Transcript Q1 Business Update

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.
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.
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
START
Different
downstream
processing
END
Probably same
gene sequence
Typical Protein Production Process
Different vector
Different host cell
Different
fermentation/culture
conditions
Unwanted Immunogenicity
Proteins
Patients
Induce antibodies
Neutralise biological
effects and compromise
further therapy
e.g., Factor VIII, GM-CSF
Alter
Pharmacokinetics
No effect
Cross-react with native
protein and induce adverse
reactions
e.g., EPO
What’s In A Name?
Follow-on
Protein
Products
(FOPP)
Follow-on
Biologics
(FOB)
Subsequent
Entry
Biologics
(SEB)
Biosimilars
Similar
Biotherapeuti
c 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
Commercial
Legislative?
European Medicines Agency scientific
guidelines for biosimilars1
TITLE
MAIN MESSAGES
Guideline on Similar Biological Medicinal Products
 Generic standards do not apply
Guideline on Similar Biological Medicinal Products
Containing Biotechnology-Derived Proteins as Active
Substance: Quality Issues
 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: Nonclinical & Clinical Issues
 Equivalent efficacy
 Similar safety (not worse)
 Similar immunogenic potential
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
 Actual non-clinical and clinical
requirements
 Study designs, post-marketing
commitments etc.
Typical Biologic new drug regulatory file
Nonclinical
Chemistry/manufacturing

Drug substance
–
–
–
–
–
–

Manufacture
Characterisation
Control
Reference standard
Container
Stability

–
–
–
–

Description
Development
Manufacture
Control
Reference standard
Container
Stability

Primary pharm.
Secondary pharm.
Safety pharm.
Interactions

Pharmacology

Pharmacokinetics/
Pharmacodynamics
–
–
–
Pharmacokinetics
–
–
Drug product
–
–
–
–
–
–
–
Pharmacology
Clinical
ADME
Interactions

–
–
–
–
–
–
Single dose
Repeat dose
Genotoxicity
Carcinogenicity
Reproduction
Local tolerance
Efficacy and safety
–
–
–
Toxicology
Single dose
Repeat dose
Special populations
Dose finding
Schedule finding
Pivotal
• Indication 1
• Indication 2
• Indication 3
• Indication 4

Immunogenicity

Risk Management Plan
–
Post-marketing
studies
Biosimilar regulatory file
Nonclinical
Chemistry/Manufacturing

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
Clinical

Pharmacology

Pharmacokinetics/
Pharmacodynamics
–
–
–

–
–
–
–
–
–
Efficacy and safety
–
–
–
Toxicology
Single dose
Repeat dose
Genotoxicity
Carcinogenicity
Reproduction
Local tolerance
Single dose
Repeat dose
Special populations
+
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®
somatropin
BioPartners
Humatrope®
Approved
April 24, 2006
Alpheon®
interferon alfa-2a
BioPartners
Roferon-A®
Rejected
June 28, 2006
Binocrit®
Epoetin alpha Hexal®
Abseamed®
epoetin alfa
Sandoz
Hexal
Medice
Eprex®
Approved
Aug. 28, 2007
Retacrit®
Silapo®
epoetin zeta
Hospira
Stada
Eprex®
Approved
Dec. 18, 2007
Insulin Rapid Marvel
soluble insulin
Marvel
Humulin®
Withdrawn
Jan. 16, 2008
Insulin Long Marvel
isophane insulin
Marvel
Humulin®
Withdrawn
Jan. 16, 2008
Insulin 30/70 Mix Marvel
biphasic insulin
Marvel
Humulin®
Withdrawn
Jan. 16, 2008
Tevagrastim®
Ratiograstim®
Filgrastim Ratiopharm®
Biograstim®
filgrastim
Teva
Ratiopharm
Ratiopharm
CT Arzneimittel
Neupogen®
Approved
Sep. 18, 2008
Zarzio®
Filgrastim Hexal®
filgrastim
Sandoz
Hexal
Neupogen®
Approved
Feb. 6, 2009
Nivestim®
filgrastim
Hospira
Neupogen®
Positive
opinion
Mar. 19, 2010
Clinical Testing is needed to determine
efficacy and patient safety
Omnitrope (somatropin)2
Alpheon (interferon alfa-2a)3
Reference product: Genotropin (Pfizer)
Reference product: Roferon-A (Roche)
 57% of patients developed antibodies
to Omnitrope in the first study
 Lower quality
 Problem was residual host-cell
protein
 Lower efficacy than Roferon-A
 Re-developed purification process
 Conducted a second phase 3 study
– Not as pure as Roferon-A
– More patients relapsed
 Safety profile worse than Roferon-A
– More side-effects
– Antibody levels reduced
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
April 22, 2009
Health Canada
approves the first
biosimilar in Canada:
Sandoz’ Omnitrope
(somatropin)
Legislative
Regulatory
Framework
Commercial
Regulatory
Framework
Commercial
Legislative?
Health Canada’s Development of a
Regulatory Approval Pathway for SEBs
“Fact Sheet”
issued
2005
Draft guidance issued
for comment
2006
2007
Face-to-Face
Consultation
2nd draft issued
for comment
2008
Final Guidance
Issued
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 postapproval 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
 Theoretical potential
for systematic
lowering of immune
tolerance
 Physicians may
specifically choose
one biologic over
another
 Repeated changes
would confound data
 Subtle potency or
safety differences
may have clinical
consequences
 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 longterm 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
 Eprex® (epoetin alfa)
 NeoRecormon® (epoetin beta)
2001
 Eprex® (epoetin alfa)
 NeoRecormon® (epoetin beta)
 Aranesp® (darbepoetin alfa)
 = Full MAA*
– = Biosimilar MAA
2009







–
–
–
–
–
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)
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
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