Follow-On Biologics:

1
Follow-On Biologics

• The New Regulatory Frontier ?

Michael S. Labson August 23, 2007
2
The Small Molecule Generic Paradigm

• Preclinical (e.g., toxicology)
• Clinical (safety effectiveness)
• CMC information
• Patent listing

NDA Reference Listed Drug

• Sameness bioequivalence
• CMC information
• Patent certification
• 30-mo. stay provisions
• 180-day exclusivity provisions

ANDA
505(b)(2) applications
3
Current Law FDA Policy -- 505(b)(2)

• Limited pool of FDCA biologics
• Two-levels of the legal debate
• Scope of 505(b)(2) generally
• Special issues for biologics, especially
  manufacturing data
• FDA policy
• Citizen petition response
• Pfizer Norvasc case came and went
• Unigene Fortical
• Sandoz Omnitrope

4
Current Law FDA Policy -- PHSA

• Reclassify biologics as drugs subject to FDCA
  505?
• Biologics are drugs
• Create a pathway within PHSA?
• But significant legal barriers
• PHSA sec. 351 a product for which a license
  has been approved under subsection (a) shall not
  be required to have an approved application under
  section 505 of such Act
• FDA statements
• Reinforced by FDA views on proprietary data

5
The Pressure for Change

• Economic and political pressure as significant
  biologic products come off patent
• Scientific advances
• E.g., better characterization of compounds
• Regulatory and administrative convergence
• Review processes both driven by PDUFA
• FDAMA creates unified BLA
• CTD
• 2003 CBER/CDER reorganization
• European developments

6
Europe

• Fewer legal barriers because no dual system for
  drugs/biologics
• General Guidance Documents
• Product-Specific Guidances
• rDNA insulin June 2006
• rDNA GCSF June 2006
• Somatropin June 2006
• rDNA EPO July 2006
• Low molecular weight heparin pending
• rDNA alfa interferon pending

7
Europe

• Action on filings
• April 16, 2006, Sandozs Omnitrope approved as
  biosimilar to Pfizers Genotropin
• May 5, 2006, Biopartners Valtropin approved as
  biosimilar to Lillys Humatrope
• June 30, 2006, CHMP issues negative opinion on
  Biopharma interferon alpha (Alpheon)
• June 2007, CHMP recommends approval of three EPO
  products biosimilar to JJs Eprex
• Sandoz, Binocrit
• Hexal Biotech
• Medice Arzneimittel Putter, Abseamed

8
FOBs the Scientific Debate

• Advances/limitations on analytical
  characterization
• Relevance of innovator comparability protocols
• Immunogenicity risks
• Importance of manufacturing process
• Select cases cited pro/con
• Berlex Avonex
• Serono Pergonal
• Eprex pure red cell aplasia episode
• Raptiva development
• Need for clinical studies remains

9
FOBs the IP Debate

• Exclusivity
• Debate around uncertainty of patents for biotech.
• Patents incentive for invention
• Exclusivity incentive to incur risk and bring
  product to market
• Need for incentives for FOBs through exclusivity
• Patent
• Link patents and regulatory schemes à la
  Hatch-Waxman?
• Challenges with listing patents
• Takings
• Reasonable investment-backed expectations
• Kelo (S. Ct. 2005)
• Broadens public use concept, but not what is a
  taking and when must there be just compensation
• Hatch-Waxman precedent from 1984?

10
State of the Congress

• Senate
• FDARA sense of the Senate
• S. 1695 (Kennedy/ Clinton/Hatch/Enzi) marked up
  by HELP Comm.
• May be further amended
• Judiciary Comm. review may be needed for patent
  provisions

• House
• Not in FDARA
• H.R. 1956 (Inslee)
• H.R. 1038 (Waxman)
• Debate over what to use as base bill, including
  potentially a new bill

August recess marches on FDARA to be enacted in
September.
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Key Issues for Legislation

• Approval standards
• Characterization requirements
• Data/study requirements
• Data for all indications
• Post-approval requirements
• FDA procedure
• Treatment of FDCA biologics
• E.g., Use of guidance documents

• Substitution/therapeutic equivalence/
  interchangeability
• Nomenclature
• Exclusivity
• Innovator
• Supplemental approvals
• FOB
• Patent provisions/linkage

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Biologics Price Competition and Innovation Act
(S. 1695)

• Sens. Kennedy, Clinton, Hatch, Enzi
• Approval standards (new PHSA 351(k))
• Analytical studies to show highly similar to
  RLB
• Animal studies
• Clinical study(ies) for 1 or more RLB use
• Same MOA(s) (to the extent known)
• Previously approved conditions of use
• Same dosage form, strength, route of adminstrn
• Facility meets standards for safety, purety,
  potency

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Biologics Price Competition and Innovation Act
(S. 1695)

• Approval standards (new PHSA 351(k))
• Analytical studies to show highly similar to
  RLB
• Animal studies
• Clinical study(ies) for 1 or more RLB use

FDA may determine unnecessary avoid needlessly
duplicative or unethical clinical testing FOB
may reference publicly available info and prior
findings for RLB
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S. 1695 (contd)

• Interchangeability
• Biosimilar expected to produce the same
  clinical result as the RLB no increased risk of
  safety or diminished efficacy due to switching
• FDA procedure
• Same review division as RLB
• Same REMS authority as for innovators
• User fees
• FDA to develop recommendations for Congress
• Transition provions
• FDA may issue guidance documents
• Genl or specific, and public comment
• Guidance not required for FOBs to be submitted or
  approved
• PHSA 351(k) is exclusive pathway for FOBs
• Limited exception for FDCA biologics, expiring in
  10 years

15
S. 1695 Patent Provisions
FOB Confidential Access

• Special negotiation period
• Mechanism for RLB suit
• Prior notice of FOB marketing mechanism for PI
• Limitations on DJs

RLB Patent List
FOB Certification Suppl Patents
RLB Response
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S. 1695 (contd)

• Innovator exclusivity
• 12-year bar on FOB approval
• 4-year bar on FOB filing
• First interchangeable exclusivity
• No further interchangeability finding until the
  earlier of
• 1 year after first commercial marketing
• 18 mos. after appeals court decision or dismissal
  in case brought under new patent provisions
• 42 mos. after approval if sued and case still
  pending at 36 months
• 18 mos. after approval if not sued

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Patient Protection and Innovator Biologic
Medicines Act (H.R. 1956)

• Rep. Inslee
• Product-class specific guidance
• Anyone may request
• Notice comment process, with adv. comm. input
  and timelines
• Required data and information
• Manufacturing process
• Stability, compatibility and integrity of active
• Data fully characterizing FOB v. RLB (active and
  product)
• Comparative nonclinical studies (PK, PD, tox.,
  immunogenicity)
• Comparative clinical trials
• Postmarketing monitoring (incl. re
  immunogenicity)
• Data for all indications

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H.R. 1956 (contd)

• FDA procedure
• New PHSA 351(k) is exclusive pathway, including
  for FDCA biologics
• Same review division as RLB
• No therapeutic equivalence and unique name
  required
• Reports to Congress on future feasibility of
  therapeutic equivalence determinations
• Innovator exclusivity
• No FOB submitted for 12 years
• No FOB approved for 14 years, plus 1 for
  clinically sign. supplement
• No patent provisions

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Access to Life-Saving Medicine Act (H.R. 1038)

• Rep. Waxman
• Approval standards
• Comparability based on non-clinical data and
  necessary confirmatory clinical study(ies) for
  one or more condition of use
• No unnecessary duplicative testing
• Highly similar principal molecular structural
  features, but minor differences in
  heterogeneity, impurities, degradation,
  post-translational events, glycosylation, etc.
  permitted
• Same MOA(s) if known
• Same dosage form, strength and route of
  administration
• Manufacturing facilities meet standards
• 505(b)(2)-type application also permitted

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H.R. 1038 (contd)

• Interchangeability
• FDA makes determination for each FOB based on
  expectation of clinical equivalence
• FDA to issue guidance on standards
• FOB and RLB shall have same designated official
  name
• Exclusivity
• Exclusive interchangeability period for first
  interchangeable FOB (including bar on authorized
  FOBs)
• No innovator exclusivity
• Patents
• FOB request for patent list at any time
• FOB notice at any time, incl. par. IV-type notice
• RLB may bring infringement action within 45 days
  for listed patents only bar on RLB DJs prior to
  commercial marketing
• Limitations on RLB citizen petitions

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Will We See Shark Fin 2?
Sales
generic entry
Time
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Questions ?

• Michael S. Labson
• Covington Burling LLP
• [phone]
• mlabson_at_cov.com