1. FDA’s Biosimilars Guidance -- Legal and Regulatory Considerations James S. Cohen, Esq. McDermott Will & Emery DIA Webinar April 10, 2012

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3. Biosimilar vs. Interchangeable Use of Foreign Data Post-Market Safety Exclusivity/Intellectual Property Combination Product/Device Delivery System Topics Drug Information Associationwww.diahome.org3

4. Biologics Price Competition and Innovation Act of 2009 (BPCIA) (part of Patient Protection and Affordable Care Act) became law (3-23-12) –Amends section 351 of the PHS Act to create biosimilar pathway February 2012, FDA issues three draft guidance documents –This suggests it will be some time before proposed and final regulations, and final guidance issue Background Drug Information Associationwww.diahome.org4

5. Provides current scientific, quality and regulatory thinking on biosimilars, but little information on interchangeability Biosimilar: –“the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product” Background Drug Information Associationwww.diahome.org5

6. Interchangeable: –biological product “is biosimilar to the reference product; and can be expected to produce the same clinical result as the reference product in any given patient; and –… [if] administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the two products is not greater than the use of the reference product without such alternation or switch” Biosimilar vs. Interchangeable Drug Information Associationwww.diahome.org6

7. Sponsors should use “stepwise approach” to showing biosimilarity –FDA will conduct “risk-based” review of “totality of evidence” submitted –Amount/type of analyses and testing required determined on case-by-case (“product-specific”) basis “Extensive” comparative analytical data using “state-of-the-art” technology expected –If reference product cannot be adequately characterized in this way, suggests meet with Agency to assess whether appropriate for biosimilar pathway Biosimilar vs. Interchangeable Drug Information Associationwww.diahome.org7

8. FDA does discuss showing of interchangeability Will consider interchangeability at time of original/supplemental application –Says would be difficult at this time “as a scientific matter” to establish interchangeability given statutory definition and “sequential nature of that assessment” Unlikely to determine if product is interchangeable in an original application Biosimilar vs. Interchangeable Drug Information Associationwww.diahome.org8

9. Like generics, interchangeable product may be automatically substituted for reference product without approval by prescriber (subject to state laws) However, no similar provision for biosimilars and, at least initially, unlikely will be eligible for substitution under state laws Biosimilar vs. Interchangeable Drug Information Associationwww.diahome.org9

10. In general, sponsor needs to provide data directly comparing products However, “under certain circumstances,” sponsor can “seek to use” data from animal or clinical studies –Must provide adequate data to scientifically justify the relevance of the non-U.S. comparative data Should discuss with FDA very early in development phase Use of Foreign Data Drug Information Associationwww.diahome.org10

11. Factors FDA will consider include: –Relevance of clinical program design to condition of use and patient population –Relationship between the two license holders, including whether non-U.S. product, and/or any of its components, are manufactured in the same facility –Whether non-U.S. product was (a) manufactured in a facility licensed/inspected by, and/or (b) licensed by, a regulatory authority with similar scientific/regulatory standards as U.S. (e.g., ICH countries), and how long product marketed –Scientific bridging between the products, including comparative physico-chemical characterization, bioassays/functional assays and comparative clinical and/or non-clinical PK and/or PD data, as well as data to address labeling and packaging differences Use of Foreign Data Drug Information Associationwww.diahome.org11

12. “At this time” unlikely clinical comparisons with non-U.S. product would be an adequate basis to support “the additional criteria required” for interchangeability FDA has suggested it would like to utilize Europe’s biosimilar experience –FDA has expanded its confidential information sharing agreements with European and other regulatory authorities for clinical data, inspection, and post- market safety information Use of Foreign Data Drug Information Associationwww.diahome.org12

13. Provides only general information, but emphasizes need for robust program Post-market safety considerations have come under increasing scrutiny –Given FDA’s cautious approach to biosimilars, will likely require (at least initially) enhanced labeling/post-market surveillance as condition of approval Post-Market Safety Drug Information Associationwww.diahome.org13

14. Should monitor/consider any particular safety concerns associated with: –use of reference product and its class, and –product in its development/clinical use if marketed outside U.S. Proposed product labeling should include clear statement that approved: –As biosimilar to reference product for the indication(s) and route(s) of administration, and (has or has not) been determined to be interchangeable Post-Market Safety Drug Information Associationwww.diahome.org14

15. May require post-market safety and effectiveness studies, and Risk Evaluation and Mitigation Strategies (REMS) Sponsors should consult with “appropriate FDA Divisions” to discuss approach Post-Market Safety Drug Information Associationwww.diahome.org15

16. BPCIA has exclusivity provisions, and provisions for resolution of patent disputes that differ from ANDA process. Exclusivity for reference product: –No 351(k) product can be approved until 12 years from first licensure of reference product –No 351(k) application can be filed until 4 years from first licensure Also, 6 months exclusivity for pediatric studies, and exclusivity provisions for first interchangeable approved Exclusivity and Patent Disputes Drug Information Associationwww.diahome.org16

17. Process for patent dispute resolution –Unlike the public patent listing process for generic drugs, the BPCIA provides for a detailed private disclosure process in which -- Applicant provides copy of application and shares manufacturing information with innovator Innovator identifies its patents, including process and process patents The parties negotiate and reduce to patents in dispute for litigation, innovator can sue towards end of this process Applicant gives 180 days notice before first commercial marketing, and innovator can seek preliminary injunction Exclusivity and Patent Disputes Drug Information Associationwww.diahome.org17

18. FDA “is continuing to review” the reference product exclusivity provisions, and has requested pubic comment on factors to consider in its interpretation of those provisions –e.g., whether 12 years applies to market and data exclusivity, or data exclusivity limited to 4 years Applicant may include a request for exclusivity –Until further guidance available, “adequate data and information’ should be included to support request Exclusivity and Patent Disputes Drug Information Associationwww.diahome.org18

19. Some biosimilars will be combination products (e.g., biologic-device, biologic-drug) Biosimilar can have different delivery/container- closure system –pre-filled syringe or auto-injector vs. vial presentation Biosimilar in delivery device may require separate device application –FDA has limited the number of CPs for which it has required separate INDs or marketing applications Combination Product/Device Delivery System Drug Information Associationwww.diahome.org19

20. If different delivery/container closure system: – for biosimilar, must show compatible for use with final formulation through appropriate studies (including extractable/leachable and stability studies), and for certain design differences, performance testing and a human factors study may be needed –For interchangeable, FDA may consider whether differences significantly alter critical design attributes, product performance, or operating principles, or would require additional instruction without the intervention of prescriber. Additional performance data may also be needed Combination Product/Device Delivery System Drug Information Associationwww.diahome.org20

21. Comments or questions welcome James S. Cohen McDermott Will & Emery, LLP 600 Thirteenth Street, N.W Washington, D.C. 20005 jscohen@mwe.com 202-756-8276 Contact Information Drug Information Associationwww.diahome.org21