Regulatory Analysis & Approval of Biosimilars

Dr. Bhaswat S. Chakraborty20.07.2012

Plenary Lecture at Ganpat University

Mehsana, Gujarat, July 20, 2012

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

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

Size & Complexity

Big Guys

How are Biopharmaceuticals Made?

Upstream & Downstream

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: journals.permissions@oxfordjournals.org

Overview of USFDA Guidelines for Biosimilars

Integration of Information to Biosimilarity

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

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: journals.permissions@oxfordjournals.org

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

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

Requirements for Approval

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

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

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×).

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.

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.

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

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.

Biosimilar EPO

Human PK

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

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

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

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

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

Patients with NAb can Develop PRCA

PRCA = Pure Red Cell Aplasia or Aplastic Anemia

Post-approval Commitment [example]

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

Thank you Very Much

Acknowledgments:Dr. Nirav DesaiMr. Chintan Patel