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

3. Biologics 101

4. Role of Biotechnology in Medicine HIV/AIDS Some antiretroviral therapies like Infuvirtide (Fuzeon) stop the HIV virus from infecting cells while others treat HIV- related anemia and other complications. Advancements in science have increased the number of biotechnology products, revolutionizing the diagnosis, prevention, cure and management of many serious diseases. DIABETES Synthetically made Human insulin was made available in the 1980’s. Before then, it was made from cows and pigs. 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. CANCER Several biologics including this image of Trastuzumab (a monoclonal antibody) treat cancers. 4

5. 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) ProductManufacturerCondition HumulinR (Insulin Injection, Human Recombinant) Eli LillyDiabetes Betaseron (Interferon beta-1b)BayerMultiple Sclerosis Genotropic (Somatropin)PfizerChildren with growth hormone deficiency; Prader-Willi syndrome, girls with Turner syndrome Follistim (Follitropin Beta)OrganonInfertility NovSeven (Coagulation Factor VIIa)Novo NordiskHemophilia Enbrel (Etanercept)AmgenRheumatoid Arthritis, Psoriasis Epogen (Epeotin alfa)AmgenAnemia caused by chronic kidney disease Rituxan (Rituximab)GenentechNon-Hodgkin’s lymphoma, Rheumatoid Arthritis Humira (Adalimumab injection)Abbot LabsRheumatoid Arthritis, Crone’s disease, ankylosing spondylitis, psoriatic arthritis Erbitux (Cetuximab injection)Bristol-Meyers Squibb Head & Neck Cancer, Colorectal Cancer Pegasys (Peginterferon alfa-2a)RocheHepatitis C, Hepatitis B Herceptin (Trastuzumab injection)GenentechMetastatic Breast Cancer Avastin (Bevacizumab)GenentechColorectal Cancer, Lung Cancer, Metastatic Breast Cancer, Gliobastoma, Metastatic Kidney Cancer

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

7. 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 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

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

11. 11 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

12. 12 Source: Bilao LLC, 2008 Small Differences

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

14. 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*

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 15 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 16 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 prescription2) Pharmacist is allowed, or required, to provide a different medicine to the patient X

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

20. Is biologic substitution [no doctor involvement] scientifically appropriate? X NEVER Different medicine Different molecule Different safety and efficacy profile X 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? 1 st biosimilars 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 1.Substitution should only occur when FDA has designated a biosimilar “interchangeable” 2.The prescribing physician should be notified when a substitution has occurred. 3.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 26 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 27 Confidence interval is + or - 5%

28. 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 29 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