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. 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

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

4. Background

5. 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)

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.
Amgen Corporate Template 6

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

8. 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

9. 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

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

11. EU developments

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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. 3.

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 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

22. Canada developments

23. 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

24. 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
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

25. Considerations Moving Forward

26. 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?

27. 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

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. 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