implementation of a u.s. biosimilar pathway - ncsl home

8/18/2011

Amgen Corporate Template 1

Implementation of a U.S. Biosimilar Pathway And Experience in Europe

National Conference of State Legislatures

Geoffrey Eich, Amgen Inc.

Global Biosimilar Strategic Planning & Operations

Aug 7, 2011

g

Amgen Policy Discussion. Geoff Eich, 8/7/2011

Amgen believes that when you put patients first, sound policy will follow

Amgen supports a responsible, science-basedregulatory pathway for biosimilars

that meets our guiding principles of:g g p p

Patient safety Sound scientific analysis

Fair incentives for the development of new therapies

2Amgen Policy Discussion. Geoff Eich, 8/7/2011

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Biosimilars are not generics; biologics are larger & more complicated than chemical drugs

Aspirin~180 daltons

BiologicsSmall

Molecule

180 daltons21 atoms

Insulin51 amino acids~5,800 daltons788 atoms

Somatropin191 amino acids~22,000 daltons3091 atoms

IgG1 antibody>1000 amino acids

150 000 d lt

Images not to scale. Data sources: www.jtbaker.com, http://www.umass.edu/microbio/chime/antibody/abquests.htm and Genazzazi, AA et. al. (2007) Biosimilar Drugs: Concerns and Opportunities. Biodrugs 2007; 21 (6) ppg 351-356

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~150,000 daltons>20,000 atoms

The Challenge With Biosimilars Is Knowing Which Differences Matter Clinically


Biotechnology is a compilation of technologies to design, produce, purify, and analyze proteins

Molecular biology and rDNAand rDNAtechnology

Fermentation and cell culture technology

Large scale protein recovery &

purification

Reliable analytics for large proteins

Image Source: Bob Stevens Photography; Amgen Usage Rights: Unlimited world-wide usage rights for an unlimited time.


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Biochemical EngineeringCell BiologyProtein Chemistry

Protein Engineering

Biologics manufacturing requires multiple disciplines working together

Molecular Biology Process Engineering

Statistics

Industrial EngineeringBiochemistry

The Cell Drug Product

Image Source: Saputo Design, Inc.; Amgen Usage Rights: Unlimited world-wide usage rights for an unlimited time.


U.S. biosimilar pathway amends the Public Health Service Act and covers key requirements

Application Requirements

Guidance Documents Patent ProvisionsRequirements

Standard of Approval Data Protection

Documents

Transition from FDCA to PHSA

Interchangeability User Fees Medicare Part B Reimbursement

Data Source: Patient Protection and Affordable Care Act. Available at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_cong_bills&docid=f:h3590pp.txt.pdf6Amgen Policy Discussion. Geoff Eich, 8/7/2011

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The U.S. law defines new standards and terms

• Standard: Biosimilarity determined on the basis of 1) analytical studies, 2) animal studies, including toxicity, and 3) clinical studies, including immunogenicity and PK/PD sufficient to demonstrate that the product is “highly similar” to the reference product and safe pure and potent for one or more approved conditions of use

• Standard: Biosimilarity determined on the basis of 1) analytical studies, 2) animal studies, including toxicity, and 3) clinical studies, including immunogenicity and PK/PD sufficient to demonstrate that the product is “highly similar” to the reference product and safe pure and potent for one or more approved conditions of useproduct and safe, pure and potent for one or more approved conditions of use

• Definition:• The biological product is highly similar to the reference product notwithstanding

minor differences in clinically inactive components.• There are no clinically meaningful differences between the biological product and

the reference product in terms of the safety, purity, and potency of the product.

product and safe, pure and potent for one or more approved conditions of use• Definition:

• The biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components.

• There are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

‘Biosimilar’ or ‘Biosimilarity’

St d d Bi i il b t d t d th li i l lt thSt d d Bi i il b t d t d th li i l lt th• Standard: Biosimilar can be expected to produce the same clinical result as the reference product in any given patient. For products administered more than once, the risk (in terms of safety or diminished efficacy) of switching can't be greater than the risk of using the reference product alone

• Definition: For a product that meets the above standard, the biological product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product

• Standard: Biosimilar can be expected to produce the same clinical result as the reference product in any given patient. For products administered more than once, the risk (in terms of safety or diminished efficacy) of switching can't be greater than the risk of using the reference product alone

• Definition: For a product that meets the above standard, the biological product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product

‘Interchangeable’ or

‘Interchangeability’

Data Source: Patient Protection and Affordable Care Act, Public Law No; 111-148, §§ 7002(b)(2)-(3) (2010)Available at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_cong_bills&docid=f:h3590pp.txt.pdf


The European pathway was designed with science as the primary consideration

European Commission Directive J 2003

EMA & CHMP Guideline: Similar Biological Medicinal ProductsOctober 2005

Outlines requirements for Marketing Authorization Applications (MAA) based on the

June 2003Directs EMA to create a regulatory pathway for biosimilars by establishing new Annex on an application for

MA with specific dossier requirements for ‘similar biological medicinal products’

q g pp ( )demonstration of the similar nature of the two biological medicines

“Due to the complexity of biological / biotechnology-derived products the generic approach is scientifically not appropriate for these products” – EMA

Guideline on Similar Biological Medicinal Products, Section 2.1: Application of “Similar Biological Medicinal Products” Approach

Data Source: Directive 2001/83/EC OF The European Parliament. Available at http://www.emea.europa.eu/pdfs/human/pmf/2001-83-EC.pdf and European Medicines Agency Guideline on similar biological medicinal products. Available at http://www.emea.europa.eu/pdfs/human/biosimilar/043704en.pdf


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European Medicines Agency scientific guidelines have set detailed approval standards

Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance:

TOPIC KEY THEMES

Similar, but not identicalJustify any differences

Quality Issues

Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance:

Nonclinical & Clinical Issues

Greater differences require more clinical data

Equivalent EfficacySimilar safety (non-inferior)Similar immunogenic potential

Product level non-clinical andEPO G-CSF Insulin Growth

Hormone

Product level non clinical and clinical requirementsRecommended study designs, post-marketing commitments

INF-α LMWHeparin

Concept Paper: FSH

Concept Paper: INF-β

Draft Guideline:

mAb

Data Source: EMA Website. Available at http://www.ema.europa.eu/htms/human/humanguidelines/multidiscipline.htm. Interpretation of themes are those of the slide author


EMA reviews demonstrate a science-based standard

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

BinocritTM

E ti l h H l ti lfSandozH l E ® A d A 28 2007Epoetin alpha Hexal

Abseamedepoetin alfa Hexal

MediceEprex® Approved Aug. 28, 2007

Retacrit®

Silapo epoetin zeta HospiraStada Eprex® Approved Dec. 18, 2007

Epostim epoetin alfa Reliance/GeneMedix Eprex® Withdrawn Mar. 15, 2011

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®

RatiograstimFilgrastim RatiopharmBiograstim

FilgrastimTeva

RatiopharmRatiopharm

CT Arzneimittel

NEUPOGEN®

(Filgrastim)* Approved Sep. 18, 2008

Zarzio®

Fil ti H l Filgrastim SandozH l

NEUPOGEN®

(Fil ti )* Approved Feb. 6, 2009Filgrastim Hexal g ast Hexal (Filgrastim)* pp o ed eb 6, 009

Nivestim® Filgrastim Hospira NEUPOGEN®

(Filgrastim)* Approved Jun 10, 2010

Some products are marketed in different jurisdictions under different brand names. Data Source: European Public Assessment Reports published on EMA Website. Available at http://www.ema.europa.eu/pdfs/human/press/pr/4031706en.pdf

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* Please see full US safety information for NEUPOGEN® (filgrastim) at the end of this presentation or at www.neupogen.com.

According to The United States Patent and Trademark Office’s on-line search tool at http://www.uspto.gov/and accessed on June 29, 2011, the following marks are registered or otherwise listed with that office:

Eprex® is a registered trademark of JOHNSON & JOHNSON CORPORATIONNEUPOGEN® is a registered trademark of Amgen, Inc.Retacrit ® is a registered trademark of Hospira, Inc. CORPORATION DELAWARETevagrastim® is a registered trademark TEVA Pharmaceutical Industries Ltd.Nivestim® is a registered trademark of Hospira UK Limited CORPORATION GREAT BRITAINGENOTROPIN® is a registered trademark of PFIZER HEALTH AB CORPORATION SWEDENNovartis AG CORPORATION SWITZERLAND has applied for trademark registration for Binocrit™ Omnitrope® and Zarzio® are registered trademarks of Novartis AG CORPORATION SWITZERLANDAlpheon® is a registered trademark of Alpheon Ltd. LIMITED LIABILITY COMPANY UNITED KINGDOMValtropin® is a registered trademark of LG Life Sciences, Ltd. CORPORATION REPUBLIC OF KOREA

The following list of marks may be registered with jurisdictions outside of the United States: Epostim, Ratiograstim, FilgrastimRatiopharm, Epoetin alfa Hexal, Filgrastim Hexal, Abseamed, Biograstim, Silapo, Humatrope, Humulin, and Roferon-A.


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Eprex® (epoetin alfa)NeoRecormon (epoetin beta)Aranesp® (darbepoetin alfa)*

Eprex® (epoetin alfa)NeoRecormon (epoetin beta)

Eprex® (epoetin alfa)NeoRecormon (epoetin beta)Aranesp® (darbepoetin alfa)*

Europe is addressing pharmacovigilance challenges with “multi-source” biologics

1998 2001 2009

Dynepo® (epoetin delta) (withdrawn)

Mircera® (peg-epoetin beta)Ratioepo (epoetin theta)Biopoin (epoetin theta)

• Binocrit™ (epoetin alfa)• Abseamed (epoetin alfa)• Epoetin alfa Hexal (epoetin alfa) o Silapo (epoetin zeta) o Retacrit® (epoetin zeta)

= Full marketing authorization• = Biosimilar authorization #1 (Aug 2007)o = Biosimilar authorization #2 (Dec 2007)

Amgen believes three levels of traceability for both biologics and biosimilars are essential to allow health authorities to trace an event to its root cause**:

D l

Some products are marketed in different jurisdictions under different brand names. Data Source: European Public Assessment Reports published on EMA Website. Available at http://www.ema.europa.eu/pdfs/human/press/pr/4031706en.pdfWithdrawal statement for Epoetin Delta available at http://www.ema.europa.eu/humandocs/PDFs/EPAR/dynepo/12666909en.pdf** Morrison A, Walker C, Fox A. PharmacoVigilance Review. 2009;3(4):12-14.

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* Please see full US safety information, including boxed warnings for Aranesp® (darbepoetin alfa) at the end of this presentation or at www.aranesp.com.

• Drug class• Individual manufacturer’s product• Manufacturer’s lot number

According to The United States Patent and Trademark Office’s on-line search tool at http://www.uspto.gov/ and accessed on June 29, 2011, the following marks are registered or otherwise listed with that office:

Aranesp® is a registered trademark of Amgen, Inc.Mircera® is a registered trademark of Hoffmann-La Roche Inc. CORPORATION NEW JERSEYDynepo® is a registered trademark of Aventis Pharma Holding GmbH CORPORATION FED REP GERMANY

The following list of marks may be registered with jurisdictions outside of the United States: NeoRecormon, Biopoin, and Ratioepo


Differences between full and biosimilar applications highlight areas of EMA emphasis

• Drug substance• Manufacture• Characterisation

• Pharmacology• Primary pharm.• Secondary pharm

• Pharmacology• Pharmacokinetics

CMC Nonclinical Clinicaltu

dy #

1

• Characterisation• Control• Reference standard• Container• Stability

• Drug product• Description• Development• Manufacture• Control• Reference standard

• Secondary pharm.• Safety pharm.• Interactions

• Pharmacokinetics• ADME• Interactions

• Toxicology• Single dose• Repeat dose• Genotoxicity

C i i it

• Single dose• Repeat dose• Special populations

• Efficacy and safety• Dose finding• Schedule finding• Pivotal

• Indication 1• Indication 2• Indication 3• Indication 4

StSt

udy

#2

Reference standard• Container• Stability

+ Comparability data+ Analytical

comparison with reference product

• Carcinogenicity• Reproduction• Local tolerance

Indication 4

• Post-marketing studies• Safety in all

indications• Efficacy in other

indications• Immunogenicity

Data Source: European Medicines Agency Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Nonclinical & Clinical Issues. Available at http://www.ema.europa.eu/pdfs/human/biosimilar/4283205en.pdf and European Medicines Agency Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues. Available at http://www.ema.europa.eu/pdfs/human/biosimilar/4934805en.pdf. Interpretation of notional requirements are those of the slide author


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Clinical development for two EU biosimilars highlights the need for class-specific approaches

40 HV (sc) 26 HV (iv) 56 HV (sc) 24 HV (sc)

Pivotal Efficacy Studies

Zarzio® (filgrastim)Zarzio® is not approved in the US

6 subjects 76 subjects 72 subjects

Binocrit® (epoetin alfa)Binocrit® is not approved in the US

PK/PD Studies in Healthy Volunteers

( )single armPK

( )single armPK

( )vs. NeupogenPD

( )vs. NeupogenPD

Pivotal Safety Study& Supportive Efficacy

170 breast ca patients (sc)single armEfficacy, Safety & Immunogenicity

single dosesc/ivvs. Eprex

multi-doseivvs. Eprex

multi-dosescvs. NeoReco

Pivotal Efficacy & Safety Study

480 haemodialysis patients (iv)vs. Eprex (maintenance)Efficacy, Safety & Immunogenicity

6 subjectsmulti-dosescsingle arm

74 subjectsmulti-dosescvs. Eprex

Total in studies before approval:146 healthy volunteers170 breast cancer patients

Total in studies before approval:234 healthy volunteers480 renal patients114 cancer patients

Supportive Study114 cancer patients (sc)vs. EprexEfficacy & Safety

HV= healthy volunteers, SC= subcutaneous, IV= intravenous. Data Source: Sandoz Binocrit®(HX575) European Public Assessment Report. Available at: http://www.ema.europa.eu/humandocs/PDFs/EPAR/binocrit/H-725-en6.pdf and Sandoz Zarzio® European Public Assessment Report. Available at: http://www.ema.europa.eu/humandocs/PDFs/EPAR/Zarzio/H-917-en6.pdf . Emphasis added in red boxes and red text is that of slide author


EMA has allowed extrapolation of indications for biosimilars as seen in the ESA class

EU ESA Indications

Renal anaemia – on dialysisIV only

Renal anaemia – not on dialysisIV only

Anaemia in cancer chemotherapy

Increasing yield for autologous transfusions

Reducing need for allogeneic transfusions

Anaemia in premature infants

Extrapolated indication(s)

All products shown are approved in EU. Binocrit®, Retacrit® and NeoRecormon® are not approved in the US. All brand names are registered TM of their respective owners. Data Source: EMEA Website Product Information. Available at: http://www.ema.europa.eu/humandocs/Humans/EPAR/retacrit/retacrit.htm and http://www.ema.europa.eu/humandocs/Humans/EPAR/binocrit/binocrit.htmand http://www.ema.europa.eu/humandocs/Humans/EPAR/aranesp/aranesp.htm and http://www.ema.europa.eu/humandocs/Humans/EPAR/neorecormon/neorecormon.htm and http://www.ema.europa.eu/humandocs/Humans/EPAR/mircera/mircera.htm and electronic Medicines Compendium available at: http://www.medicines.org.uk/EMC/company/69/Janssen-Cilag+Ltd/

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* Please see full US safety information, including boxed warnings for Aranesp®

(darbepoetin alfa) at the end of this presentation or at www.aranesp.com.


8/18/2011


Many EU Member State Regulators (e.g. UK & France) link pharmacovigilance & substitution

Prescribing of biosimilars

“When prescribing biological products, it is good practice to use the brand name. This will ensure that automatic substitution of a biosimilar product does not occur when the medicine is dispensed by the pharmacist.”

“Products (biosimilar and reference) that have the same international non-proprietary name (INN) are not to be presumed identical for the reasons given above.”

Reporting suspected ADRs for biosimilars

Substitution

“systematic and uncontrolled substitution ….. does not appear reasonable at this time.”

“… physicians should be involved in decisions to substitute any BMP [biological medicinal product]”

“it is also essential to have excellent records of the t t t i d ll i h i i t t“To ensure that any ADR that you report is assigned to

the correct product, it is important that the product name rather than the substance name is used for reporting.”

treatments received …. allowing physicians to trace closely the products used in case of occurrence of an adverse event.”

Both regulatory agencies are acknowledging the need for product identification and accurate attribution of adverse events

Data Source: MHRA Drug Safety Update: Volume 1, Issue 7, February 2008: Available at: http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON2033917 and published views of French Regulatory Agency (AFSAAPS) reviewers in 2008. Available at: http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ArtikelNr=111790&Ausgabe=234194&ProduktNr=224036&filename=111790.pdf


An EMA Pharmacovigilance Working Party communication highlights the challenge

Data Source: Monthly report from the EU Pharmacovigilance WP December 2009 meeting. Available at: http://www.ema.europa.eu/pdfs/human/phvwp/81624809en.pdf


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FDA is currently considering public input on important aspects of the law

• Biosimilarity

• InterchangeabilityInterchangeability

• Patient Safety and Pharmacovigilance

• Supportive Data

• Definition of a Biologic Product

• Guidance

• Exclusivity

• User fees


1. Use well-designed clinical trials to establish biosimilarity

Amgen believes that when patients are put first, sound policy will follow

2. Ensure product, manufacturer and lot number are known for each biological given to a patient

3. Set scientific and practical criteria for interchangeability

It is not whether you can analyze structural differences; what matters is the result in the human body


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Questions?
