Biosimilars in Canada: A Perspective from Innovative Industry

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.
•  

3
Overview

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

4
Background
5
Biologic versus Small Molecule

• Larger molecular sizeand weight than small
  molecules (traditional pharmaceuticals)
• Derived from living organisms
• Each cell line is unique
• Difficult to produce and replicate

Sensipar (chemical drug)Small molecular size
(weight 393)
Enbrel (protein)Immense molecular size
(weight 150,000)
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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.

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When is The Same Not the Same?
Images of EPO alfa purported to be the same,
made throughout the world.
8
Typical Protein Production ProcessDifferent
manufacturers will have different processes
START
END
Typical Protein Production Process
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Unwanted Immunogenicity
Patients
Proteins

• Induce antibodies

No effect
Cross-react with native protein and induce
adverse reactions e.g., EPO
Neutralise biological effects and compromise
further therapy e.g., Factor VIII, GM-CSF
Alter Pharmaco- kinetics
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Whats In A Name?
Follow-on Biologics(FOB)
Follow-on Protein Products (FOPP)
Subsequent Entry Biologics(SEB)
Similar Biotherapeutic Products (SBP)
Biosimilars
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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
Regulatory Framework
Legislative
Commercial
Regulatory Framework
Legislative?
Commercial
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European Medicines Agency scientific guidelines
for biosimilars1
TITLE MAIN MESSAGES

• Generic standards do not apply

Guideline on Similar Biological Medicinal Products

• 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 HumanG-CSF
Recombinant HumanInsulin
Recombinant Human Growth Hormone
1 http//www.emea.europa.eu/htms/human/humanguide
lines/multidiscipline.htm
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Typical Biologic new drug regulatory file
Chemistry/manufacturing
Nonclinical
Clinical

• 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

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Biosimilar regulatory file
Chemistry/Manufacturing
Nonclinical
Clinical

• 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

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EU DevelopmentsSix approved 1 rejected 3
withdrawn plus 1 positive opinion
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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
REJECTED
APPROVED
Practical experience from Europe informs the SEB
discussion elsewhere
2. http//www.emea.europa.eu/humandocs/Humans/EPA
R/omnitrope/omnitrope.htm
3. http//www.emea.europa.eu/humandocs/PDFs/EPAR/
alpheon/H-585-RAR-en.pdf
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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/7456206e
n.pdf
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US developments
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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.

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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.

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Canada developments
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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
Regulatory Framework
Legislative
April 22, 2009 Health Canada approves the first
biosimilar in Canada Sandoz Omnitrope
(somatropin)
Commercial
Regulatory Framework
Legislative?
Commercial
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Health Canadas Development of a Regulatory
Approval Pathway for SEBs
Fact Sheet issued
Draft guidance issued for comment
Final Guidance Issued
Face-to-Face Consultation
2nd draft issued for comment
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 implementationwill be
key
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Considerations Moving Forward
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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
Reliable data for post-approval studies
Physician opinion or Different approved clinical
use
Uncertain clinical consequences of repeated
switching
Accurate and Clear Pharmacovigilance

• 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

How to ensure this is understood by ALL
participants in the healthcare system?
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Europe is Tackling the Traceability Challenge
of ESAs after the Fact
1998
2001
2009

• 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)

• 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 manufacturers product distinct name
• Manufacturers lot number

Can our current systems in Canada manage this?
Marketing Authorization Application
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A Possible Solution Australian approach

• A distinct name was assigned clearly
  differentiating from epoetin alfa
• This would be highly useful to overcome
  pharmacovigilance challenges

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In Conclusion

• Though some concerns remain, Canadas 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