6th Science & Standards SymposiumJanuary 16, 2013Istanbul

Biosimilars

Roger L. Williams, M.D.CEO and Chair, Council of Experts

BPCI USP Summary

Topics

Generic Versus Pioneer Product Equivalence Concepts (CFR 320)

• Pharmaceutical Equivalence– Same active ingredient– Same strength– Same dosage form and route of administration– Comparable labeling– Meet compendial or other standards of identity, strength,

quality, purity and potency• Bioequivalence

– In vivo measurement of active moiety (moieties) in biologic fluid (blood/urine)

– In vivo pharmacodynamic comparison– In vivo clinical comparison– In vitro comparison– Other

THEN: THERAPEUTIC EQUIVALENCE

Compiled by the PRIME Institute, Univ. of Minnesota from data found in PriceChek PC and PriceRx (Wolters Kluwer Health, 2009), and AARP, Rx Watchdog Report series, 2009.

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-98

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-99

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-08

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9%

10%

1.7% 2.0%2.4%

3.1%

5.3%6.2%

7.0%

6.3%

7.1%7.4%

8.7%

0.8% 0.9% 1.1% 1.1%1.7% 1.9%2.5%

6.8%

7.9% 8.7%

8.8%9.3%

Top Drugs Most Used by Elderly Brand & Specialty Price Inflation: 1998 to 2008

Annual %Change

Specialty Rxs

Brand Name Rxs

Predicates

• David M. DudzinskiReflections on Historical, Scientific, and Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Therapeutics and Monoclonal Antibodies, Food and Drug Law Journal, Volume 60, 143-260, 2005 (FDLI’s 2003-4 H. Thomas Austern Memorial Writing Awards Competition--long papers), with acknowledgements to Peter Barton Hutt, Esq.

• Public Health Service Act—fits within the FDCA– Section 351(j) …the FDCA otherwise applies to biological

products subject to regulation under its section – Section 351(g)…nothing contained in this chapter shall be

construed as in any way affecting, modifying, repealing, or superseding the provisions of the [FDCA]

ICH

• Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process

The tripartite harmonised ICH guideline was finalised (Step 4) in November 2004. The objective of this document is to provide principles for assessing the comparability of biotechnological/ biological products before and after changes are made in the manufacturing process for the drug substance or drug product. Therefore, this guideline is intended to assist in the collection of relevant technical information which serves as evidence that the manufacturing process changes will not have an adverse impact on the quality, safety and efficacy of the drug product. The document does not prescribe any particular analytical, nonclinical or clinical strategy. The main emphasis of the document is on quality aspects.

• Final: September 2004

• Comparability: One-Way Interchangeability (Hidden from Public)

FDA

• Comparability– Guidance Concerning Demonstration of Comparability of Human Biologic

Products, Including Therapeutic Biotechnology-derived Products (April 1996)—CBER and CDER

– Guidance on Comparability Protocols: CMC Information (Draft February 2003)—CDER, CBER, CVM

• Menotropins 505(j) approval/court cases• Draft 505(b)(2) guidance/citizen petitions (draft 1999)• Omnitrope approval—505(b)(2), May 31, 2006• Nature Reviews Drug Discovery 6 437 2007• CDER Testimony March 26, 2007• FDA Presentations

– Deputy Director/Office of Pharmaceutical Science/September 2007– Office of Biotechnology Products/Office of Pharmaceutical

Science/September 2007

BPCIA: 2009 Public Hearing: November 2010 NEJM Article: August 2011 Guidances: February 2012 Public Hearing: May 2012

– Demonstrating interchangeability– Obtaining reference product exclusivity– Naming issues– Clinical pharmacology evaluation of biosimilars

– Additional topics

FDA Timeline

FDA Guidances

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

• Quality Considerations in Demonstrating Biosimilarity to a Reference Product

• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

February 2012

Title VII—IMPROVING ACCESS TO INNOVATIVE MEDICAL THERAPIES

Subtitle A—Biologics Price Competition and Innovation Section 7001. Short Title

Biologics Price Competition and Innovation Act of 2009 Section 7002. Approval Pathway for Biosimilar Biological Products

(a) Licensure of Biological Products as Biosimilar or Interchangeable-Section 351 of the Public Health Service Act (42 U.S.C. 262) is amended—

– ‘(k) Licensure of Biological Products as Biosimilar or Interchangeable(1) IN GENERAL – Any person may submit an application for licensure of a biologic product under this section.(2) CONTENT(3) EVALUATION BY THE SECRETARY(4) SAFETY STANDARDS FOR DETERMINING INTERCHANGEABILITY(5) GENERAL RULES(6) EXCLUSIVITY FOR FIRST INTERCHANGEABLE BIOLOGICAL PRODUCT(7) EXCLUSIVITY FOR REFERENCE PRODUCT(8) GUIDANCE DOCUMENTS

– (l)Patents

Patient Protection and Affordable Care Act

(A) IN GENERAL– (i) REQUIRED INFORMATION-An application submitted under this

subsection shall include information demonstrating that-• (I) the biological product is biosimilar to a reference product based

on data derived from—– (aa) analytical studies that demonstrate that the biological

product is highly similar to the reference product notwithstanding minor differences in clinical inactive components;

– (bb) animal studies (including assessment of toxicity); and – (cc) A clinical study or studies (including the assessment of

immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product.

BPCIA and USP (1)

• (II) the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use precribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product;

• (III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biologic product have been previously approved for the reference product;

• (IV) the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; and

• (V) the facility in which the biologic product is manufactured, processed, packed, or held meets standards designed to assure that the biologic product continues to be safe, pure, and potent.

– (ii) DETERMINATION BY SECRETARY- The Secretary may determine, in the Secretary’s discretion, that an element described in clause (i)(I) is unnecessary in an application submitted under this subsection.

– (iii) ADDITIONAL INFORMATION- An application submitted under this subsection—• (I) shall include publicly-available information regarding the Secretary’s previous

determination that the reference product is safe, pure, and potent; and• (II) may include any additional information in support of the application, including

publicly available information with respect to the reference product or another biological product.

(B) INTERCHANGEABILITY- An application (or a supplement to an application) submitted under this subsection may include information demonstrating that the biological product meets the standards described in paragraph (4).

BPCIA and USP (2)

Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that—

– (A) the biologic product—• (i) is biosimilar to the reference product; and• (ii) can be expected to produce the same clinical result as the

reference product in any given patient; and– (B) for a biological product that is administrated more than once to an

individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

BPCIA and IBE

Individual Bioequivalence: Bioavailability of the new formulation is sufficiently close to that of the standard in most individuals. … When switching a patient [between formulations] want reasonable assurance that the patient will get the same efficacy .. individual bioequivalence is requiredAnderson & Hauck, 1990, JPB

Current Biologic Products in the Market

From Kozlowski et al., NEJM 265;5, 2011

BPCI USP Summary

Topics

An Early USP Monograph

FDC Act : Section 501(b) - Adulteration

A drug or device shall be deemed to be adulterated if it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium.

Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium…

2010–2015 USP Council of Experts

18

Biologics Standards

Horizontal Standards

BPCI USP Summary

Topics

Biologics In India

Drug Trade Name

Nonproprietary Name

Molecule Class InnovatorMarket Entry

2008 Sales in B$

Monograph in-house?

IndiaProduct

Avastin Bevacizumab Monoclonal antibody Roche/Genentech 2004 9.2 NO YES

Enbrel Etanercept Antibody fusion protein Amgen 1998 8 YES YES

Remicade Infliximab Monoclonal antibody Centocor 1998 7.9 NO  

Humira Adalimumab Monoclonal antibody Abbot 2002 7.3 NO  

Rituxan Rituximab Monoclonal antibody Roche/Genentech 1997 7.3 NO YES

Herceptin Trastuzumab Monoclonal antibody Roche/Genentech 1998 5.7 NO YES

Lantus Insulin glargine Peptide hormone analog Sanofi Aventis 2000 5.1Submission pending

YES

Epogen/Procrit Erythropoetin Glocoprotein hormone Amgen/J&J 1989 5.1 YES YES

Neulasta PegfilgrastimPegylated peptide hormone

Amgen 2002 4.2 NO YES

Novolog Insulin Aspart Peptide hormone analog Novo Nordisk 2000 3.7 YES YES

Erbitux Cetuximab Monoclonal antibody ImClone/BMS 2004 3.6 NO  

Aranesp DarbepoeitinSynthetic glycoprotein hormone

Amgen 2001 3.2 NO  

RecombinateFactor VIII recombinant

Coagulation Factor Baxter/Wyeth 1998 2.9 NO  

Biologics In India

Drug Trade Name

Nonproprietary Name

Molecule Class InnovatorMarket Entry

2008 Sales in B$

Monograph in-house?

IndiaProduct

Lucentis Ranibizumab Monoclonal antibody Roche/Genentech 2006 2.7 NO  

AvonexInterferon beta 1a

Cytokine Biogen Idec 1996 2.6Submission pending as of 11/3/2011

YES

NovolinRecombinant Human Insulin

Peptide HormoneNovo Nordisk, Eli Lilly

1991 2.5 YES YES

Humalog Insulin Lispro Peptide hormone analog Eli Lilly 1996 2.2 YES YES

PEGASYSPeginterferon alpha 2a

Pegylated cytokine Roche/Genentech 2002 2.0 NO  

Rebif Interferon beta 1a Cytokine Merck/Serono 2002 1.7 NO  

Cerezyme Imiglucerase Enzyme Genzyme 1994 1.5 NO  

Tysabri Natalizumab Monoclonal antibody Biogen Idec/Elan 2004 1.4 NO  

NovosevenRecombinant Factor VII

Coagulation Factor Novo Nordisk 1999 1.4 NO  

Synagis Palivizumab Monoclonal antibody MedImmune 1998 1.3 NO  

Neupogen Filgrastim Peptide Hormone Amgen 1991 1.3 YES YES

Betaseron Interferon beta 1b Cytokine Bayer Healthcare 1993 1.2 NO YES

HumulinInsulin isophane/insulin zinc suspension

Peptide hormone analog Eli Lilly 1992 1.1 YES YES

IU

Result

Primary Reference Measurement Procedure

USP Compendial Procedure

Manufacturer’s reference measurement procedure

Manufacturer’s working measurement procedure

Routine measurement procedure

WHO Global Primary Reference Material

Manufacturer’s house standard

USP National Primary Reference Standard

Manufacturer’s working standard

Manufacturer’s product sample

Measurement Hierarchy

Materials Procedures

Metrology: Towards a Global Understanding

The Ideal State

Practitioners and Patients

• Naming– Ingredient: INN (USAN in US)– Product: FDA and USP– Switching prevented by different names– USP can name product without ‘alphas’

• Comparable and interchangeable—relates to risks: who will explain?; who will understand?

• Who controls: payor, physician (with detailing); health care system/pharmacist (interchangeable)

• ?Orange Book• Different administration techniques and labeling