Follow-on or Biosimilar Biologic s Points to Consider Paul Kim Foley Hoag LLP Massachusetts Biotechnology Council Thurs

1. Follow-on or Biosimilar BiologicsPoints to ConsiderPaul KimFoley Hoag LLPMassachusetts Biotechnology CouncilThursday, May 28, 2009 © 2008 Foley Hoag LLP. All Rights Reserved.

2. Topics • Overview • Details • Overview • Details

3. Health Care – To Do • Health Care Reform -- Medicare Reform? • Swine Flu Pandemic • Comprehensive Food Safety Legislation • Stem Cells and NIH Reauthorization • FY2010 Appropriations • FDA Import Safety Legislation Crises and Conflicts

4. Generic Brand BLA ANDA Loophole Food, Drug, and Cosmetic Act Public Health Service Act NDA

5. Patent Extensions Market Exclusivity Generic Brand Simpler Approvals Food, Drug, and Cosmetic Act Public Health Service Act First Generic Exclusivity BLA NDA ANDA Hatch-Waxman Amendments

6. Generic Brand Exclusivity? Simpler Approvals Food, Drug, and Cosmetic Act First Biosimilar Exclusivity? Europe= 8+2+1 BLA NDA Waxman=5 (+3) (+1) ? ? Eshoo-Barton =12 ANDA Inslee=14 “ABLA” Biological Products Public Health Service Act

7. Topics • Overview • Details • Overview • Details

8. Legislation • Approval Pathway, Interchange and Naming • Exclusivity • Resolving Patent Disputes

9. Senate bill House bill Committee hearing, markup Committee hearing, markup Senate floor House floor Conference Legislation

10. Approval Pathway The Pathway for Biosimilars Act of 2008—H.R. 1548 (Eshoo, Barton) Promoting Innovation and Access to Life-Saving Medicine Act of 2009—H.R. 1427 (Waxman, Pallone, Deal, and Emerson) • Creates an abbreviated application for “highly similar” biological products • Requires aBPA applicants to submit information demonstrating that biosimilarity based on: • Analytical studies; animal studies; and clinical studies, including PK/PD and immunogencitiy studies sufficient to demonstrate “safety, purity and potency for each condition of use for which the reference product is approved.” • Data demonstrating the use of the samemechanism(s) of action for the condition(s); has the same route of administration, dosage form and strength; and that the manufacturing facility is safe. • FDA may waive any of these requirements on a case-by-case basis— if guidance has been issued Creates an abbreviated application for biosimilar and interchangeable biologicalproducts Requires demonstration of “biosimilarity” based on, at the Secretary’s discretion, chemical, physical, and biological assays, other non-clinical laboratory studies, and “any necessary clinical study or studies sufficient to confirm safety, purity, and potency.” Any required clinical studies must “avoid duplicative and unethical testing” “Biosimilar” defined as: “no clinically meaningful differences between the biological product and the reference product would be expected in terms of the safety, purity and potency if treatment were to be initiated with the biological product instead of the reference product”

11. Approval Pathway The Pathway for Biosimilars Act of 2008—H.R. 1548 (Eshoo, Barton) Promoting Innovation and Access to Life-Saving Medicine Act of 2009—H.R. 1427 (Waxman, Pallone, Deal, and Emerson) Requires FDA to issue guidance documents for approval of biosimilars Requires immunogenicity studies (may be waived after guidance that the current state of scientific evidence allows for a determination of immunogenicity safety without the need for a study Requires clinical studies to assess immunogenicity, pharmacokinetics/dynamics (may be waived after guidance) Applies the REMS requirement to aBPAs in the same manner it is applied to innovators. Does not require guidance documents Only requires regulations within 2 years on processes for review and approval No requirements on immunogenicity No specific REMS provision; provides the FDA with discretion to require post-market safety studies for biosimilars

12. Interchangeability The Pathway for Biosimilars Act of 2008—H.R. 1548 (Eshoo, Barton) Promoting Innovation and Access to Life-Saving Medicine Act of 2009—H.R. 1427 (Waxman, Pallone, Deal, and Emerson) • Allows interchangeability if the FOB is: • “Biosimilar” to the reference product; • Can be expected to produce the same clinical result in any given patient for each condition of use prescribed, recommended, or suggested in the label; and • Risk in terms of safety or diminished efficacy of alternating or switching between use of the FOB and innovator is not greater than the risk of using the reference product without suchalternation or switch. • Determinations of interchangeability require final guidance, advising that it is feasible in the current state of scientific knowledge to make such determinations with respect to products in that biological class; and explaining the data that will be required to support such a determination. • Defines “interchangeable” as: • the biologic product is biosimilar to the reference product; and • (B) the patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, compared to the expected risks form continuing to use the reference product without such switching. • Requires guidance regarding standards and requirements for interchangeability within 2 years of enactment.

13. Naming The Pathway for Biosimilars Act of 2008—H.R. 1548 (Eshoo, Barton) Promoting Innovation and Access to Life-Saving Medicine Act of 2009—H.R. 1427 (Waxman, Pallone, Deal, and Emerson) If the Secretary determines that designation of an official name for a biosimilar biological product is necessary or desirable in the interests of usefulness or simplicity, the Secretary shall designate the same official name for the biosimilar biological product as the Secretary designated for the reference product. Requires the Secretary to ensure that the labeling and packaging of each FOB product licensed bears a name that uniquely identifies the biological product and distinguishes it from the reference product.

14. Exclusivity The Pathway for Biosimilars Act of 2008—H.R. 1548 (Eshoo, Barton) Promoting Innovation and Access to Life-Saving Medicine Act of 2009—H.R. 1427 (Waxman, Pallone, Deal, and Emerson) Provides 12 years data exclusivity, from first licensed or until final class-specific guidance is issued, whichever is later. aBPA cannot be submitted for 4 years after approval Provides two years of exclusivity for the first approved interchangeable FOB for a reference product. • An innovator biologic, if “no major substance of which has been previously approved,” is entitled to 5 years of exclusivity. • “Major substance” is novel concept, not defined in the bill • Only applies for products approved after enactment and for BLAs that do not rely on studies in other applications • Exclusivity is withheld for: • biologics differing in minor structural ways • products identified by the FDA in regulation • Borrows from FDA’s orphan drug regulations to deny exclusivity to products different from, but structurally related to, previously approved products • Provides 180 day market exclusivity for first biosimilar deemed interchangable.

15. Exclusivity The Pathway for Biosimilars Act of 2008—H.R. 1548 (Eshoo, Barton) Promoting Innovation and Access to Life-Saving Medicine Act of 2009—H.R. 1427 (Waxman, Pallone, Deal, and Emerson) Provides 3 years of exclusivity for conditions of use, if the product: -includes major substance (or any “highly similar” major substance) approved in another BLA, after enactment -includes new clinical investigations (other than PK/PD) -represents a “significant therapeutic advance” *Modest but meaningful advances not eligible; approval on the basis of surrogate endpoints do not qualify *Protects only the new condition of use; does not extend the 5 years into 8, so off-label use greatly attenuates value Provides 6 months exclusivity for supplemental BLAs, which: -report “new clinical investigations essential to the approval of the application,” and -provide changes representing a “significant therapeutic advance” for a “significant new indication” -6 months reduced to 3, if annual U.S. gross sales exceed $1 billion Provides 6 months pediatric exclusivity, if studies are requested by the FDA Provides additional 2 years of exclusivityfor approval of a supplemental application that represents a medically significant new indication; must be approved within 8 years of licensure. Provides 6 months of pediatric exclusivity, for conducting clinical investigations essential to the approval of a supplemental application

16. Resolving Patent Disputes The Pathway for Biosimilars Act of 2008—H.R. 1548 (Eshoo, Barton) Promoting Innovation and Access to Life-Saving Medicine Act of 2009—H.R. 1427 (Waxman, Pallone, Deal, and Emerson) Requires FDA to publish notice of aBPA filings Requires applicant to provide notice to reference product sponsor; innovator and relevant third-parties provides a list of all relevant patents it will seek to enforce, and applicant must respond. Innovator or third-party may bring infringement action, and FDA may not approve a application until patent expiration. Declaratory judgments brought by applicants are not allowed against identified patents prior to three year before exclusivity expiration. Allows an applicant to request patent information from a BLA holder at any time during development, and BLA holder must respond with all relevant patents within 30 days and must send updates with any new patent information for the following 2 years. Applicant may provide notice of its application, but does not have to provide extensive materials. BLA holder can bring infringement action only to patents identified in the notice and may only recover reasonable royalties. BLA holder cannot bring declaratory judgment actions until commercial marketing of biosimilar product; applicant may bring declaratory judgment however.

17. Thank you FOLEY HOAG | Life Sciences Government Strategies