Biosimilars in Canada: A Perspective from Innovative Industry Karen A. Burke, Ph.D.Director, Regulatory Affairs and SafetyAmgen Canada

Montreal Forum Pharmaceutical DiscussionsMay 28, 2010

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

Background – biologics and subsequent entry biologics / biosimilars

Developments worldwide– EU– US– Canada

Considerations moving forward

Overview

Background

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

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.

Images of EPO alfa purported to be “the same”, made throughout the world.

When is “The Same” Not the Same?

Typical Protein Production Process

Probably same gene sequence

START

Different vector Different host cell

Different fermentation/culture

conditions

Different downstream processing

Typical Protein Production ProcessDifferent manufacturers will have different processes

EN

D

Will result in different biophysical characteristics

Unwanted Immunogenicity

Induce antibodies

Proteins Patients

AlterPharmaco-

kinetics

Cross-react with native protein and induce adverse

reactions e.g., EPO

No effect

Neutralise biologicaleffects and compromise

further therapy e.g., Factor VIII, GM-CSF

What’s In A Name?

Follow-on Biologics

(FOB)

Similar Biotherapeuti

c Products (SBP)

Subsequent Entry

Biologics(SEB)

Follow-on Protein

Products (FOPP)

Biosimilars

EU developments

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Legislative Legislative Regulatory FrameworkRegulatory Framework CommercialCommercial

Regulatory FrameworkRegulatory Framework

Commercial Commercial

RegulatoryFrameworkRegulatoryFramework Legislative? Legislative? Commercial

Biosimilars/SEBs have been in Europe for the past few years

Legislative Legislative

European Medicines Agency scientific guidelines for biosimilars1

Guideline on Similar Biological Medicinal Products

Guideline on Similar Biological Medicinal ProductsContaining Biotechnology-Derived Proteins as Active

Substance: Quality Issues

Guideline on Similar Biological Medicinal ProductsContaining Biotechnology-Derived Proteins as Active

Substance: Nonclinical & Clinical Issues

TITLE MAIN MESSAGES

Recombinant Human

Erythropoietin

Recombinant HumanG-CSF

Recombinant HumanInsulin

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 http://www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm

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 Nonclinical Clinical

Typical Biologic new drug regulatory file

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 Nonclinical Clinical

Biosimilar regulatory file

EU DevelopmentsSix approved; 1 rejected; 3 withdrawn; plus 1 positive opinion

Trade Name Generic/Common Name

Owner of Trade Name

ReferenceProduct

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 SandozHexalMedice

Eprex® Approved Aug. 28, 2007

Retacrit® Silapo®

epoetin zeta HospiraStada

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 TevaRatiopharmRatiopharmCT Arzneimittel

Neupogen® Approved Sep. 18, 2008

Zarzio® Filgrastim Hexal®

filgrastim SandozHexal

Neupogen® Approved Feb. 6, 2009

Nivestim® filgrastim Hospira Neupogen® Positive opinion

Mar. 19, 2010

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

European Medicines Agency Review

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

http://www.emea.europa.eu/pdfs/human/pcwp/7456206en.pdf

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

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

21

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

Canada developments

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Legislative Legislative Regulatory FrameworkRegulatory Framework CommercialCommercial

Regulatory FrameworkRegulatory Framework

Commercial Commercial

RegulatoryFrameworkRegulatoryFramework Legislative? Legislative? Commercial

Canada is unique in establishing a regulatory framework without new biosimilar-specific legislation or regulations

April 22, 2009Health Canada approves the first biosimilar in Canada: Sandoz’ Omnitrope (somatropin)

Legislative Legislative

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 implementationwill be key

Clearly, application and implementationwill be key

2005 2006 2007 2008 2009 2010

“Fact Sheet” issued

“Fact Sheet” issued

Draft guidance issued for comment

Draft guidance issued for comment

Final Guidance Issued

Final Guidance Issued

Face-to-Face ConsultationFace-to-Face Consultation

• Numerous opportunities for dialogue• Written comments always welcomed • Numerous opportunities for dialogue• Written comments always welcomed

2nd draft issued for comment

2nd draft issued for comment

Considerations Moving Forward

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 orDifferent approved

clinical use

Uncertain clinical consequences of

repeated switchingAccurate 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, 2009

1 2 3 4

Considerations Moving Forward

How to ensure this is understood by ALL participants in the healthcare system?

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

1998 2001 2009

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

A Possible Solution – Australian approach

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

challenges

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