Transcript Morris - Hauck ICD2 2012

6th Science & Standards Symposium
January 16, 2013
Istanbul
Biosimilars
Roger L. Williams, M.D.
CEO and Chair, Council of Experts
Topics

BPCI
 USP
 Summary
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
Top Drugs Most Used by Elderly Brand & Specialty Price
Inflation: 1998 to 2008
Annual %
Change
0%
8.8%
Specialty Rxs
7.9% 8.7%
9%
8%
8.
7.0%
7%
6.8%
6.2%
7.1%
5.3%
6%
Brand Name Rxs
3.1%
4%
2.4%
1.7% 2.0%
1.7%
2.5%
1.9%
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.
Aug-08
Apr-08
Dec-07
Aug-07
Apr-07
Dec-06
Aug-06
Apr-06
Dec-05
Aug-05
Apr-05
Dec-04
Aug-04
Apr-04
Dec-03
Aug-03
Apr-03
Dec-02
Aug-02
Apr-02
Dec-01
1.1%
Aug-01
1.1%
Apr-01
Apr-00
Dec-99
Aug-99
Apr-99
Dec-98
0%
0.8% 0.9%
Dec-00
1%
Aug-00
2%
7.4%
6.3%
5%
3%
9.
Predicates
• David M. Dudzinski
Reflections 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
FDA Timeline





BPCIA:
Public Hearing:
NEJM Article:
Guidances:
Public Hearing:
–
–
–
–
2009
November 2010
August 2011
February 2012
May 2012
Demonstrating interchangeability
Obtaining reference product exclusivity
Naming issues
Clinical pharmacology evaluation of biosimilars
– Additional topics
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
Patient Protection and Affordable Care Act

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 InterchangeableSection 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
BPCIA and USP (1)

(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 (2)

• (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 IBE

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.
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 required
Anderson & Hauck, 1990, JPB
Current Biologic Products in the Market
From Kozlowski et al., NEJM 265;5, 2011
Topics

BPCI
 USP
 Summary
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
Topics

BPCI
 USP
 Summary
Biologics In India
Drug Trade
Name
Nonproprietary
Name
Molecule Class
Innovator
Market
Entry
2008 Sales
in B$
Monograph
in-house?
India
Product
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
5.1
Submission
pending
YES
Epogen/Procrit
Erythropoetin
Glocoprotein hormone
Amgen/J&J
1989
5.1
YES
YES
Neulasta
Pegfilgrastim
Pegylated 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
Darbepoeitin
Synthetic glycoprotein
hormone
Amgen
2001
3.2
NO
Recombinate
Factor VIII
recombinant
Coagulation Factor
Baxter/Wyeth
1998
2.9
NO
Biologics In India
Drug Trade
Name
Nonproprietary
Name
Molecule Class
Innovator
Market
Entry
2008 Sales
in B$
Monograph
in-house?
India
Product
Lucentis
Ranibizumab
Monoclonal antibody
Roche/Genentech
2006
2.7
NO
Avonex
Interferon
beta 1a
Cytokine
Biogen Idec
1996
2.6
Submission
pending as
of 11/3/2011
YES
Novolin
Recombinant
Human Insulin
Peptide Hormone
Novo Nordisk, Eli
Lilly
1991
2.5
YES
YES
Humalog
Insulin Lispro
Peptide hormone analog
Eli Lilly
1996
2.2
YES
YES
PEGASYS
Peginterferon
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
Novoseven
Recombinant
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
Humulin
Insulin
isophane/insulin
zinc suspension
Peptide hormone analog
Eli Lilly
1992
1.1
YES
YES
Metrology: Towards a Global Understanding
The Ideal State
IU
Materials
Procedures
WHO Global Primary
Reference Material
Primary Reference
Measurement Procedure
USP National Primary
Reference Standard
USP Compendial
Procedure
Manufacturer’s house
standard
Manufacturer’s reference
measurement procedure
Manufacturer’s working
standard
Manufacturer’s working
measurement procedure
Manufacturer’s product
sample
Routine measurement
procedure
Result
Measurement Hierarchy
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