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Biosimilars

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

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Biosimilars

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

  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. 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 Approved Biosimilars

  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 ActSmall 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: • Quality • Performance characteristics • intended use • among other things • Active ingredient • Dosage form • Strength • Route of administration • Labeling 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” Defined351(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. Interchangeable351(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. 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 Litigation SchemeCOMPLICATED!

  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 andPharmacovigilance 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 andPharmacovigilance • 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 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

  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

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