to the reference product Animal studies (including the assessment of toxicity); and Clinical studies
assessment of immunogenicity and pharmacokinetics (PK) PD studies or RCTs to demonstrate
efficacy & safety purity, and potency in 1 or more appropriate conditions of use for which the reference
product is licensed.
Overall Guiding Principles
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Requirements for Approval
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PK/TK: Same Platform Technology,if possible Since the assay will quantitate both biosimilar (B) and
innovator (R) compounds Preferable to develop an assay using the same platform
technology (RIA, ELISA, TOF) However, it is not necessary to utilize the same assay
platform Use a comparability test for quantitation of both B & R To demonstrate comparability, at a minimum, accuracy
and precision tests should be conducted using B as CC When comparable, use one assay for both B & R Assays can be developed and validated using either B or R Often B is used for CC
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PK/TK contd. Use both B and R QCs throughout the entire assay range (from
ULOQ to LLOQ) The same assay acceptance criteria should apply for both Meeting the accuracy and precision acceptance criteria will
demonstrate that both compounds are comparable, since one standard curve is used to quantify both. Make Calibration (CC) samples with R [or B] Analyze QCs at least of 3 levels of both B & R Acceptance criteria: Intra- and inter-batch imprecision (%CV) and
inaccuracy (%RE) ≤20% except at LLOQ where up to 25% can be allowed
Method total error (sum the % of the CV and absolute %RE) < 30% Demonstrate absence of matrix effect
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Dilutional Linearity Dilutional linearity must be tested For single dilutions, back-calculated concentration for each
diluted sample be <20% of the nominal within the linear range (< 25% at ULOQ and LLOQ).
For multiple dilutions, the back-calculated conc. for cumulative diluted samples should be within < 20% of the nominal original value.
The precision of the cumulative back calculated concentration should be < 20% (< 25% at ULOQ and LLOQ).
The presence or absence of hook (or prozone) effect should also be evaluated at the higher QC conc. (>1000×).
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Selectivity (Non-interference from Matrix) Matrix interference should be performed using B QC
spiked samples
spiked at high and low concentrations into at least 10 individual matrix samples
It should also include the blank individual controls that will be tested at the minimum required dilution (MRD).
Acceptable non-interference should be seen in >80% matrices tested.
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Sample Stability Stability experiments should mimic, as best as
possible the conditions under which study samples will be
collected, stored and processed The duration during which….
The effect of freeze-and-thaw cycles should also be assessed.
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Structural Analysis Sponsors should use an appropriate analytical methodology
with adequate sensitivity and specificity for structural characterization of the proteins. Generally, such tests include the following comparisons of the drug substances of the proposed product and reference product: Primary structures, such as amino acid sequence Higher order structures, including secondary, tertiary, and quaternary
structure (including aggregation) Enzymatic post-translational modifications, such as glycosylation and
phosphorylation Other potential variants, such as protein deamidation and oxidation Intentional chemical modifications, such as PEGylation sites and
characteristics
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Protein Characterization Assays Use validated bioassays or receptor-binding assays;
quantitative PCR would be excellent
Show equivalency of potency and batch consistency
Usual acceptance criteria: 80-125% but could be wider for bioassays
When wider, this assay may not be used for PK/TK comparability
Isotyping – significant issue in characterizing assays It is important to evaluate if assay is indeed due to
immunoglobulin and, if so, what type of antibody If not IgG but IgE class, it could have potentially serious
safety outcomes.
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Biosimilar EPO
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Human PK
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Immunogenicity Assays The immunogenicity of therapeutic proteins must be assessed
for safety and efficacy concerns small process changes during the production can change immunogenicity
rate & extent
Immunogenicity rate is difficult to measure, particularly at low incidence e.g., from autoimmune reactions to self proteins Large sample size would be required if the rate of immunogenicity
incidence is low
It is critical to assess the immunogenicity of the B relative to R An assay using the same platform technology, the same
reagents under the same assay conditions to evaluate antidrug antibodies (ADAs) would be desirable to assess reactogenicity
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Immunogenicity Assays.. Initiate very early during development of B, immunization of
animals to develop a positive control (against both B & R)
Evaluate the two ADA positive controls (ADA B & R)
Differences in the starting titers of the positive control antisera against either the B or are possible due to the individual immune response of each animal
Assay platform could be ELISA, bridging assays, electrochemi-luminescence (ECL) or RIA addressing:
Can the assay reagents detect both B & R comparably?
Can the assay tolerate both biosimilar and B & R conc. comparably?
B = Biosimilar; R = Reference Innovator
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Bioassay practicesAssessing “linearity” and similarity
Significance testing versus equivalence testing
Laboratory A
-1.2
-0.8
-0.4
0
0.4
0.8
0.5 1 1.5 2 2.5
Log10 Concentration
Lo
g1
0 R
es
po
ns
e
Standard Data
Test Data
Standard Line
Test Line
Laboratory B
-1.2
-0.8
-0.4
0
0.4
0.8
0.5 1 1.5 2 2.5
Log10 Concentration
Lo
g1
0 R
es
po
ns
e
Standard Data
Test Data
Standard Line
Test Line
p = 0.02 (p < 0.05, i.e., significantly different)
Conclude nonparallel!
Penalized for good assay performance
p = 0.08 (p > 0.05, i.e., not significantly different)
Conclude parallel!
Rewarded for poor assay performance
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Non-comparable (Non-similar) Assays If comparability is not demonstrated, separate assays
should be validated for B & R Immunogenicity Assays If separate assays are to be used for future preclinical or
clinical comparability studies, interpretation is difficult samples from different arms of the study will be tested using
different assays
B = Biosimilar; R = Reference Innovator
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Neutralizing-antibody (NAb) Assays For clinical studies, once a test sample is confirmed to be ADA
positive, evaluate it for Nab assay to see if it is neutralizing the biologic activity of the drug (B or R)
Regulatory agencies usually prefer to have a cell-based NAb assay but other assay formats (e.g., immuno-based assays) are OK when
appropriate cell-lines are not available during development
If a cell-based assay exists for R, use the same platform for NAb of B
Validating cell-based NAb assays is technically difficult due to higher variability and a longer turnaround time for these
assays
B = Biosimilar; R = Reference Innovator
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Patients with NAb can Develop PRCA
PRCA = Pure Red Cell Aplasia or Aplastic Anemia
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Post-approval Commitment [example]
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Thus Biosimilars are not like small molecule generics Differences between B & R would affect the B’s
potency, Clinical & PK characteristics and safety profile
A particular B might never be interchangeable with R Assays are complex, challenging but doable
Validations are not only based on drug conc. alone but also on biologic activity especially immunogenicity
Demonstrate highly similar first in characterization and animal studies (including the assessment of toxicity); then clinical biosimilarity through immunogenicity, PK & PD and clinical outcomes
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Thank you Very Much
Acknowledgments:Dr. Nirav DesaiMr. Chintan Patel