1. Assessing Global Standards for Biologic Medicines Richard Dolinar, MD Endocrinologist Chairman of the Alliance for Safe Biologic Medicines Presented at the Center for Business Intelligence 8th Annual Biosimilars Summit March 5, 2013

2. Presentation Overview

3. 3 Global Quality Standards for Biologics in Regulated and Unregulated Markets - Why is this important? Patient safety must ALWAYS be placed first. Biosimilars must be introduced without incident, or their adoption will be undermined. Physicians require confidence in the medication they prescribe. Manufacturers should be held accountable for their products. In this global market, there should be no “EASY point of approval”, such as in an emerging market with lower standards, that can jeopardize the above principles.

4. 4 Potential Areas For Creation of Global Standards Approval Processes: Should biosimilars have to undergo clinical trials? Biosimilar Naming: Should biosimilars have unique names? Biosimilar Substitution: When? By whom?

5. 5 Approval Pathways for Biosimilars… Currently No Global Standards. 2003 EU Biosimilar Pathway 2009 Canadian Biosimilar Pathway US in the process Colombia recently proposed a 3-tier approval pathway: 1.full dossier, 2.abbreviated dossier with comparability/biosimilary demonstrated to an approved product, 3.approved in another jurisdiction w/ similar standards (which are unspecified) Brazil similar pathway to (3), limited to certain jurisdictions. Thailand has a substantial spike in Pure Red Cell Aplasia, > 30 RBC stimulating products. Which is the culprit?

6. 6 Global Standards on Naming Being Discussed WHO Guidance on Naming: WHO has been the leader on "developing, establishing and promoting international standards with respect to biological, pharmaceutical and similar products". International Nonproprietary Names (INN) facilitate the identification of pharmaceutical substances or active pharmaceutical ingredients. WHO will be discussing the need for unique names in biosimilars at the 56 th Consultation on INNs for Pharmaceutical Substances (April 15-17, 2013).

7. ASBM/FDLI Whitepaper on Biosimilar Naming, Nov. 2012 7 1.All biologics should receive distinct non- proprietary names. 2.United States Pharmacopeia (USP) should work with FDA to adapt the product monograph system to accommodate the unique attributes of structurally-related, but distinct, biologic medicines. 3.The non-proprietary name of a reference product and product/s biosimilar to it should have a common, shared root but have distinct and differentiating suffixes. 4.Products designated interchangeable should have a distinct name from the reference product for which they are considered interchangeable to facilitate accurate attribution of adverse events.

8. 8 How is substitution of biosimilars addressed? US has “interchangeability” and as a result the FDA has laid out in its draft guidance substitution guidelines that differ from those of the EMA, Health Canada, and the World Health Organization, particularly in regard to the role played by the physician. 15 U.S. States are currently considering legislation which regulates biosimilar substitution: Virginia, Indiana, Texas, Florida, North Dakota, Washington, Colorado, Arkansas, Massachusetts, Oregon, Arizona, Maryland, Pennsylvania, Utah, Illinois.

9. About ASBM

10. Founded 2010 Advisory Board consists of PATIENTS PHYSICIANS RESEARCHERS PHARMACISTS The Alliance for Safe Biologic Medicines The Four Pillars: PRIORITIZING PATIENT SAFETY over cost savings, speed, or politics LEVERAGING WHAT WE HAVE LEARNED the EU’s science-based approach PROMOTING PHARMACOVIGILANCE: holding manufacturers accountable for the quality of their product KEEPING DOCTORS RELEVANT: Physicians and their patients should determine treatment, not a third party

11. ASBM: Engaging Stakeholders to Shape the US Biosimilars Pathway 11 APRIL 16: ASBM submits Formal Comments to US FDA MAY 11: 9 ASBM members and ASBM Chairman testify at FDA Hearing JUNE: ASBM Presented at Toronto Patient Experts Conference AUGUST: 380-Physician Survey conducted on Biosimilar Naming and Interchangability SEPTEMBER: Presented at 3 Conferences in US including FDA/DIA Conference

12. Why Are New Standards Needed?

13. 13 One Example: Immunogenicity FDA released draft guidance February 2013, saying: “Immune responses to therapeutic protein products may pose problems for both patient safety and product efficacy. [Immunological adverse events] have caused sponsors to terminate the development of therapeutic protein products or limited the use of what might otherwise be effective therapies.” - FDA Center for Drug Evaluation and Research, in-PharmaTechnologist.com, 2/25/2013

14. 14 Biologic vs. Chemical Medicines: Differences SIZE: significantly larger, more complex STRUCTURE: Highly complex, minor manufacturing differences can cause adverse effects DRIFT: biologics can change with time STABILITY: Biologic medicines are sensitive to light, heat, denaturing or degradation

15. Key differences between chemical drugs and biologics Source: GenentechGenentech ASPIRIN ~180 daltons 21 atoms lgL1 ANTIBODY >1000 amino acids ~150,000 daltons >20,000 atoms SIZE HUMAN GROWTH HORMONE 191 amino acids ~22,000 daltons 3091 atoms

16. 16 Source: New England Journal of Medicines, “Developing the Nation’s Biosimilars Program,” August 4, 2011 Molecular Comparison: Aspirin vs. Biologic Monoclonal Antibody

17. 17 A Highly Complex Manufacturing Process Design the gene sequence Place gene sequence inside a vector Place vector inside a specific cell Fermentation – cells produce the protein defined by the vector Purification – removing the impurities Highly complex protein with 3 or 4 levels of structure IgG1 antibody >1000 amino acids ~150,000 daltons >20,000 atoms

18. Low risk and common change = Minimal data required Higher risk / less common changes = Maximal Data Required (Clinical Testing, Analytical and Process) *It is not scientifically possible to exactly copy biologic medicines at this time. The degree of change determines the level of risk and thus the data required to demonstrate the product remains equally safe and effective: Degree of Manufacturing Change Supplier for tubing changed Relocate equipment within same facility Relocate to new facility Manufacturing scaled up to production level New cell line New process*

19. 19 Source: Bilao LLC, 2008 Small Differences

20. 20 Source: Bilao LLC, 2008 Small Differences = Large Impact Testosterone Progesterone Estradiol

21. What are Biosimilars? Biosimilars are often referred to as “follow-on biologics” or “follow-on proteins”. Biosimilars are copies of existing trade-name biological products whose patents have expired. While “highly similar” biosimilars are not “identical” to the reference product. They do not utilize the same living cell line, production process, or raw material as the innovator drug. SIMILAR, BUT NOT IDENTICAL ≠ INNOVATOR MEDICINE EU-APPROVED BIOSIMILAR

22. Creating a US Biosimilars Pathway 1984 – Hatch-Waxman Act March 23, 2010 – Patient Protection and Affordable Care Act Biologics Price, Competition, and Innovation Act (BPCIA) November 2010 – FDA began consulting with various individuals and groups 22 February 9, 2012 – FDA draft guidance issued February 27, 2012 – ASBM hosts Capitol Hill Biosimilars Forum