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Regulatory analysis & approval of Biosimilars


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  • Overview of EMEA guidelines for biosimilars.
  • Recombinant protein production: sources of variation between manufacturers.
  • 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); and • 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.
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    • 1. Regulatory Analysis &Approval of Biosimilars Plenary Lecture at Ganpat University Mehsana, Gujarat, July 20, 2012 Dr. Bhaswat S. Chakraborty 20.07.2012
    • 2. 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
    • 3. 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
    • 4. Size & Complexity Big Guys
    • 5. How are Biopharmaceuticals Made? Upstream & Downstream
    • 6. 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:
    • 7. Overview of USFDA Guidelines for BiosimilarsIntegration of Information to Biosimilarity
    • 8. General Regulatory Approach forAssessment 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
    • 9. 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:
    • 10. 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
    • 11. 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
    • 12. Requirements for Approval
    • 13. 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
    • 14. 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
    • 15. 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×).
    • 16. 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.
    • 17. 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.
    • 18. 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
    • 19. 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.
    • 20. Biosimilar EPO
    • 21. Human PK
    • 22. 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
    • 23. 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
    • 24. Bioassay practices Assessing “linearity” and similarity Significance testing versus equivalence testing Laboratory B 0.8p = 0.08 (p > 0.05, i.e., not Standard Data Test Datasignificantly different) 0.4 Standard Line Test Line Log10 ResponseConclude parallel! 0 0.5 1 1.5 2 2.5Rewarded for poor assay -0.4performance -0.8 -1.2 Log10 Concentration Laboratory A 0.8 Standard Data Test Datap = 0.02 (p < 0.05, i.e., 0.4 Standard Line Test Linesignificantly different) Log10 Response 0 0.5 1 1.5 2 2.5Conclude nonparallel! -0.4Penalized for good assayperformance -0.8 -1.2 Log10 Concentration
    • 25. 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
    • 26. 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
    • 27. Patients with NAb can Develop PRCAPRCA = Pure Red Cell Aplasia or Aplastic Anemia
    • 28. Post-approval Commitment [example]
    • 29. 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
    • 30. Acknowledgments:Dr. Nirav DesaiMr. Chintan Patel Thank you Very Much