1. Final Canadian Guidelines for “Biosimilars” Subsequent Entry Biologics (SEBs) DIA RA SIAC RD/RI Working Groups 11-May-2010 Stephen Sherman

2. 11-May-2010 Stephen Sherman 2 Disclaimer The views expressed in this presentation are the personal views of the author and do not necessarily represent the views of sanofi-aventis.

3. 11-May-2010 Stephen Sherman 3 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Legislative Framework Health Canada believes that the current Canadian regulatory framework provides an adequate legal foundation for approval of SEBs –Section C.08.002(2) of the Food & Drug Regulations: “A New Drug Submission shall contain sufficient information to assess the safety and effectiveness of a new drug” –The regulatory framework may be revised in the ongoing Legislative and Regulatory Modernization (LRM)

4. 11-May-2010 Stephen Sherman 4 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Development of the Current Canadian Guidelines Final version of the “GUIDANCE FOR SPONSORS: Information and Submission Requirements for Subsequent Entry Biologics (SEBs)” 2010/03/05 was released on March 8, 2010 –Circulated twice for comments: Jan 30 until Apr 16, 2008 and Mar 30 until May 26, 2009 –Parallel revisions to: Guidelines on Data Protection: Explaining SEBs in context of section C.08.004.1 of the Food & Drug Regulations Guidelines on Patented Medicines (NOC) Regulations –Immediate implementation

5. 11-May-2010 Stephen Sherman 5 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Definition An SEB is a biologic drug that enters the market subsequent to and is ‘similar’ to an approved innovator product Relies in part on prior safety and efficacy information that is deemed relevant due to similarity to the “reference biologic product” SEB Scope Pharmaceutical form and route of administration: “Products employing clearly different approaches to manufacture than the reference biologic drug will not be eligible…” Applies to well characterized proteins Harmonization (section 2.6) Recommends referring to the EMA’s product class specific guidances “as the scientific principles are consistent with those of Health Canada”

6. 11-May-2010 Stephen Sherman 6 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Distinction from generics: SEBs are not “generic biologics” and many aspects of the generic authorization process and marketed use do not apply to SEBs Once a Notice of Compliance (NOC = market authorization) is granted, the SEB becomes a new biologic drug like any other new biologic drug However, an SEB may not be used as a reference biologic drug SEBs “Similar” to reference biologic drug Full quality data PLUS comparability exercise data Safety & efficacy trials required, but reduced data acceptable Same regulatory pathway as for innovator biologics (NDS) No declaration of pharmaceutical and/or therapeutic equivalence Generics “Identical” to Canadian Reference Product Full quality data Bioequivalence trials required in lieu of efficacy & safety clinical trials Specific abbreviated regulatory pathway (ANDS) Declaration of pharmaceutical equivalence

7. 11-May-2010 Stephen Sherman 7 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) The following “should be considered” when using a Non- Canadian Reference Biologic Drug: –SEB sponsor needs to “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…in the same dosage form…in Canada” –Reference must be “widely marketed in a jurisdiction that that formally adopts ICH guidelines and has regulatory standards and principles…similar to Canada” –HC considers use of reference biologic drug as supportive of data submitted using the SEB

8. 11-May-2010 Stephen Sherman 8 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Sections of the PM(NOC) Guidelines explaining the application of the PM(NOC) Regulations to SEBs: –Section 3.4.1 of the guideline clarifies that Section 5 of the of the PM(NOC) Regulations applies to SEBs (i.e. Notice of Allegation) for: An NDS demonstrating similarity to a biologic marketed in Canada An NDS demonstrating similarity to non-Canadian reference biologic drug (considered to contain a comparison with the Canadian product) Supplemental submissions for a change in formulation, a change in dosage form, or a change in conditions of use, that rely on a demonstration of similarity to a reference biologic drug to reduce clinical and non-clinical data Section 3.5.1 of the PM(NOC) Guidelines: Responsibilities of the OPML in determining if a submission makes a direct or indirect comparison with a biologic reference product

9. 11-May-2010 Stephen Sherman 9 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Sections of the Data Protection Guidelines explaining the application of section C.08.004.1 of the Food and Drug Regulations to SEBs –Section 2.1 of the guideline states that an SEB is not considered to be an “innovative drug” –Section 3.1 of the guideline: Prohibits SEB approval until 8 years after the innovator drug approval Provides a 6-year no-filing period (C.08.004.1(3)) where SEB sponsors are prohibited from filing a submission that: –Compares directly or indirectly with the innovative drug –Demonstrates similarity with a non-Canadian reference biologic drug (considered a comparison between the SEB and the Canadian reference biologic drug) 6-month pediatric extension is applicable

10. 11-May-2010 Stephen Sherman 10 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Informational Requirements for SEB NDS Quality: Comparability exercise to ascertain if SEB is “highly similar” to the chosen reference Quality considerations for side-by-side comparison include: –Analytical techniques –Characterization –Physicochemical properties –Biological activity –Immunochemical properties –Purity and impurities –Specifications –Stability “If the similarity of an SEB to the reference biologic drug cannot be established based on the C&M data package, reduced clinical data cannot be justified and the product cannot be considered as an SEB”

11. 11-May-2010 Stephen Sherman 11 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Informational Requirements for SEB NDS Non-clinical: Follow principles recommended by ICH S6 (Preclinical Evaluation of Biotechnology-Derived Products). In vivo studies should include: –Pharmacodynamics –At least one repeat-dose toxicity study, including toxicokinetics Clinical PK: It is expected that the criteria for the comparative bioavailability studies for generic pharmaceuticals can generally be met in studies of SEBs

12. 11-May-2010 Stephen Sherman 12 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Informational Requirements for SEB NDS Non-inferiority vs. Equivalence Trials for Safety & Efficacy “In line with the principle of similarity, equivalence trials are generally preferred” If non-inferiority trials are considered: –Consult BGTD in advance –If the results of a non-inferiority study suggest: Clinically meaningful superiority and/or Increased AEs vs. the reference the product would no longer be considered an SEB –Demonstration of non-inferiority may limit extrapolation to other indications

13. 11-May-2010 Stephen Sherman 13 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) CMC Drug Substance Manufacture Characterization Control Reference Standard Container Stability Drug Product Description Development Manufacture Control Reference Standard Stability Innovator New Drug Submission Non-clinical Pharmacology Primary Pharmacology Secondary Pharmacol. Safety Pharmacology Interactions Pharmacokinetics ADME Interactions Toxicology Single Dose Repeat Dose Genotoxicity Carciogenicity Reproduction Local Tolerance Clinical Pharmacology Pharmacokinetics Single Dose Repeat Dose Special Populations Efficacy & Safety Dose finding Pivotal – –Indication 1 – –Indication 2 – –Indication 3 Post-market Studies Adapted Slide: BIOTECanada

14. 11-May-2010 Stephen Sherman 14 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) CMC Drug Substance Manufacture Characterization Control Reference Standard Container Stability Drug Product Description Development Manufacture Control Reference Standard Stability + Comparability SEB vs Reference Biologic Drug SEB New Drug Submission Non-clinical Pharmacology Primary Pharmacology Secondary Pharmacol. Safety Pharmacology Interactions Pharmacokinetics ADME Interactions Toxicology Single Dose Repeat Dose Genotoxicity Carciogenicity Reproduction Local Tolerance Clinical Pharmacology Pharmacokinetics Single Dose Repeat Dose Special Populations Efficacy & Safety Dose finding Pivotal – –Indication 1 – –Indication 2 – –Indication 3 Post-market Studies + Risk Mgmt Plan + Studies in larger population + Immunogenicty monitoring Adapted Slide: BIOTECanada

15. 11-May-2010 Stephen Sherman 15 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Extrapolation of the efficacy & safety data to other indications Any claims should be supported by suitable scientific data –Additional indications may be granted to the SEB in the absence of such clinical data, if: PK/PD data sufficient to bridge two or more indications Rationales are sufficiently persuasive –Extrapolation should be justified based on: Mechanism(s) of action Pathophysiological mechanism(s) of the disease(s) or conditions Safety profile in the conditions and/or populations Clinical experience with the reference biologic drug

16. 11-May-2010 Stephen Sherman 16 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Extrapolation of the efficacy & safety data to other indications Where a clinical indication is not held by the reference biologic drug: –“full clinical trial data shall be provided in support of that indication.”

17. 11-May-2010 Stephen Sherman 17 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Post-market Surveillance Requirements for SEBs Risk Management Plan (RMP) –Health Canada will work with sponsors to ensure a suitable RMP is developed prior to market authorization –RMP should consider experiences from the use of the reference –Periodic Safety Update Reports (PSURs) consistent with ICH E2E for new products Specific wording not included in the guideline regarding “Look- alike Sound-alike (LA/SA) Health Product Names” Policy However, the applicability of this guidance was addressed in a HC communication (Jan 2010)

18. 11-May-2010 Stephen Sherman 18 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Specific recommendations for Interchangeability (at prescriber level) or Substitution (at pharmacy level): –The SEB guidance does not make a specific statement on interchangeability/substitutability –However, it does state that authorization of an SEB is not a declaration of pharmaceutical and/or therapeutic equivalence to the reference biologic –Implies that the SEB not substitutable or interchangeable with its reference product

19. 11-May-2010 Stephen Sherman 19 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) Labelling Requirements (Product Monograph) Part 1 of the PM must include a statement indicating that the product is an SEB Unique labelling necessary (unlike generic drug) Information on the approved indications of the SEB Include key data used to support marketing authorization Include comparative tables No claims of bioequivalence or of clinical equivalence between the SEB and reference biologic drug

20. 11-May-2010 Stephen Sherman 20 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) First SEB approved in Canada OMNITROPE (somatropin, Sandoz) was approved for: –Growth Hormone Deficiency (GHD) in Children –Adult Growth Hormone Deficiency Approval based on a reduced development program using Genotropin ® (Pfizer) as a reference biologic product: –1 repeat-dose toxicity study –6 comparative PD studies in rats (2 of these studies were head- to-head with Genotropin® ) –2 local tolerance studies in rabbits –1 human bioavailability study –4 comparative PK/PD studies in healthy adults –5 phase III clinical efficacy and safety studies in GHD children

21. 11-May-2010 Stephen Sherman 21 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) First SEB approved in Canada OMNITROPE (somatropin, Sandoz) was approved for: –Growth Hormone Deficiency (GHD) in Children –Adult Growth Hormone Deficiency No clinical studies were conducted in adult GHD patients to support the 2nd indication –Approval was based on similar product quality characteristics and similar pathophysiology of GHD in adults and children Genotropin ® is approved, but has never been marketed in Canada

22. 11-May-2010 Stephen Sherman 22 Final Canadian Guidelines for Subsequent Entry Biologics (SEBs) REGULATIONS AND GUIDELINES RELEVANT TO SEBs Information and Submission Requirements for Subsequent Entry Biologics (SEBs) Patented Medicines (Notice of Compliance) Regulations Guidance Document: Patented Medicines (Notice of Compliance) Regulations Food and Drug Regulations (e.g. C.08.004.1: Data Protection) Guidance for Industry: Drug Name Review: Look-alike Sound-alike (LA/SA) Health Product Names ICH Q1A (R2): Stability Testing of New Drug Substances and Products ICH Q2 (R1): Validation of Analytical Procedures: Text and Methodology ICH Q5C Quality Testing of Biotechnology Products: Stability Testing ICH Q6B Product Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals ICH E2E Periodic Safety Update Reports (PSURs)

23. 11-May-2010 Stephen Sherman 23 Questions? stephen.sherman@sanofi-aventis.com