Biosimilars : A Framework to Ensure Safe Substitution

1. Biosimilars: A Framework to Ensure Safe Substitution Richard Dolinar, MD Endocrinologist, Chairman of the Alliance for Safe Biologic Medicines Presented at the University of Rhode Island College of Pharmacy December 13, 2012

2. The Alliance for Safe Biologic Medicines • Patients • Physicians • Scientists • CROs • Innovator industry ASBM MEMBERS

3. Biologics 101

4. Role of Biotechnology in Medicine Advancements in science have increased the number of biotechnology products, revolutionizing the diagnosis, prevention, cure and management of many serious diseases. RHEUMATOID ARTHRITIS This disorder attacks healthy parts of the body, including its own joints, causing swelling, pain and even disfigurement. New biotech drugs target the affected area without suppressing the entire immune system. HIV/AIDS Some antiretroviral therapies like Infuvirtide (Fuzeon) stop the HIV virus from infecting cells while others treat HIV-related anemia and other complications. DIABETES Synthetically made Human insulin was made available in the 1980’s. Before then, it was made from cows and pigs. CANCER Several biologics including this image of Trastuzumab(a monoclonal antibody) treat cancers.

5. Examples of Biologic Medicines By 2014, it is projected that six out of the 10 top-selling drugs in the U.S. will be biologics, some of which may face biosimilar entry. Analysis Group Health Care Consulting Bulletin (Fall/Winter 2010)

6. The differences between Chemical Drugs and Biotech Medicines you can see • BIOTECH MEDICINES: • Made by living cells-unique cell lines, from bacteria, yeast, or mammals • Heterogenous structure, difficult to characterize • Usually injected, prescribed by specialists • CHEMICAL DRUGS: • Made by chemical synthesis • Defined structure, easy to characterize • Usually taken by mouth, prescribed by general practitioner

7. Biologic vs. Chemical Medicines - Differences that Matter: 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

8. 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

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

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

11. A Highly Complex Manufacturing Process IgG1 antibody >1000 amino acids ~150,000 daltons >20,000 atoms

12. Small Differences Source: Bilao LLC, 2008

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

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

15. Creating a U.S. 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 • February 9, 2012 – FDA draft guidance issued • February 27, 2012 – ASBM hosts Capitol Hill Biosimilars Forum

16. ASBM Recommendations made at FDA May 11 Hearing • Clinical testing • Thorough evaluation and understanding of biosimilar before designation as “interchangeable” • Only biosimilars determined to be “interchangeable” should be substituted

17. Safe Substitution of Biologics

18. What is substitution? 1) Physician writes a prescription 2) Pharmacist is allowed, or required, to provide adifferent medicine to the patient X

19. Congress defined 2 different levels of biologic copies • BIOSIMILARS: • HIGHLY Similar • INTERCHANGEABLE • BIOSIMILARS: • HIGHLY Similar • SAME EFFECT in any given patient is expected • NO ADDED RISK from switching

20. Is biologic substitution [no doctor involvement] scientifically appropriate? • NEVER • Different medicine • Different molecule • Different safety and efficacy profile • NEVER • Only Similar. FDA has not approved as safe for substitution. • Highly Similar but … • Not expected to have same effect in any given patient • Not determined to have the same risk if patient is switched. • ✓SOMETIMES • FDA has determined safe for substitution • Highly Similar • Safe effect in any given patient • No greater risk if switch vs no switch • OK to switch UNLESS Dr. has specified no switching

21. Who decides if substitution is allowed? • Congress said “interchangeable” means switching without physician involvement • FDA determines if a product meets the criteria for “interchangeable” – this is a scientific decision. • States historically have decided what pharmacists are allowed to do.

22. States handle generic drug substitution in different ways • 2/3rds reference the orange book in some way • Some require substitution • Some permit substitution • Some prohibit substitution

23. When will doctors and patients face substitution questions for biologics? • 1stbiosimilars expected to be approved in 2013

24. Providing a Biosimilar-Substitution Framework for States Goal: Have legislation in place when the first biosimilars are approved in 2013 • Avoid substitution of biologics that are not designated “interchangeable” • Prevent a potentially harmful substitution from occurring

25. Principal Safeguards for State Policy • Substitution should only occur when FDA has designated a biosimilar “interchangeable” • The prescribing physician should be notified when a substitution has occurred. • The prescribing physician should be able to prevent substitution by writing “Dispense as Written” (DAW) or “Brand Medically Necessary” (BMN) instruction.

26. May 24: Physician Notification Working Group • Meeting of ASBM National Advisory Board members, most of whom are practicing physicians. • Overwhelming concern about harm to patients if prescribed product is substituted. • Outgrowth of the call was to commission a SURVEY of physicians regarding physician notification of medication switching, for use in promotion of our policies on naming and interchangeability.

27. Importance of Physician Notification of Medication Switching, with or without known risks ASBM September Survey: 376 U.S. physicians, distributed equally across: • Endocrinology • Dermatology • Oncology • Rheumatology • Nephrology • Neurology • Confidence interval is + or - 5%

28. Upcoming Pharmacist Survey • Pharmacist Survey Scheduled for January 2013 • Follow-up to ASBM’s September Physician Survey • Designed to inform our recommendations with hard data from an additional, vital constituency

29. Learn More at www.SafeBiologics.com • Issue Background • FDA Process • The EU Experience • Policy Resources • FAQs • Comments Submitted to FDA • Additional Regulatory Outreach • Recent News • Event Calendar • In the States • European Product Assessment • Reports (EPARs) for Biosimilar • Products Documents • Key Websites • Biosimilar Laws and Regulations Around The World www.SafeBiologics.com