follow-on proteins and biosimilars cle final... · hr 5629 – pathway for biosimilars bill ......
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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions
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Hatch-Waxman AimsCongress wanted branded manufacturers to have incentives to innovate.Congress also wanted to ensure that there was incentive for generics to enter market immediately upon patent expiration.
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Hatch-Waxman GenerallyAutomatic 30-Month StayStreamlined process for approval of generic –Abbreviated New Drug Application (ANDA)First filer of ANDA receives 180-day generic drug exclusivity provision
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Standard of Review for Generic DrugsA generic drug contains the same active ingredient as an innovator or brand name drug and has the same dosage form, strength, route of administration, labeling, and conditions of use.
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Legal Background: 1984 Hatch-Waxman Act
Before Hatch-Waxman
Generics 19% of pharmaceutical market (prescriptions filled)(1984)
After Hatch-Waxman
Generics 63% percent of pharmaceutical market (prescriptions filled)(2006)
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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions
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Biological Product or Biosimilar?“Biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product …applicable to the prevention, treatment, or cure of a disease or condition of human beings. (PHSA, 42 U.S.C. § 262)Biosimilars (or Follow-on proteins) refer to new versions of proteins or peptides intended to be sufficiently similar to innovator biological products
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Variation in product complexity
AspirinMW 158
Monoclonal AntibodyMW 150,000
InsulinMW 5800
Diazepam (valium)MW 284
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Difficult to define and quantify; Viral/bacteria/fungal/TSEDefined Standards/SpecsImpurities
Variable potential for antibody formationExtremely RareImmunogenicity
Difficult to quantifyDefined ActivityBioactivity
Complex/Heterogeneous LimitationsSimple Definitive Detail/StandardsCharacterization
Living Systems - Inherent heterogeneity affected by minor changes
Chemical Synthesis -predictable & well definedManufacturing
Large (>5000)Small (<5000)Size
BiologicsChemical DrugParameter
Chemical Drugs versus Biologics
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Inherent biologics product variabilityCarbamylationCarboxylationFormylationO-linked GlycosylationN-linked GlycosylationMethylationOxidationPhosphorylationSulphation
Amino Acid SubstitutionTruncationMismatched S-S bondsN- and C-terminal differenceAggregationMultimer DissociationDenaturationAcetylationAcylationAddition of lipidAmidation/Deamidation
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Immunogenicity concernsMany biologics cause an immune reactionUsually the immune reaction is benignPotential risks
Inactivation of the biologic productInactivation of the body’s naturally occurring proteins
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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent US Regulatory Framework United States Legislative ProposalsEuropean ApproachConclusionQuestions
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FDA Registration PathwaysPHSA
Biologics License Application (BLA)» Covers vaccines, blood and blood products, some but not all therapeutic
proteins, and cell/gene therapyFDCA
New Drug Application (NDA): 505(b)(1)» Must show safety, efficacy, and quality based on ‘full reports’
New Drug Application (NDA) 505 (b)(2)» References previously approved innovator product» May rely on third party data to show safety and efficacy» Differences must be justified by additional studies on safety and
efficacyAbbreviated New Drug Application (ANDA): 505 (j)
» Must be therapeutically equivalent predicate product — innovator approved under 505(b)(1)
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Scientific principles for 505(j)“Therapeutic Equivalence” requires:
Bioequivalence» same “rate and extent” of absorbance & availability at site
PLUS
Pharmaceutical Equivalence» same active ingredients, dosage form, route of administration,
strength, GMPs
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Scientific principles for 505(b)(2)Suitable Applications (1999 FDA Guidance)
Changes in dosage form, dosing regimen, strength, formulation, or route of administrationA new combination product, including substitution of an active ingredientNew indicationsRx/OTC Switch
Not generally suitable for PHSA-licensed biologics products
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FDA Assessment of Follow-on ProteinsFactors that influence data required for FOP approval:
robustness of the manufacturing processdegree to which structural similarity can be assessedextent to which mechanism of action was understoodexistence of valid, mechanistically related pharmacodynamic assayscomparative pharmacokineticscomparative immunogenicityamount of clinical data available andextent of experience with the original product, or products
» Nature Reviews Drug Discovery 6, 437-442 (June 2007)
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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions
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Current Proposals GenerallyHR 1038 – Access to Life Saving Medicine Act
Sponsored by Henry Waxman (D-CA)Generic LeaningBIO Strongly Opposes this bill
HR 1956 – Patent Protection and Innovative Biologic Medicines ActSponsored by Jay Inslee (D-WA)Brand LeaningBIO Strongly Supports this bill
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Current Proposals GenerallyHR 5629 – Pathway for Biosimilars Bill
Sponsored by Anna G. Eshoo (D-CA) Joe Barton (R-TX) Bipartisan SupportBIO Strongly Supports this BillGPhA Strongly Opposes this Bill
S 1695 – Biologic Price Competition Innovation ActSponsored by Edward Kennedy (D-MA)Bipartisan SupportBIO Appears to Support this bill
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Current Congressional Proposals
No stay, but the innovator may seek a preliminary injunction to prohibit generic from manufacturing the product
N/A
Requires biosimilarity and limits FDA discretion
HR 1038Access to Life-Saving
Medicine Act
No stay, but the innovator may seek a preliminary injunction to prohibit generic from manufacturing the product
No stay, but the innovator may seek a preliminary injunction to prohibit generic from manufacturing the product
No stay, but the innovator may seek a preliminary injunction to prohibit generic from manufacturing the product
30-month stay of generic approval if patent litigation suit is filed
12-year innovator exclusivity
12 year innovator exclusivity plus additional two years for medically significant indication.
14-year innovator exclusivity
5-year new chemical entity exclusivity for innovator
Requires biosimilarity and gives FDA discretion
Requires biosimilarity plus analytical studies, animal studies and clinical studies.
Requires biosimilarity and creates committee to set standards
Requires bioequivalence
S 1695 Biologic Price
Competition Innovation Act
HR 5629Pathway for Biosimilars
Act
HR 1956Patient Protection and
Innovative Biologic Medicines Act
Hatch-Waxman
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Current Congressional Proposals
N/A
N/A
HR 1956Patient Protection and
Innovative Biologic Medicines Act
Reference applicant must provide a list of patents for which an infringement claim could be made within 60 days of receiving generic application.
Reference applicant must provide a list of patents for which an infringement claim could be made within 60 days of receiving generic application.
Generic may request list of patents, and the holder of the approved reference must provide the information within 60 days, but may demand up to $100 to cover costs.
Patents must be listed in the Orange Book.
At least one year of generic exclusivity for interchangeable products.
At least two years of generic exclusivity for interchangeable products.
At least 180 days of generic exclusivity for interchangeable products.
180-day generic exclusivity for generic approval under Paragraph IV.
S 1695 Biologic Price Competition
Innovation Act
HR 5629Pathway for
Biosimilars Act
HR 1038Access to Life-Saving
Medicine Act
Hatch-Waxman
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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions
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European ApproachBiosimilars approvals beginning in 2006Marketing Authorization Application
“Similar biological medicinal product”» Not suitable for generic products
Comparable to “Reference Product”» Requirements set forth in 2004/27/EC» Comparability in terms of quality, safety and efficacy
Data Exclusivity“8+2+1” for Reference Product
» Period of data protection as incentive for innovation
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EU Legal Framework for BiosimilarsComparability
Safety, quality and efficacyComparability data requirement to determine the risk/benefit balance
Biosimilar Guidelines General guidelines
» EMEA/CHMP/437/04Specific topic guidelines
» EMEA/CHMP/49348/05 (quality)» EMEA/CHMP/42832/05 (non-clinical, clinical)
Specific product class guidelines
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EC Biosimilar Approvals
28 August 2007Eprex/Erypo (Janssen-Cilag) Epoetin alfa Abseamed (Medice)
28 August 2007Eprex/Erypo (Janssen-Cilag) Epoetin alfa Epoetin alfa Hexal (Hexal)
28 August 2007Eprex/Erypo (Janssen-Cilag) Epoetin alfa Binocrit (Sandoz)
24 April 2006Humatrope (Eli Lilly) Somatropin Valtropin (Biopartners)
12 April 2006Genotropin (Pfizer) Somatropin Omnitrope (Sandoz)
Approval dateReference product INN Biosimilar
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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions
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ConclusionUS Legislation is going to happenDrawbacks and benefits for incumbentsBetter to prepare for the worstPotential impact on licensing and deals
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