Subsequent-entry Biologics: Comparability and other Product Quality-Related Issues

1. Subsequent-entry Biologics: Comparability and other Product Quality-Related Issues . Anthony Ridgway, Ph.D. Senior Regulatory Scientist Biologics & Genetic Therapies Directorate Health Canada Montréal Forum Pharmaceutical Discussions Montréal, June 21, 2010

3. Presentation Outline .. • Background to quality essentials for SEBs • Origins & approaches to the guidance • Concept and demonstration of comparability • Key elements and considerations • (characterization, characterization, characterization) • Subsequent-Entry Biologics: challenges and current regulatory approach • Significant issues and some “highlights” from the draft guidance

4. Science-based Practical Considerations Origins & Approaches to Guidance • “Copies” of innovator biologics are inevitable; need to decide on “sufficient evidence of quality safety and efficacy” • Many years of safe use and real-world experience for a similar product must have value • There are multiple innovator versions of some biologics, all safe and effective, and none identical (therefore, some differences are not critical) • Innovators often make manufacturing changes with minimal or no clinical data

5. Science-based Practical Considerations Origins & Approaches to Guidance • Use as a model the comparability exercise undertaken by innovators after a manufacturing change • Incorporate need for new clinical data generated with SEB (therefore, data bridged through similarity is considered supportive) • Adapt international guidance, especially ICH Q5E; and consider EMEA clinical guidance

6. Biologicals Beyond 2000September, 1999 From a photo by Dr. Wendy Mooney

7. Regulation of SEBs is possible within the scope of current regulations. “Outline Document” on the Canadian regulatory approach to SEBs has been made available since 1999. • “Fact Sheet” on SEBs posted to HC website, July, 2006. • Work has progressed towards a clearly described regulatory approach for SEBs and to develop appropriate scientific & clinical guidance. • External Consultation/Workshop held in May, 2008. • New draft guideline posted for comment in March, 2009 • Final guidance released March 8, 2010 • New authorities and product-life-cycle approaches relevant SEBs are captured within the current, broader initiative on “Legislative and Regulatory Modernization” Specific & Related Activities at Health Canada

8. Comparability The Question ? Product of Process X Product of Process Y

9. Extent of Studies Comparability • Stage/extent of changes • Impact on the product • Analytical capability • Link between quality criteria and safety and efficacy

10. ICH Quality - Biotechnology Q5 A Viral Safety Q5 B Genetic Stability Q5 C Product Stability Q5 D Cell Substrates Q6 B Product Specifications Q5 E Comparability (S6 Safety Studies)

11. Q5E - General Principles The demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and post-change products are identical; but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product.

12. Comparability Key Elements • Characterization • Specifications • Validation • changes to materials or process

13. ICH Q6B Characterization • Chemical structure • Physicochemical properties • Biological activity • Purity • Impurities • Quantity

14. ICH Q6B Characterization Structural Characterization/Confirmation • Amino acid sequence • Amino acid composition • Terminal amino acid sequence • Peptide map • Sulfhydral groups & disulfide bridges • Carbohydrate structure

15. ICH Q6B Characterization Physicochemical Properties • Molecular weight/size • Isoform pattern • Extinction coefficient • Electrophoretic patterns • Liquid chromatographic patterns • Spectroscopic profiles

16. Characterization ICH Q6B Biological Activity • Animal-based assays • Cell culture-based assays • Biochemical assays • Others ?

17. Characterization Purity/Impurity Profile Drug substance = Multiple entities • Desired product (microheterogeneity) • Product-related substances • Product-related impurities • Process-related impurities • Contaminants

18. Characterization a. Truncated forms clipped cleaved b. Modified forms deamidated isomerized mismatched S-S linked oxidized c. Aggregates dimers higher multiples Product-related impurities

19. Characterization Process-related impurities a. Cell substrate - derived host proteins nucleic acid viruses b. Culture - derived inducers antibiotics media components c. Downstream - derived enzymes processing reagents inorganic salts solvents carrier/ligands other leachables

22. Comparability Additional Testing • Tests specifically directed at fully evaluating the impact of the change on the product • In-process assays at the manufacturing steps which are most likely affected by the manufacturing change

23. Clinical Considerations bridging study vs larger trial Comparability • Indication • mode of action • outcome measures • Dosing and Patient Response • units of activity • route of administration • narrow therapeutic index • Safety Versus Efficacy • immunogenicity • active ingredient vs impurities

24. Immunogenicity Issues • Most biopharmaceuticals induce antibodies • Manufacturing changes can cause unexpected changes in immunogenicity • Current analytical methods cannot fully predict biological properties • Immunogenicity of biopharmaceuticals may have serious clinical consequences

25. Presentation Outline .. • Background to quality essentials for SEBs • Origins & approaches to the guidance • Concept and demonstration of comparability • Key elements and considerations • (characterization, characterization, characterization) • Subsequent-Entry Biologics: challenges and current regulatory approach • Significant issues and some “highlights” from the draft guidance

26. Comparability Challenges: Biologic vs Chemical Drug • Size and complexity of the “desired product” • Heterogeneity (inherent, process-related, etc.)and the purity/impurity profile of drug product • Adventitious agents • Limitations of methods for characterization • Immunogenicity

27. Innovator Advantages for Demonstration of Comparability for a Biologic • Broad experience with product and process • Availability of drug substance • Linkages between quality attributes of product and clinical safety and efficacy are known • Ability to examine any observed change in the context of the range of historical values for clinical trial materials

28. The Regulatory Pathway Dilemma • Approach and set of requirements for less complex products will be inadequate for complex products • Approach and set of requirements for complex products may be excessive for less complex products • Furthermore, clinical parameters (indication, posology, therapeutic index, etc.) influence data requirements • Therefore: • Detailed guidance must be specific to product or class • Regulatory approach must be case-by-case

29. General guidance is provided (specific requirements for drug classes may differ) • Comparative studies are required • Trials designed to show equivalence are preferred • Trials to show non-inferiority are possible but must be justified; if clinically meaningful superiority is identified, cannot be approved as a SEB. • As a SEB, clinical indications are limited to those: • held by reference biologic in Canada • supported by data (some possible via rationale) • New indications are possible through full clinical studies Important Clinical Elements

30. EMEA Guidelines on Similar Biological Medicinal Products • CHMP/437/04: Guideline on Similar Biological Medicinal Products • Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: • CHMP/49348/2005: Quality Issues • CHMP/42832/2005: Non-Clinical and Clinical Issues • CHMP/94526/2005: Annex – Recombinant Erythropoietins • CPMP/31329/2005: Annex – Recombinant Granulocyte-Colony Stimulating Factor • CPMP/32775/2005: Annex – Recombinant Human Insulin • CPMP/94528/2005: Annex – Somatropin • Website = www.emea.eu.int/index/indexh1.htm ..

31. Challenges – SEBs/Biosimilars • Developing/rationalizing regulatory approaches • Applying appropriate level of regulatory oversight • How similar is “similar”? How much new clinical data is needed? • Addressing public and health sector concerns • Few drugs in total but with stakeholder and political interest • Non-voluntary medication changes

32. Opportunities – SEBs/Biosimilars • Greater choice, cheaper products • Potential for greater / simpler access • Two NOCs for GM-CSF but only available on SAP • Lower cost may have favourable impact on cost-effectiveness data and formulary listings • Incentive for new developments by innovators

33. Canadian Perspective Subsequent-Entry Biologics • Examined on a case-by-case basis • Full chemistry & manufacturing data required • plus comparability study with “reference biologic” • Clinical data is required • extent is negotiable (influenced by several factors) • same reference product throughout development program • One indication will not support all indications • However - same mechanism of action + rationale ….. ? • “Stand-alone” products • Approval does not imply suitability for substitution or interchange • Scientific & pharmacovigilance issues (SEBs not generics!)

36. Presentation Outline .. • Background to quality essentials for SEBs • Origins & approaches to the guidance • Concept and demonstration of comparability • Key elements and considerations • (characterization, characterization, characterization) • Subsequent-Entry Biologics: challenges and current regulatory approach • Significant issues and some “highlights” from the draft guidance

37. Significant lssues • Most general scientific concepts are accepted / understood but there will probably be some product-class-specific issues. • By the end of stakeholder consultations, most significant issues related to patent protection, period of market exclusivity, and market access (rules and/or choice regarding new or already treated patients). • Canadian vs non-Canadian reference biologic • Substitution and Therapeutic Interchange • Product labelling

38. Scientific Considerations Choice of Reference Biologic • The SEB must be “subsequent” to a product approved for the Canadian Market • Capable of meeting criteria for similar / comparable • Similar manufacturing process = logical advantage • Suitable analytical capability available & used • Weight of evidence provided by “quality” studies • Similarity brings suitable data on safety and effectiveness into relevance

39. Scientific basis for requiring a Canadian Reference Biologic (CRB) is weak Choice of Reference Biologic • NOC for CRB was likely many years earlier and original submission and review report may be of limited value due to evolving standards and approaches. • Recent review experience may be limited (no recent manufacturing changes or product not marketed). • SEB is not for automatic substitution therefore physician experience with RB is not critical to SEB use. • (Also, possible legal issues around use of files associated with innovator product).

40. Substitution / Interchange • Terminology: • “Automatic substitution” → required by payer • “Substitution” → at discretion of pharmacist • “Therapeutic interchange”→switch by physician • “Manufacturing drift” → biologics are sensitive to manufacturing changes so, as the innovator and SEB sponsor make multiple independent manufacturing changes, over time the products become less similar

41. Therapeutic interchangeability can be supported by specifically designed clinical studies (but such studies are unlikely in most situations). • Data used in the demonstration of “similarity” or “therapeutic interchangeability” are only truly valid at the time generated due to possible “manufacturing drift.” • Once approved, a SEB is a “stand-alone” product like any innovator product and the sponsor may gain approval for additional strengths, presentations and indications. • Therefore, • Health Canada’s position is that any substitution or therapeutic interchange must involve the physician and should be very carefully considered. Substitution / Interchange

42. Product Monograph (PM) for SEB should be developed according to PM guidance. Cannot use PM of reference biologic in its entirety (like a generic drug). • PM information contents: • Statement indicating product is a SEB • Key data supporting authorization • Tables with results of comparisons to named reference biologic • Approved clinical indications • No claims for clinical equivalence or bioequivalence • Although not clearly stated in the guidance, each SEB requires a distinct name to allow implementation of: Risk Management Plan, Pharmacovigilance Plan, ADR Reporting, Periodic Safety Update Reports (PSURs) Product Labelling for SEB

43. Elements of the SEB Guidance: Choice of reference biologic (comparator) • “The reference biologic drug should have adequate safety, efficacy and effectiveness data accumulated such that the demonstration of similarity will bring into relevance a substantial body of reliable data” • “An SEB should not be used as a reference biologic drug” • “Products employing clearly different approaches to manufacture than the reference biologic drug may not be suitable for authorization as SEBs”

44. Elements of the SEB Guidance: Choice of reference biologic (comparator) • “the product (i.e. SEB) can be well characterized by a set of modern analytical methods” • “… the SEB, through extensive characterization and analysis, can be judged similar to the reference biologic drug by meeting an appropriate set of pre-determined criteria” • “The same reference biologic drug should be used throughout the studies supporting the safety, quality and efficacy of the product”

45. Elements of the SEB Guidance: Choice of reference biologic (comparator) • Health Canada will, in appropriate and special circumstances, permit the use of a reference biologic drug that is not authorized for sale in Canada. • “The sponsor is responsible for showing that the non-Canadian reference biologic used for the purposes of demonstrating similarity is a suitable proxy for the version of the product approved in Canada. The submission should explicitly explain the link between the two products and confirm that both are marketed by the same innovator company or corporate entity that is approved to market the medicinal ingredient in the same dosage form in Canada”

46. Elements of the SEB Guidance: Issues surrounding comparability/similarity • “If the reference drug substance used for characterization is isolated from a formulated reference drug product, additional studies must demonstrate that the drug substance is not changed by the isolation process.” • “A final determination of similarity can be based on a combination of analytical testing, biological assays, and non-clinical and clinical data. However, to be considered an SEB, the weight of evidence should be provided by the analytical and biological characterization.”

47. Elements of the Draft Guidance: Issues surrounding comparability/similarity • “Once granted a NOC, a SEB is considered to be a new (stand-alone) product with all of the associated regulatory requirements. For any changes to the manufacturing process that warrant a demonstration of comparability, the products to be compared will be the pre-change and post-change versions of the SEB. Comparisons with the original reference biologic drug are not required.” • (N.B., This has implications regarding “substitution”) • NOC = Notice of Compliance (for sale) • SEB = Subsequent-entry Biologic

48. Conclusions • Health Canada has adopted a regulatory approach to SEBs (Biosimilars) that is science-based • Where possible, principles and guidance from ICH documents are applied • Opportunities for collaborative regulatory approaches are being actively pursued and relevant guidance from regulatory partners will be referenced or adopted C