1. 6 th Science & Standards Symposium January 16, 2013 Istanbul Biosimilars Roger L. Williams, M.D. CEO and Chair, Council of Experts

2.  BPCI  USP  Summary Topics

3. Generic Versus Pioneer Product Equivalence Concepts (CFR 320) Pharmaceutical Equivalence –Same active ingredient –Same strength –Same dosage form and route of administration –Comparable labeling –Meet compendial or other standards of identity, strength, quality, purity and potency Bioequivalence –In vivo measurement of active moiety (moieties) in biologic fluid (blood/urine) –In vivo pharmacodynamic comparison –In vivo clinical comparison –In vitro comparison –Other THEN: THERAPEUTIC EQUIVALENCE

4. Compiled by the PRIME Institute, Univ. of Minnesota from data found in PriceChek PC and PriceRx (Wolters Kluwer Health, 2009), and AARP, Rx Watchdog Report series, 2009. Top Drugs Most Used by Elderly Brand & Specialty Price Inflation: 1998 to 2008 Annual % Change Specialty Rxs Brand Name Rxs

5. Predicates David M. Dudzinski Reflections on Historical, Scientific, and Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Therapeutics and Monoclonal Antibodies, Food and Drug Law Journal, Volume 60, 143-260, 2005 (FDLI’s 2003-4 H. Thomas Austern Memorial Writing Awards Competition--long papers), with acknowledgements to Peter Barton Hutt, Esq. Public Health Service Act—fits within the FDCA –Section 351(j) …the FDCA otherwise applies to biological products subject to regulation under its section –Section 351(g)…nothing contained in this chapter shall be construed as in any way affecting, modifying, repealing, or superseding the provisions of the [FDCA]

6. ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process The tripartite harmonised ICH guideline was finalised (Step 4) in November 2004. The objective of this document is to provide principles for assessing the comparability of biotechnological/ biological products before and after changes are made in the manufacturing process for the drug substance or drug product. Therefore, this guideline is intended to assist in the collection of relevant technical information which serves as evidence that the manufacturing process changes will not have an adverse impact on the quality, safety and efficacy of the drug product. The document does not prescribe any particular analytical, nonclinical or clinical strategy. The main emphasis of the document is on quality aspects. Final: September 2004 Comparability: One-Way Interchangeability (Hidden from Public)

7. FDA Comparability –Guidance Concerning Demonstration of Comparability of Human Biologic Products, Including Therapeutic Biotechnology-derived Products (April 1996)—CBER and CDER –Guidance on Comparability Protocols: CMC Information (Draft February 2003)—CDER, CBER, CVM Menotropins 505(j) approval/court cases Draft 505(b)(2) guidance/citizen petitions (draft 1999) Omnitrope approval—505(b)(2), May 31, 2006 Nature Reviews Drug Discovery 6 437 2007 CDER Testimony March 26, 2007 FDA Presentations –Deputy Director/Office of Pharmaceutical Science/September 2007 –Office of Biotechnology Products/Office of Pharmaceutical Science/September 2007

8.  BPCIA: 2009  Public Hearing: November 2010  NEJM Article: August 2011  Guidances: February 2012  Public Hearing:May 2012 –Demonstrating interchangeability –Obtaining reference product exclusivity –Naming issues –Clinical pharmacology evaluation of biosimilars –Additional topics FDA Timeline

9. FDA Guidances Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Quality Considerations in Demonstrating Biosimilarity to a Reference Product Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 February 2012

10.  Title VII—IMPROVING ACCESS TO INNOVATIVE MEDICAL THERAPIES  Subtitle A—Biologics Price Competition and Innovation  Section 7001. Short Title Biologics Price Competition and Innovation Act of 2009  Section 7002. Approval Pathway for Biosimilar Biological Products (a) Licensure of Biological Products as Biosimilar or Interchangeable- Section 351 of the Public Health Service Act (42 U.S.C. 262) is amended— –‘(k) Licensure of Biological Products as Biosimilar or Interchangeable (1) IN GENERAL – Any person may submit an application for licensure of a biologic product under this section. (2) CONTENT (3) EVALUATION BY THE SECRETARY (4) SAFETY STANDARDS FOR DETERMINING INTERCHANGEABILITY (5) GENERAL RULES (6) EXCLUSIVITY FOR FIRST INTERCHANGEABLE BIOLOGICAL PRODUCT (7) EXCLUSIVITY FOR REFERENCE PRODUCT (8) GUIDANCE DOCUMENTS –(l)Patents Patient Protection and Affordable Care Act

11.  (A) IN GENERAL –(i) REQUIRED INFORMATION-An application submitted under this subsection shall include information demonstrating that- (I) the biological product is biosimilar to a reference product based on data derived from— –(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinical inactive components; –(bb) animal studies (including assessment of toxicity); and –(cc) A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product. BPCIA and USP (1)

12. (II) the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use precribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product; (III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biologic product have been previously approved for the reference product; (IV) the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; and (V) the facility in which the biologic product is manufactured, processed, packed, or held meets standards designed to assure that the biologic product continues to be safe, pure, and potent. –(ii) DETERMINATION BY SECRETARY- The Secretary may determine, in the Secretary’s discretion, that an element described in clause (i)(I) is unnecessary in an application submitted under this subsection. –(iii) ADDITIONAL INFORMATION- An application submitted under this subsection— (I) shall include publicly-available information regarding the Secretary’s previous determination that the reference product is safe, pure, and potent; and (II) may include any additional information in support of the application, including publicly available information with respect to the reference product or another biological product.  (B) INTERCHANGEABILITY- An application (or a supplement to an application) submitted under this subsection may include information demonstrating that the biological product meets the standards described in paragraph (4). BPCIA and USP (2)

13.  Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that— –(A) the biologic product— (i) is biosimilar to the reference product; and (ii) can be expected to produce the same clinical result as the reference product in any given patient; and –(B) for a biological product that is administrated more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. BPCIA and IBE Individual Bioequivalence: Bioavailability of the new formulation is sufficiently close to that of the standard in most individuals. … When switching a patient [between formulations] want reasonable assurance that the patient will get the same efficacy.. individual bioequivalence is required Anderson & Hauck, 1990, JPB

14. Current Biologic Products in the Market From Kozlowski et al., NEJM 265;5, 2011

15.  BPCI  USP  Summary Topics

16. An Early USP Monograph

17. FDC Act : Section 501(b) - Adulteration  A drug or device shall be deemed to be adulterated if it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium.  Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium…

18. 2010–2015 USP Council of Experts 18

19. Biologics Standards

20. Horizontal Standards

21.  BPCI  USP  Summary Topics

22. Biologics In India

24. IU Result Primary Reference Measurement Procedure USP Compendial Procedure Manufacturer’s reference measurement procedure Manufacturer’s working measurement procedure Routine measurement procedure WHO Global Primary Reference Material Manufacturer’s house standard USP National Primary Reference Standard Manufacturer’s working standard Manufacturer’s product sample Measurement Hierarchy MaterialsProcedures Metrology: Towards a Global Understanding The Ideal State

26. Practitioners and Patients Naming –Ingredient: INN (USAN in US) –Product: FDA and USP –Switching prevented by different names –USP can name product without ‘alphas’ Comparable and interchangeable—relates to risks: who will explain?; who will understand? Who controls: payor, physician (with detailing); health care system/pharmacist (interchangeable) ?Orange Book Different administration techniques and labeling