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  • Is the United States prepared for biosimilars/follow-on biologics? FDA and biotechnology industry says there’s no such thing as a generic biolgic. The US has suggested approaches to FOBs with 4 legislative models propoed; EPUnion taken the lead…
  • Bisimilar does not mean gerneric Generic for traditional molecules – small organics synthesized in lab; easy to verify structure and purity; Typical US generics have same active ingredient - generic drug has same active but may have different formulation
  • Biologics are more complicated – they are natural or synthetic products, generally produced in living cells; the structure (and function) is generally dependent on the process of making, for example, the cell type used to produce ; more complicated to purify.
  • Biologic drugs are different from small molecule drugs They are of biological origin; are much larger and more complex, heterogeneous and variable, self-replicating, multifunctional, structure/function is dependent on manufacturing processes; small changes can be clinically relevant; can cause immunogenicity
  • More than 174 products have been approved , most since 2000 Many more in the pipeline as big pharma acquires small bio firms; Success established by humanized antibodies for cancer, with more approvals for new indications helped vault the industry and follow along products
  • Biosimilar products have been approved worldwide; Omnitrope (hGH), EPO, various cytokines, insulin
  • The US public has come to expect low cost generic drugs; Hatch Waxman Act provides for generic approval for small molecules that are the same as the approved drug. Generally thought sucessful, economists differ – problem is lack of innovator drugs (loss of time to recoup investment) No legislation as yet for FOBs – take care not to destroy this new industry – must get return on investment else no new drugs will be developed in US (compare origins of biotech industry.. US only one to patent and protect, industry started here until other countries protected innovation. Problem for new legislation, how to protect adequately, how to protect public safety when copy biologic is not the same
  • Hatch Waxman Act, FDCA 505j – abbreviated new drug application – uses safety and efficacy data of innovator’s drug; need to show proposed generic drug is identical to the previously approved drug in active ingredient, dosage form, strength, administration route, labeling, quality, performance, intended use, and others.
  • Not interchangeable means new active ingredient
  • Peds extension: House version, extension is in the legislation Senate version amends subsection (a)(1) of 409I of PHSA and § 505A(p) of FDCA
  • FOB market exclusivity provided in the legislation – varies HW - 180 days from first commercial marketing differs when litigation ensues Inslee, like EP provides not FOB exclulsivity; Others require interchangable label.. None yet
  • Each of the new bills varies the HW model of generics; but there is no plan for an ORANGE book. Instead, parties will exchange patent information and be provided with access to confidential information as needed to determine infringement. Only HR5629 addresses the rights of third parties, e.g., Universities and other parties that may have an interest in the patents. None provides for an automatic stay of approval for patent litigation, nor provides for control of patent litigation

Transcript

  • 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)
  • 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 1 st 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 1 st FOB if 1 st applicant still has litigation pending; or
    • 18 months after approval of 1 st FOB if 1 st 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:
    • whether the product is highly similar; and
    • determining the appropriate studies to assess nature & impact of structural differences
  • 22. Biosimilarity
    • What range of structural differences b/t biosimilar & ref product is consistent & acceptable w/ “biosimilar”?
    • Under what circumstances should FDA consider animal or clinical studies unnecessary for 351(k) app
  • 23. Interchangeability
    • What factors should FDA
    • consider in:
    • determining whether biosimilar can be expected to produce same clin result
    • evaluating potential risk related to alternating or switching
  • 24. Patient Safety and Pharmacovigilance
    • FDA mush be able to distinguish between
    • Reference product;
    • Related biological product that has not been demonstrated to be biosimilar;
    • Biosimilar product; and
    • Interchangeable product.
  • 25. Patient Safety and Pharmacovigilance
    • Factors in establishing its pharmacovigilance program
    • Approaches to be undertaken by FDA, industry, or health care to ensure appropriate pharmacovigilance
    • Nonproprietary names
    • Safeguards when prescribing, administering, & dispensing to prevent unsafe substitution
    • 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
    • Developing regulatory definition of “protein” (as distinguished from peptide or polypeptide)
    • 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 2 nd 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 EMEA/CHMP/BMWP/102046/2006 Draft guideline on similar rIFNa EMEA/CHMP/BMWP/496286/06 Concept Paper On Similar Low Molecular Weight Heparins - (Non) Clinical Issues July 06 EMEA/CHMP/94526/05 similar rEPOs June 06 EMEA/CHMP/94528/05 biosimilar somatropin June 06 EMEA/CHMP/32775/05 biosimilar rhInsulin June 05 CHMP/31329/05 biosimilar rGC-SF
  • 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
    • [email_address]
    • [email_address]
    • Merchant & Gould, PC