Subsequent Entry Biologics (SEBs) – Canada Presentation to AIPLA Biotechnology Committee January 25, 2012

1. Subsequent Entry Biologics (SEBs) – CanadaPresentation to AIPLA Biotechnology CommitteeJanuary 25, 2012 Daphne C. Lainsondclainson@smart-biggar.ca

2. Health Canada • Health Canada approval, Food and Drugs Act: • Human and veterinary pharmaceuticals • Human biologics • Canadian Food Inspection Agency • Veterinary biologics

3. Innovator Regulatory Pathway • Clinical trial application (CTA) • New drug submission (NDS) • Post-approval changes • “Administrative” NDS - changes in name of manufacturer, brand name • Supplemental NDS (SNDS) - non-administrative changes, (e.g., changes in formulation, dosage form or use) • Approval = Notice of Compliance (NOC) or NOC with Conditions (NOC/c)

4. Subsequent Entry Pathway • NDS – Full data package • Generic pharmaceutical submissions: • Abbreviated NDS (ANDS) • Supplemental ANDS (SANDS) • Subsequent entry biologics (SEB) submissions: • No abbreviated or SEB pathway in Food and Drugs Act and Regulations • Guidance only • Q & A document

5. Guidance Document • Released March 5, 2010: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/notice-avis_seb-pbu_2010-eng.php • SEB approval: NDS with reduced data package • SEB sponsor to show a “demonstrated similarity” between the SEB and a suitable reference biologic drug • Well characterized products • Example: well characterized proteins

6. Reference Biologic • Should not be another SEB • Has significant safety and efficacy data accumulated • Should be same dosage form, strength and route of administration as SEB • Should be authorized for sale and marketed in Canada • Foreign reference biologic permitted where marketed by same innovator or corporate entity in Canada in same dosage form as approved Canadian biologic

7. Guidance – Other Highlights • Extrapolation of indications permitted • Generics following ANDS pathway not permitted to extrapolate • Post-marketing changes to manufacturing process: comparison is to SEB submission only • Not required to compare to original reference biologic – product drift (?) • SEB approval not a demonstration of pharmaceutical or therapeutic equivalence • NOC Regulations and data protection provisions to apply

8. “Hatch-Waxman” Canadian Style • Broad “Bolar” exemption • It is not an infringement of a patent for any person to make, construct, use or sell the patented invention solely for uses reasonably related to the development and submission of information required under any law of Canada, a province or a country other than Canada that regulates the manufacture, construction, use or sale of any product. • Patented Medicines (Notice of Compliance) Regulations • Not limited to pharmaceuticals

9. NOC Regulations – Notable Distinctions with US • Patent Register – similar to Orange Book, but: • Linkage to any product approved by NOC, and therefore includes human biologics, some devices • Firm patent listing deadlines (late listing not possible) • Listing not automatic: government eligibility review (timing, subject-matter, relevance) • Stay = up to 24 months • NOC proceeding: not final determination of merits • Patent infringement or validity trial may follow • No patent term restoration (also, no PTE or SPCs)

10. Trigger • NOC Regulations engaged where subsequent manufacturer makes a direct or indirect comparison or reference to another drug marketed in Canada with patents listed on Patent Register • Questions: • Hybrid submissions based on new and significant clinical studies? • Extrapolated indications: relevant patents not listed? • Product drift: infringement of a valid patent claim where previously no infringement?

11. Data Protection First NOC issued after June 17, 2006 for an “innovative drug”: “a drug that contains a medicinal ingredient not previously approved in a drug by the Minister and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate or polymorph” Includes human biologics, and human or veterinary pharmaceuticals Independent of patent status Can be lost if innovator is not marketing in Canada

12. Data Term Pharmaceuticals and biologics: same data terms 6-year “no-file” period Data period: subsequent entry manufacturer cannot file its submission for a period of 6 years after the date of the first NOC for the innovative drug 8-year “no-grant” period Market exclusivity period: NOC cannot be granted for a period of 8 years after the date of the first NOC for the innovative drug 8½ years if pediatric extension applies No extensions or supplemental terms

13. SEB – Innovative Drug? • Guidance: SEB is not entitled to its own data term • Definition of “innovative drug”: excludes same medicinal ingredient and variations • “variation” not fully defined

14. Trigger • Subsequent entry sponsor must make direct or indirect comparison to innovative drug • Questions: • Hybrid submissions

15. Status of SEBs Omnitrope approved 2009 Health Canada is accepting SEB submissions, but no further SEBs have yet been approved Government is considering a SEB pathway in its comprehensive review and revision of the Food and Drug Act and Food and Drug Regulations

16. PMPRB Jurisdiction Controls price over which patented medicines are sold in Canada Broad jurisdiction “merest slender thread” of a connection between patented invention and medicine sold in Canada Applies to patentee and its licensees Authorized generics encompassed ratiopharm ordered to pay $65 million for sales of ratio-salbutamol HFA to offset excessive price revenue Same rationale would apply to authorized SEB

17. Hot Topics • Monoclonal antibodies – working examples (preparation and characterization) may be required • Utility: demonstration vs. sound prediction • Teva Canada Limited v. Pfizer Canada Inc. (VIAGRA), SCC hearing in February 2012 • CETA – Comprehensive Economic and Trade Agreement between Canada and Europe

18. Thank You