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

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Presentation on theme: "Biosimilars in Canada: A Perspective from Innovative Industry Karen A. Burke, Ph.D. Director, Regulatory Affairs and Safety Amgen Canada Montreal Forum."— Presentation transcript:

1 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

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

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

4 Background

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

6 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.

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

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

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

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

11 EU developments

12 Legislative Regulatory Framework Regulatory Framework Commercial Regulatory Framework Regulatory Framework Commercial Regulatory Framework Regulatory Framework Legislative? Commercial Biosimilars/SEBs have been in Europe for the past few years Legislative

13 European Medicines Agency scientific guidelines for biosimilars 1 Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Nonclinical & Clinical Issues TITLEMAIN MESSAGES Recombinant Human Erythropoietin Recombinant Human G-CSF Recombinant Human Insulin Recombinant Human Growth Hormone  Similar, but not identical  Justify any differences  Greater differences require more clinical data  Equivalent efficacy  Similar safety (not worse)  Similar immunogenic potential  Generic standards do not apply  Actual non-clinical and clinical requirements  Study designs, post-marketing commitments etc. 1

14  Drug substance –Manufacture –Characterisation –Control –Reference standard –Container –Stability  Drug product –Description –Development –Manufacture –Control –Reference standard –Container –Stability  Pharmacology –Primary pharm. –Secondary pharm. –Safety pharm. –Interactions  Pharmacokinetics –ADME –Interactions  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 NonclinicalClinical Typical Biologic new drug regulatory file

15  Drug substance –Manufacture –Characterisation –Control –Reference standard –Container –Stability  Drug product –Description –Development –Manufacture –Control –Reference standard –Container –Stability +Analytical comparison with reference product  Pharmacology –Primary pharm. –Secondary pharm. –Safety pharm. –Interactions  Pharmacokinetics –ADME –Interactions  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 Chemistry/Manufacturing NonclinicalClinical Biosimilar regulatory file

16 EU Developments Six approved; 1 rejected; 3 withdrawn; plus 1 positive opinion Trade NameGeneric/Common Name Owner of Trade Name Reference Product DecisionDecision Date Omnitrope ® somatropinSandozGenotropin ® ApprovedApril 12, 2006 Valtropin ® somatropinBioPartnersHumatrope ® ApprovedApril 24, 2006 Alpheon ® interferon alfa-2aBioPartnersRoferon-A ® RejectedJune 28, 2006 Binocrit ® Epoetin alpha Hexal ® Abseamed ® epoetin alfaSandoz Hexal Medice Eprex ® ApprovedAug. 28, 2007 Retacrit ® Silapo ® epoetin zetaHospira Stada Eprex ® ApprovedDec. 18, 2007 Insulin Rapid Marvelsoluble insulinMarvelHumulin ® WithdrawnJan. 16, 2008 Insulin Long Marvelisophane insulinMarvelHumulin ® WithdrawnJan. 16, 2008 Insulin 30/70 Mix Marvelbiphasic insulinMarvelHumulin ® WithdrawnJan. 16, 2008 Tevagrastim ® Ratiograstim ® Filgrastim Ratiopharm ® Biograstim ® filgrastimTeva Ratiopharm Ratiopharm CT Arzneimittel Neupogen ® ApprovedSep. 18, 2008 Zarzio ® Filgrastim Hexal ® filgrastimSandoz Hexal Neupogen ® ApprovedFeb. 6, 2009 Nivestim ® filgrastimHospiraNeupogen ® Positive opinion Mar. 19, 2010

17 Clinical Testing is needed to determine efficacy and patient safety  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 Omnitrope (somatropin) 2 Reference product: Genotropin (Pfizer)  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 Alpheon (interferon alfa-2a) 3 Reference product: Roferon-A (Roche) APPROVED REJECTED European Medicines Agency Review Practical experience from Europe informs the SEB discussion elsewhere

18 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

19 US developments

20 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.”

21 US healthcare reform legislation passed March 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. One aspect was a pathway for biosimilar approvals

22 Canada developments

23 Legislative Regulatory Framework Regulatory Framework Commercial Regulatory Framework Regulatory Framework Commercial Regulatory Framework Regulatory Framework Legislative? Commercial Canada is unique in establishing a regulatory framework without new biosimilar-specific legislation or regulations April 22, 2009 Health Canada approves the first biosimilar in Canada: Sandoz’ Omnitrope (somatropin) Legislative

24 Health Canada’s Development of a Regulatory Approval Pathway for SEBs –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 “Fact Sheet” issued Draft guidance issued for comment Final Guidance Issued Face-to-Face Consultation Numerous opportunities for dialogue Written comments always welcomed Numerous opportunities for dialogue Written comments always welcomed 2 nd draft issued for comment

25 Considerations Moving Forward

26  Post-approval studies are a fundamental basis of biosimilar approval  Repeated changes would confound data  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  Theoretical potential for systematic lowering of immune tolerance  Subtle potency or safety differences may have clinical consequences  11 ESAs in EU  Repeated changes would confound long- term safety data  Repeated or undocumented changes could compromise traceability Reliable data for post- approval studies Physician opinion or Different approved clinical use Uncertain clinical consequences of repeated switching Accurate and Clear Pharmacovigilance “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, Considerations Moving Forward How to ensure this is understood by ALL participants in the healthcare system?

27 Europe is Tackling the “Traceability” Challenge of ESAs after the Fact  Eprex ® (epoetin alfa)  NeoRecormon ® (epoetin beta)  Aranesp ® (darbepoetin alfa)  Eprex ® (epoetin alfa)  NeoRecormon ® (epoetin beta)  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) Can our current systems in Canada manage this?  = 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 * Marketing Authorization Application

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

29  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 In Conclusion Patient safety must always remain the highest priority


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