Biosimilars in Canada: A Perspective from Innovative Industry Karen A. Burke, Ph.D. Director, Regulatory Affairs and Safety Amgen Canada Montreal Forum Pharmaceutical Discussions May 28, 2010

Disclaimer The comments provided here are solely those of the presenter and are not necessarily reflective of the positions, policies and practices of Amgen Inc.   2

Overview Background – biologics and subsequent entry biologics / biosimilars Developments worldwide EU US Canada Considerations moving forward

Background

Biologic versus “Small Molecule” Sensipar ® (chemical drug) Small molecular size (weight = 393) Larger molecular size and weight than “small molecules” (traditional pharmaceuticals) Derived from living organisms Each cell line is unique Difficult to produce and replicate Enbrel ® (protein) Immense molecular size (weight = 150,000)

What is an SEB / Biosimilar? An SEB is biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug. Amgen Corporate Template 6

When is “The Same” Not the Same? Images of EPO alfa purported to be “the same”, made throughout the world.

Typical Protein Production Process Different manufacturers will have different processes Will result in different biophysical characteristics Different downstream processing START END Probably same gene sequence Typical Protein Production Process Different fermentation/culture conditions Different vector Different host cell

Unwanted Immunogenicity Patients Proteins Induce antibodies No effect Neutralise biological effects and compromise further therapy e.g., Factor VIII, GM-CSF Cross-react with native protein and induce adverse reactions e.g., EPO Alter Pharmaco- kinetics

What’s In A Name? Follow-on Protein Products (FOPP) Follow-on Biologics (FOB) Subsequent Entry Biologics (SEB) Biosimilars Similar Biotherapeutic Products (SBP)

EU developments

Biosimilars/SEBs have been in Europe for the past few years Legislative Regulatory Framework Commercial 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Legislative Regulatory Framework Commercial Regulatory Framework Legislative? Commercial

European Medicines Agency scientific guidelines for biosimilars1 TITLE MAIN MESSAGES Guideline on Similar Biological Medicinal Products Generic standards do not apply Similar, but not identical Justify any differences Greater differences require more clinical data Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues Equivalent efficacy Similar safety (not worse) Similar immunogenic potential Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Nonclinical & Clinical Issues Actual non-clinical and clinical requirements Study designs, post-marketing commitments etc. Recombinant Human Erythropoietin Recombinant Human G-CSF Recombinant Human Insulin Recombinant Human Growth Hormone 1 http://www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm

Typical Biologic new drug regulatory file Chemistry/manufacturing Nonclinical Clinical Drug substance Manufacture Characterisation Control Reference standard Container Stability Drug product Description Development Pharmacology Primary pharm. Secondary pharm. Safety pharm. Interactions Pharmacokinetics ADME Toxicology Single dose Repeat dose Genotoxicity Carcinogenicity Reproduction Local tolerance Pharmacology Pharmacokinetics/ Pharmacodynamics Single dose Repeat dose Special populations Efficacy and safety Dose finding Schedule finding Pivotal Indication 1 Indication 2 Indication 3 Indication 4 Immunogenicity Risk Management Plan Post-marketing studies

Chemistry/Manufacturing Biosimilar regulatory file Chemistry/Manufacturing Nonclinical Clinical Drug substance Manufacture Characterisation Control Reference standard Container Stability Drug product Description Development Analytical comparison with reference product Pharmacology Primary pharm. Secondary pharm. Safety pharm. Interactions Pharmacokinetics ADME Toxicology Single dose Repeat dose Genotoxicity Carcinogenicity Reproduction Local tolerance Pharmacology Pharmacokinetics/ Pharmacodynamics Single dose Repeat dose Special populations Efficacy and safety Dose finding Schedule finding Pivotal Indication 1 Indication 2 Indication 3 Indication 4 Clinical comparison with reference product Immunogenicity Risk Management Plan Post-marketing studies

EU Developments Six approved; 1 rejected; 3 withdrawn; plus 1 positive opinion Trade Name Generic/Common Name Owner of Trade Name Reference Product Decision Decision Date Omnitrope® somatropin Sandoz Genotropin® Approved April 12, 2006 Valtropin® BioPartners Humatrope® April 24, 2006 Alpheon® interferon alfa-2a Roferon-A® Rejected June 28, 2006 Binocrit® Epoetin alpha Hexal® Abseamed® epoetin alfa Sandoz Hexal Medice Eprex® Aug. 28, 2007 Retacrit® Silapo® epoetin zeta Hospira Stada Dec. 18, 2007 Insulin Rapid Marvel soluble insulin Marvel Humulin® Withdrawn Jan. 16, 2008 Insulin Long Marvel isophane insulin Insulin 30/70 Mix Marvel biphasic insulin Tevagrastim® Ratiograstim® Filgrastim Ratiopharm® Biograstim® filgrastim Teva Ratiopharm Ratiopharm CT Arzneimittel Neupogen® Sep. 18, 2008 Zarzio® Filgrastim Hexal® Sandoz Hexal Feb. 6, 2009 Nivestim® Hospira Positive opinion Mar. 19, 2010

Clinical Testing is needed to determine efficacy and patient safety Omnitrope (somatropin)2 Reference product: Genotropin (Pfizer) Alpheon (interferon alfa-2a)3 Reference product: Roferon-A (Roche) 57% of patients developed antibodies to Omnitrope in the first study Problem was residual host-cell protein Re-developed purification process Conducted a second phase 3 study Antibody levels reduced Lower quality Not as pure as Roferon-A Lower efficacy than Roferon-A More patients relapsed Safety profile worse than Roferon-A More side-effects European Medicines Agency Review European Medicines Agency Review APPROVED REJECTED Practical experience from Europe informs the SEB discussion elsewhere 2. http://www.emea.europa.eu/humandocs/Humans/EPAR/omnitrope/omnitrope.htm 3. http://www.emea.europa.eu/humandocs/PDFs/EPAR/alpheon/H-585-RAR-en.pdf

Substitution EU states are preventing automatic substitution Substitution by pharmacist without physician consent has been rejected by more than half of the EU member states – including France, Germany, UK, Italy and Spain http://www.emea.europa.eu/pdfs/human/pcwp/7456206en.pdf

US developments

President Obama speech to American Medical Association – June 2009 On Health Care Reform: “…we need to introduce generic biologic drugs into the marketplace. These are drugs used to treat illnesses like anemia. But right now, there is no pathway at the FDA for approving generic versions of these drugs.”

US healthcare reform legislation passed March 2010 One aspect was a pathway for biosimilar approvals Some requirements specified in text of legislation: Information showing same mechanism of action for proposed condition(s) of use (to the extent MOA is known for reference product) Information showing same dosage form, strength, and route of administration Next, the FDA will determine how to bring this new pathway to implementation. 21

Canada developments

Canada is unique in establishing a regulatory framework without new biosimilar-specific legislation or regulations Legislative Regulatory Framework Commercial 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Legislative Regulatory Framework April 22, 2009 Health Canada approves the first biosimilar in Canada: Sandoz’ Omnitrope (somatropin) Commercial Regulatory Framework Legislative? Commercial

Health Canada’s Development of a Regulatory Approval Pathway for SEBs “Fact Sheet” issued Draft guidance issued for comment Face-to-Face Consultation 2nd draft issued for comment Final Guidance Issued 2005 2006 2007 2008 2009 2010 Numerous opportunities for dialogue Written comments always welcomed Open consultation Stakeholder comments appear to be taken into consideration Final guidance appears science-based, with attention to patient safety Clearly, application and implementation will be key

Considerations Moving Forward

Considerations Moving Forward “It is noteworthy that once approved, an SEB, like any new drug, cannot be substituted or used interchangeably with the reference product used in the studies.” Health Canada letter to BIOTECanada, June 23, 2009 1 2 3 4 Reliable data for post-approval studies Uncertain clinical consequences of repeated switching Physician opinion or Different approved clinical use Accurate and Clear Pharmacovigilance Post-approval studies are a fundamental basis of biosimilar approval Repeated changes would confound data Theoretical potential for systematic lowering of immune tolerance Subtle potency or safety differences may have clinical consequences Physicians may specifically choose one biologic over another Different biologics may have different labels e.g. EU Sandoz EPO has no sc use in renal anemia 11 ESAs in EU Repeated changes would confound long-term safety data Repeated or undocumented changes could compromise traceability How to ensure this is understood by ALL participants in the healthcare system?

Europe is Tackling the “Traceability” Challenge of ESAs after the Fact 1998 2001 2009 Eprex® (epoetin alfa) NeoRecormon® (epoetin beta) Eprex® (epoetin alfa) NeoRecormon® (epoetin beta) Aranesp® (darbepoetin alfa) Eprex® (epoetin alfa) NeoRecormon® (epoetin beta) Aranesp® (darbepoetin alfa) Dynepo® (epoetin delta) Mircera® (peg-epoetin beta) Ratioepo® (epoetin theta) Biopoin® (epoetin theta) Binocrit® (epoetin alfa) Abseamed® (epoetin alfa) Epoetin alfa Hexal (epoetin alfa) Silapo® (epoetin zeta) Retacrit® (epoetin zeta) = Full MAA* = Biosimilar MAA Three levels of information are needed for biologics and biosimilars to allow health authorities and manufacturers to trace an event to its root cause: Drug class Individual manufacturer’s product – distinct name Manufacturer’s lot number Can our current systems in Canada manage this? * Marketing Authorization Application

A Possible Solution – Australian approach A distinct name was assigned – clearly differentiating from epoetin alfa This would be highly useful to overcome pharmacovigilance challenges

Patient safety must always remain the highest priority In Conclusion Though some concerns remain, Canada’s SEB regulatory environment is evolving well Further considerations should include education of stakeholders on criticality of knowing what was prescribed and what was dispensed distinct naming (INNs) Our approach should be always be supported by science Patient safety must always remain the highest priority