Presented to MIPLA 10-21-2010

1. Biosimilars
Katherine Kowalchyk. Ph.D., J.D.
Brian R. Dorn, Ph.D., J.D.
October 21, 2010
Merchant & Gould, PC

2. U.S. Biosimilars
• US Regulatory approach to “follow-on biologics” (FOB)
Approval Pathway
Litigation Scheme
• FDA-Upcoming Hearings (Nov.2-3, 2010)
Issues for FDA
Strategic Ramifications
• European Union’s “Biosimilars” lead
Guidance for Antibody Biosimilars-November

3. Biosimilar is not Generic
• Traditional pharmaceutical
– small organic molecule
– synthesized in the lab
– purity can be verified
• A generic drug
– has same active ingredient
– but may have a different formulation
– such as other ingredients
• affect absorption or half life

4. Biological Molecules
• Natural or synthetic products
– typically produced in cells
• Structure dependent on
– process of making
– cell type used to produce
• More complicated to purify

5. Biologics are Different
• Biological origin
• Large molecules
• Heterogeneous
• Self-replicating
• Multifunctional
• Variable
• Manufacturing
process-dependent
• Immunogenicity
• Changes clinically
relevant

6. Biologic Products
• >174 biological products approved
– most since 2000
• More products in pipeline (>500)
– pharma acquiring biotech firms
• Humanized antibodies for cancer
– Success established products
• More approvals for new indications

7. Approved Biosimilars
• Europe
– Omnitrope (hGH)
– Binocrit-(epoetin alpha “EPO”)
– Zarzio (filgastrim-neutropenia)
– Valtropin (hGH)
– Hexal –EPO version
– Tevagrastim (filgastrim-CSF)
• U.S.
– Omnitrope
– Enoxaparin
– 8 others
• China
– EPO versions
– Interferons
– IL-2, IL-11, GM-CSF
– hGHs
• India
– hGH
– EPO
– Interferon alpha
2b
– insulin
• Australia
– Omnitrope
(Sandoz)
• Cuba, Egypt,
Africa
– EPO versions

8. Public Expectations
• Inexpensive generic drugs that are safe and
effective-may not understand differences between
small molecule and biologic
• Physicians expect clinical trials but generally view
innovators and generic companies as trustworthy
and may be more likely to prescribe a biosimilar
• Some discount expected but not as great as small
molecule

9. Pathways for approval of
drugs
• PHSA:BLA
– Biosimilars do not fit the
generic H-W model
• FDCA:NDA/505b1 and 505b2
• Hatch-Waxman Act :ANDA/505j

10. FDCA 505(j) – Hatch
Waxman Act
Small Molecules
• Abbreviated New Drug Application (ANDA)
– Use safety/efficacy data of allowed drug
– Show proposed drug product is identical to previously
approved drug product in:
• Active ingredient
• Dosage form
• Strength
• Route of administration
• Labeling
• Quality
• Performance
characteristics
• intended use
• among other things
FFDCA 505(j)(2)(A)FFDCA 505(j)(2)(A)

11. Biologics Price Competition
and Innovation Act
• Signed into law March 30, 2010-retroactive
• Amended Public Health Service Act (BLA
standard)
• Key features
– 12 years market exclusivity before
approval of biosimilar-4 years before
first app
– Two standards of approval
• Biosimilarity
• Interchangeability(if labeled or if
exclusivity)
– Exclusivity for first approved
interchangeable product
– Complicated litigation scheme
– No orange book

12. “Biosimilar” Defined
351(k)
• “Biosimilar” or “biosimilarity” means
(A) highly similar notwithstanding
minor differences in clinically
inactive components; and
(B) No clinically meaningful
differences in terms of safety, purity,
and potency

13. Interchangeable
351(k)
“Interchangeable” or
“Interchangeability”
• Expected to produce the same
clinical result in any given patient
and the risk in terms of safety or
diminished efficacy of is not > the
risk of using the reference product
without a switch
• May be substituted without
intervention of the health care
provider

14. Content of Biosimilar
Application
• Data to show proposed product biosimilar
and interchangeable (if labeled or
exclusivity)
• Same mechanism as Ref Product
• Labeling has been previously approved for
Ref product
• Same route of administration, dosage form
and strength
• Facilities standard assure that product is
safe, pure, and potent

15. Data
• Analytic studies showing product is highly
similar
• Animal studies (including toxicity)
• Clinical Studies showing safety, purity,
and efficacy including immunogenicity
• If given more than once the risk of
switching from the ref product is not
greater than the ref product without
switching

16. Reference Product Exclusivity
• 4 years of data exclusivity-no app
accepted
• 12 years market exclusivity-no approval
• +6 extra months pediatric for both
This is irrespective of patents, which are
tied to a filing date and may expire prior
to market exclusivity expiration

17. FOB Market Exclusivity
First Approved Interchangeable
Biosimilar/Earlier of
• 1 year after 1st
commercial marketing after
approval as interchangeable;
• 18 months after final court decision(s) or
dismissal(s) on all patents in suit; or
• 42 months after approval of the 1st
FOB if 1st
applicant still has litigation pending; or
• 18 months after approval of 1st
FOB if 1st
applicant has not been sued.

18. Litigation Scheme
COMPLICATED!
• NO ORANGE BOOK!
– Exchange of patent information within 20
days of approval
– Access to confidential information
needed to determine infringement
– 60 days innovator must give notice of
patents
– Sanctions
– Tight Deadlines: Innovator must sue
within 30 days of agreement on the
patent list or only entitled to reasonable
royalty
• Patent Litigation
– No automatic stay of approval

19. Exchange of Information
• Patent lists-both sides and includes
process patents
• Claim charts-both sides
• Mandatory negotiation on which
patents are subject to suit
• Bring suit in 30 days/ no stay
• 180 days notice of intent to market
biosimilar

20. FDA Hearings
• FDA policy:
permitting appropriate
reliance on what is already
known about a drug
• Purpose:
Receive info and comments
from broad group

21. Biosimilarity
What scientific & technical factors
should the agency consider in:
1. whether the product is highly
similar; and
2. determining the appropriate
studies to assess nature &
impact of structural differences

22. Biosimilarity
3. What range of structural
differences b/t biosimilar &
ref product is consistent &
acceptable w/ “biosimilar”?
4. Under what circumstances
should FDA consider
animal or clinical studies
unnecessary for 351(k) app

23. Interchangeability
What factors should FDA
consider in:
1. determining whether
biosimilar can be expected
to produce same clin result
2. evaluating potential risk
related to alternating or
switching

24. Patient Safety and
Pharmacovigilance
FDA mush be able to distinguish between
1. Reference product;
2. Related biological product that has not
been demonstrated to be biosimilar;
3. Biosimilar product; and
4. Interchangeable product.

25. Patient Safety and
Pharmacovigilance
1. Factors in establishing its
pharmacovigilance program
2. Approaches to be undertaken by FDA,
industry, or health care to ensure
appropriate pharmacovigilance
3. Nonproprietary names
4. Safeguards when prescribing,
administering, & dispensing to prevent
unsafe substitution
5. Mechanisms to communicate findings

26. Use of Supportive
Data and Information
• What extent, if any, should
animal or clinical data
comparing biosimilar with
non-US licensed comparator
product be used to support a
demonstration of biosimilarity
to a US licensed ref product?

27. Definition of
Biological Product
BPCI Act changes the statutory authority
under which certain protein products will
be regulated
1. Developing regulatory definition of
“protein” (as distinguished from peptide or
polypeptide)
2. Developing regulatory definition of “any
chemically synthesized polypeptide

28. Guidances
• Types of guidance docs
should be a priority during
early implementation
• Factors to determine if the
existing science & experience
are sufficient to allow
approval for a product or
product class

29. Exclusivity
• What types of related entities
should be ineligible for a 12
exclusivity for a subsequent BLA?
• What type of modification to the
structure of a product that results
in a change in safety, purity, or
potency, such that a subsequent
BLA may be eligible for a 2nd
12-
year period of market exclusivity?

30. Transition Provisions
• What “product classes” may
be submitted under the FD&C
during 10 year transition
period?
• What should be considered
when determining whether a
351(k) approval can be a ref
product to a 351(a)?

31. The EU Experience
• 2005-6 EMA Guidelines produced
• 2006: EU approvals
– hGH biosimilars (Omnitrope and Valtropin)
– other evaluations started
– Data from ~200 patients, 9-12 months study
– Same INN-name as brand name product
– No EMA guidance regarding interchangeability
– Comparatively simple biotech-generated
products

32. EU Directive Biosimilars
• Biological medicinal product
– Similar to a reference biological product
– But differences
• in raw materials or manufacturing
– Pre-clinical or clinical trials must be provided
• Appropriate to the changed conditions
• type and quantity must comply with relevant criteria
• and related detailed Guidelines
• results of other tests and trials from the reference medicinal
product's dossier shall not be provided

33. EU product specific
guidelines
biosimilar rGC-SF CHMP/31329/05 June 05
biosimilar rhInsulin EMEA/CHMP/32775/05 June 06
biosimilar somatropin EMEA/CHMP/94528/05 June 06
similar rEPOs EMEA/CHMP/94526/05 July 06
Concept Paper On Similar Low
Molecular Weight Heparins - (Non)
Clinical Issues
EMEA/CHMP/BMWP/4
96286/06
Draft guideline on similar rIFNa EMEA/CHMP/BMWP/1
02046/2006

34. Basic Requirements
• Comparability in quality, safety, and efficacy to
ref. product
• Product is evaluated based on its characteristics
(eg purity), process, and formulation
need to justify any differences such as post
translation modifications or impurities
 Analytical procedures:
physicochemical (primary-tertiary structure),
biological activity,
purity and impurities (process based
impurities are evaluated for clinical effect)

35. EMA Monoclonal Antibody
Guidelines 2009
• Monoclonal antibodies:
Immunochemical(affinity, epitopes,
crossreactivity, isotype, allotype)
Physico chemical-sequence,
carbohydrates, disulfide bonds
Biological activity-effector function
 Manufacturing:
Changes in disulfide bonds, truncation,
aggregation
Impurities
Virus: Transmissable spongiform
Encephalopathy,
Endotoxin

36. Analysis Chimeric and
Humanized Antibodies
• Many approved in 1997-1998 including
Rituxan,Remicade, Herceptin
• 6 requests for biosimilar antibody
products-Teva/Rituxan
• Improved characterization:MALDI-
TOF,NMR, Surface Plasmon
resonance, Circular dichroism-is
sensitivity sufficient
• Complex processing
• Is mechanism of action understood
• Antibodies do not substitute for natural
product so is immunogenicity a concern
• Are amino acid differences acceptable?

37. Summary
• US – leads biologic drug industry
– Need a system in place-waiting for FDA regs
• FOB/Biosimilar industry is growing
– High cost of biologics
– Incentive 75% price
– Regulatory approval hurdles
• US legislation
– More complicated than EU
– Patent litigation issues

38. Questions or Comments?
Thank You
kkowalchyk@merchantgould.com
bdorn@merchantgould.com
Merchant & Gould, PC