Covance Biosimilars: Nonclinical & Clinical Development Challenges & Considerations


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With many blockbuster biological drugs now, or soon to be off patent, there has been great interest in developing follow-on versions, termed biosimilars. Biosimilars have emerged as one of the fastest growing development opportunities in the biopharmaceutical sector. Unlike generic small molecule drugs creating an exact copy of a therapeutic protein is impossible. As a result regulatory agencies evaluate this category of biologics based on their level of similarity to, rather than the exact replication of the innovator drug.

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Covance Biosimilars: Nonclinical & Clinical Development Challenges & Considerations

  1. 1. Biosimilars: Nonclinical and ClinicalDevelopment Challenges and Considerations
  2. 2. Agenda Regulatory Environment Early Development Challenges • Regulatory landscape • Characterization • CMC and in vitro • Animal studies • Assays Clinical Development Challenges • Phase I • Phase III Conclusions2
  3. 3. Regulatory Environment
  4. 4. Global Regulatory Landscape EMA (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Act passed in 2010 • Empowers FDA to develop standards to evaluate and approve biosimilars • FDA February 2012 draft guidance documents • Risk-based “totality-of-the-evidence” approach Health Canada • Guidance came out in 2010 Japan • Guideline came out in 2009 WHO • Guideline document came out in 2009 ROW • Argentina, Australia (amending), Brazil, Jordan, Korea, Malaysia, Saudi Arabia, Singapore, Taiwan, Turkey, Venezuela – Guidelines available • Colombia, Cuba, India, Mexico, South Africa, and Thailand – Draft Guidelines available Biosimilar Regulatory Guidance documents and discussions are on-going and expanding globally.4
  5. 5. 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 approaches5
  6. 6. 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.6
  7. 7. 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 licence7
  8. 8. Poll Question 1 Can extensive in vitro testing of reference from various regions support single-region reference in clinical studies? A. Yes B. No, clinical studies needed with all reference product C. Not sure8
  9. 9. Regulatory Comparability Package Extensive 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 issues9
  10. 10. Early Development Challenges
  11. 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 It’s all about comparability11
  12. 12. Regulatory LandscapeHarmonization of regulatory expectations • Most regulatory regions are in general agreement • Main issue is reference material sourcingDiscuss plans early • Early engagement with the regulators is key (especially in the USA) • Characterization differences need to be fully understood and explained12
  13. 13. CharacterizationComprehensive Characterization • Physicochemical as well as biological • Multiple batches of innovator spanning a number of years • Understand innovator variability • Specification changes over life of product • No label change13
  14. 14. CMC and In Vitro Detailed characterization of biosimilar and reference product needed before clinical trial work with consideration for: • Physical properties • Amino acid sequence • High-order structure and post-translation form • Product-related impurities (aggregates, oxidized forms, deaminated forms) • Process-related impurities and contaminants (host cell protein, residual genomic DNA, reagents, downstream impurities) • Receptor-binding or cell-based assays14
  15. 15. CMC and In Vitro Recommendations • High resolution analysis • Multiple methods • Multiple batches • Characterize reference over a number of batches (years) to understand specification range • Confirm reference product labelled concentration or potency for each batch15
  16. 16. CMC and In Vitro Detailed characterization of biosimilar and reference product needed before clinical trial work with consideration for:16
  17. 17. CMC and In Vitro Cell-based assays • Critical to assess the biological activity of the biosimilar • Related to the actual function • Target binding • Pharmacological effect e.g. proliferation inhibition • mAb effector function (ADCC, CDC or FC-binding)17
  18. 18. CMC and In Vitro Cell-based assays • Can be based on batch release assay • Takes time to setup and validate • May be possible to use as a basis for NAb assay (consider matrix effects) • Will be required to support Phase III and pharmacovigilance18
  19. 19. Animal Studies When to perform these? • Regulators suggest a step-wise approach • Characterization differences need to be identified and fully explained • If differences are seen and not adequately characterized then in vivo studies may be required • Use of novel excipient in formulation may necessitate in vivo studies • Use of NHPs not recommended • PK/PD endpoints rather than toxicity?19
  20. 20. Animal Studies Examples • rHu-EPO • 28d comparative multiple dose study in rat • Multiple dose levels to assess dose response • Primary endpoint was PK/PD but organs also assessed • No toxicity seen • mAb • Primate toxicology study • Single dose level of innovator and biosimilar • 28d repeat dose toxicology study • No toxicity seen20
  21. 21. Animal Studies Recommendations • In vivo efficacy studies • Very useful if models exist • Models may be proprietary and thus difficult to obtain • Where good PD marker exists • Useful to have comparative PK/PD and dose response • May take organs for assessment but not necessarily in the first instance • ADA samples taken but not routinely tested unless effect on PK/PD • Where no PD marker exists • Consider relevance of animal testing, especially if NHP is only relevant species • If performed then minimal groups and maximum of 28d dosing21
  22. 22. Poll Question 2 Do comparative toxicology studies add to the body of evidence in determining comparability? A. Definitely B. Minimally C. Not at all D. Not sure22
  23. 23. Immunogenicity Relative Immunogenicity • Difficult to show statistical significance in animal studies • Applicability to human? • Useful in considering differences in TK/PK or PD Immunogenicity recommendations • ADA assay developed for animal studies but not necessarily validated in first instance • Samples taken but not analyzed unless TK/PK or PD effect seen • Used to interpret difference in TK/PK or PD but not for prediction of human immunogenicity23
  24. 24. Immunochemistry Assays General principles for demonstration of bioequivalence are applicable: • Ratio analysis of mean result should be between 0.80 and 1.25 to demonstrate bioequivalence • This criteria should be demonstrated for validated assays using either option 1 or 2 Option 1: Separate Assays for Option 2: Single Assay for innovator/reference: innovator/reference: - Innovator Calibration standards & QCs - Single Innovator Calibration curve - Reference Calibration standards & QCs with reference and innovator QCs Advantages of Option 2: • Less resource intensive • Blinding can be maintained24
  25. 25. Poll Question 3 Do you always aim for a single assay for PK/TK assessment? A. Yes B. No, always aim for separate assays C. First test feasibility of single assay D. Not sure25
  26. 26. Clinical Development Challenges
  27. 27. ClinicalDesign trials with right endpoints and right populationDifficulty in identifying sites and patients in Phase I and IIICan take a long time and a lot of patientsPhase I Phase IIIPhase I studies supporting dose(s) for targeted • Single Pivotal (therapeutic category)indications • Extrapolatability within categoryPhase I Study: • Leverage established PD and Surrogate • Healthy volunteers vs patients endpoint(s) • Ethics committee considerations • Part 1 - Initial safety and comparative PK • PK/PD assessments with shorter cycles of arms (at labeled dose) therapy • Part 2 - Comparative PK/PD, Immunogenicity • Immunogenicity determined with full and Safety/Efficacy run in parallel to Phase III study submissions regimen of therapy • N=40 for Phase III start & Interim Analysis for • “Interchangeability” not yet addressed by PK/PD powering FDADifficulties • Cross-over designs • Sentinel dosing group for Phase I
  28. 28. Conclusions
  29. 29. Conclusions Characterization is absolutely critical Animal toxicology studies add little value but may be required by certain regulators. Animal studies should focus on efficacy models and PK/PD where possible Relative immunogenicity is assessed most appropriately in clinical studies and post-marketing Planning and multidisciplinary approach is key29
  30. 30. Drug Development Solutions from Discovery Through Commercialization DISCOVERY DEVELOPMENT COMMERCIALIZATION RESEARCH PRECLINICAL PHASE I PHASE III PHASE IV Efficacy Model Development/Biomarker Development Immunogenicity, PK, TK Immunotoxicity: CDC & ADCC Tissue Cross Reactivity Pharmacokinetics/Toxicity Viral Clearance Process Development Support, Biomanufacturing Support, Biosafety Testing In vivo/In vitro Biopotency Physicochem & Biological Characterization Serum Production Health Economics Assessment Clinical Feasibility Reimbursement Phase I to Phase III Clinical Trials Clinical Development: Target Population Clinical Development: Special Populations Stability and Release Outcomes/PE Studies Central Labs Data: Safety and Genotyping Post-Marketing Commitments Molecular Development (Program Management & Clinical) Regulatory Strategy, EMA/FDA Documentation Prep & Meeting Attendance, CTA/IND/BLA Support and Submission Covance is uniquely positioned to be a valued partner at every stage in the biosimilar drug development process30