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1、Follow-On Biologics: Economic, Innovation and Policy Reflections The Fuqua School of BusinessDuke UniversityNovember 6-7, 2021av72電影 av72Charles DiLibertiV.P. Global Pharmacokinetics and Bioequivalence,Barr Laboratories, Inc.“Commercial Opportunities and Challenges for Follow-on BiologicsPresentatio

2、n OverviewGeneric BiologicsCommercial Opportunities & SavingsScience & Technology ChallengesRegulatory & Intellectual Property IssuesSummaryCommercial Opportunities & SavingsBenefits of Generic CompetitionSignificant Cost Saving OpportunitiesSavings for consumers and taxpayersGeneric Competition Wil

3、l Fuel InnovationBrand companies will have the incentive needed to vigorously pursue new biologicsIncreasing Significance of Biologic ProductsUS Biologic Revenues1997: $17.4 Billion2007: $ 65.2 Billion*400 Biologics & Vaccines Currently in Clinical Trials Targeting 200 Diseases*Between 2003 and 2006

4、, biologics represented 24% of all new chemical entities approved by the US* Sales of biotech products in the US showed an annual growth rate of 20% between 2001 and 2006 compared with 6% to 8% in the pharmaceutical market* Ernst & Young* Biotechnology Industry Organization * Journal of American Med

5、ical Association, October 22, 2021High Cost of Brand BiologicsAnnual Cost per Patient Enbrel (Arthritis) $20,000*Cerezyme (Gaucher Disease) $200,000* Remicade (Arthritis) $35,000-$66,000*Generic Competition Will Reduce These Costs*Baltimore Sun January 28, 2007*Bloomberg January 11, 2007*Philadelphi

6、a Inquirer September 19, 2006 Significant Cost Savings OpportunityGeneric Biologics Represent Significant Cost Savings Opportunities and Stimulate InnovationEpogenMarket Before Generic Launch: $2.5 Billion*Brand/Year Today: $9,000*Generic Savings/Year assuming 50% savings: $4,500EnbrelMarket Before

7、Generic Launch: $2.7 Billion*Brand/Year Today: $20,000*Generic Savings/Year assuming 50% savings: $10,000*ABN AMRO February 2021*National Journal February 10, 2007*Baltimore Sun January 28, 2007Generic Competition Price Drops as Number of Manufacturers IncreasesMarket Size for Select Biologic Produc

8、tsProduct2006 Sales ($ Millions)Patent ExpirationAranesp (Darbapotein alfa) $2,790 2016Enbrel (Etanercept) $2,7362012Epogen (Epotein alfa)$2,5112004Remicade (Infliximab) $2,3552013Rituxan (Rituximab) $2,0712013Eprex (Ortho Biotech) $2,0642004Avastin (Bevacizumab)$1,7462019Rebetron (Ribavirin & Inter

9、feronalfa-2B)$1,3612001Lantus (Insulin glargine)$1,2602015Source: ABN AMRO February 2021Market Size for Select Biologic ProductsProduct2006 Sales ($ Millions)Patent ExpirationHumira (Adalimumab)$1,1762013Avonex (Interferon beta-1a)$1,0222003Cerezyme (Imiglucerase) $1,0072010Neupogen (Filgrastim) $83

10、02013Humalog (Insulin lispro) $8112013Ceredase (alglucerase)$5372001Rebif (Interferon beta-1a)$4932005Neulasta (Pegfilgrastim)$4932015Source: ABN AMRO February 2021Perspective:Historical Growth in SubstitutionSource: IMS Health, Banc of America Securities LLC estimatesGeneric BiologicsOpportunityGen

11、eric Pharmaceuticals - A Vital Part in Health Care SystemApproximately 67% of the Prescriptions Dispensed in the US Are Generics*BiologicsWorldwide Market Estimated around $75 Billion*Per Patient Cost for Biologic Products Can Exceed $100,000 Per Year Generic BiologicsUS Consumers Could Save $43 Bil

12、lion Between 2021 and 2020*Estimated Value of Biologics that have already lost Patent Protection: $10 Billion*Estimated Value of Biologics to lose Patent Protection in the Next Ten Years: $20 Billion* IMS Health*Citizens Against Government Waste (CAGW) Release, May 2, 2007*ABN AMRO February 2021Scie

13、nce & Technology ChallengesScientific Challenges for Generic BiologicsCharacterizationSafety AssessmentTherapeutic EquivalenceManufacturing ControlsGeneric BiologicsGeneric biologics, sometimes called follow-on biologics (FOBs), are protein products that are pharmaceutically and therapeutically equi

14、valentGeneric biologics do not utilize the reference products proprietary process, specifications or clinical data For established products, therapeutic equivalence can be demonstrated usingIn vitro studies and/orPharmacokinetics and/orSurrogate markers and/orClinical outcomesdepending on the charac

15、teristics of the proteinInterferon2804 atomsMonoclonalAntibody21112 atomsrDNA Technology Drugs:Filgrastim (G-CSF)2659 atomsBiologics Size Does Matter.Azithromycin124 atomsChemical Drug:Misinformation Campaign About Generic BiologicsMyth:Raw materials of biologic origin are hard to source and only br

16、and biotechs know where to find them.Reality:Raw materials are available today for many generic biologics including insulin, G-CSF, erythropoietin, interferons, etc. Misinformation Campaign About Generic BiologicsMyth:Biologics are too complicated to be characterized.Reality:Numerous highly sophisti

17、cated analytical methods have been developed, permitting complete characterization. More advances will be achieved each year. Misinformation Campaign About Generic BiologicsMyth:Generic companies lack the medical, scientific, and technical ability to produce safe and effective biotech products.Reali

18、ty:Generic companies can and do make safe and effective biologics. Many safe and effective biologics currently are made in controlled environments and marketed by generic companies outside the U.S. Generic Biologics (Biosimilars) in the EUThe ability to make generic biologics is far from a theoretic

19、al possibility.In 2004 EU issued EMEA Draft Guidelines for four classes of generic biologics, referred to as biosimiliars in the EU.Since 2004, the EU has approved several biosimilar products.EU Biosimilar ApprovalsDRUG EU MARKET AUTHORIZATION DATESandozs Omnitrope (somatropin) April 12, 2006BioPart

20、ners Valtropin (somatropin) April 24, 2006Sandozs BinocritMedices AbseamedHexal Biotechs Epoetin alfa Hexal (recombinant human erythropoietin alfa) August 28, 2007Stada Arzneimittels Silapo Hospiras Retacrit (epoetin zeta)December 18, 2007Tevas TevagrastimRatiopharms RatiograstimRatiopharms Filgrast

21、im ratiopharmCT Arzneimittels Biograstim(human G-CSF)September 15, 2021 current through September 25, 2021FDA Approves Sandozs OmnitropeThere has been some movement in the US to approve generic biologics.FDA approved Omnitrope in May 2006.FDA stated, however, that this approval does not create a pat

22、hway for all generic biologics. Omnitrope referenced a brand product (Genotropin) approved under the FDCA.Misinformation Campaign About Generic BiologicsMyth:“The Product is the Process.Reality:“Old models and mantras are inhibiting progress the product is no longer the process. (Statement of Mathia

23、s Hukkelhoven, Ph.D., Senior V.P., Global Head, Drug Regulatory Affairs, Novartis, Sept. 14-15, 2004). Misinformation Campaign About Generic BiologicsReality (continued):Biotech products can be fully characterized and compared analytically.Biotech Firms routinely justify their own process changes vi

24、a FDA approved comparability protocols.Development of Generic BiologicsStrictly Controlled Process (Validated)Extensive Analytical Comparability (Characterization)Comparable Biological Activity (In Vitro/In Vivo)Non-Clinical Comparability (Safety, Immunogenicity.)Comparable pharmacokinetics (blood c

25、oncentration profile)Comparable Clinical Efficacy and SafetyDevelopment ConsiderationsProduct ComplexityFrom Development To ClinicalCharacterizationBiosynthesis, In-Process and Finished ProductNomenclatureLack of Strict Definition, INN IssueHigh Cost of Development Marketing Requirements and CostPos

26、t-Marketing Safety SurveillanceIP StrengthRegulatory & Intellectual Property IssuesChallenges for Generic BiologicsRegulatoryCongress needs to create an abbreviated approval pathwayIntellectual PropertyBrand exclusivityGeneric exclusivityResolution of patent litigation prior to generic launchRegulat

27、ory IssuesRegulatory Framework Complicated By Existence of Two Laws For BiologicsFDCA for NDA ProductsPHSA for BLA Products NDA Products Generic Pathway Exits, But FDA Implementation Is UnclearBLA ProductsThree Issues Need To Be ResolvedMechanics of Approval Pathway Need To Be DefinedBrand/Generic E

28、xclusivityAn Efficient Patent Dispute Resolution MechanismAbbreviated Generic Pathway Under PHSAA Generic Pathway Should:Give FDA Authority To Decide Approval Requirements For Generic ProductsAdopt Exclusivity Provisions No Greater Than Those Found In Hatch-WaxmanPermit Pre-Launch Adjudication of Ce

29、rtain Patent Disputes Abbreviated Generic Pathway Under PHSAFDA should be permitted to decide what tests/data are necessary for approval as a comparable or interchangeable generic.Congress should not impose unnecessary barriers to generic approvals, e.g., mandatory guidance or rule-making requiremen

30、ts; mandatory clinical trials; requirement that generics seek approval for all approved brand uses.Abbreviated Generic Pathway Under PHSACongress should carefully consider any new, additional exclusivities awarded to brand biologics.Considerable incentives already exist for brand biotech companies.E

31、xisting Incentives for Brand Biotech CompaniesINCENTIVEPatent Term RestorationDrug manufacturers get back up to 5 years of time lost to product testing and approval delays.PTO Patent RestorationIf the patent approval is delayed by PTOs fault, patentee gets back each day in excess of 3 years.Orphan D

32、rug Exclusivity7 years of exclusivity for drugs treating rare diseases.General Business R&D Tax CreditAllows manufacturers to claim 20% of qualified spending in the U.S. above the base amount.Puerto Rico Tax CreditAllows U.S. corporations to exempt 40% of income from business operations owned in P.R

33、., U.S.V.I., etc.Foreign Tax CreditAllows U.S. corporations to claim limited tax credit for taxes paid to foreign governments.URAAPatent Term RestorationThe Uruguay Rounds Agreement Act (“URAA”) gives drug companies a 20 year patent from the date it was filed (rather than 17 years from issue).Abbrev

34、iated Generic Pathway Under PHSAIf Congress decides to give additional exclusivities to brand companies, Hatch-Waxman establishes the maximum length and number of exclusivities that can be justified:- 5 years for truly new, innovative products- 3 years for certain improvements to already-approved br

35、and productsAbbreviated Generic Pathway Under PHSAUnlike the incentives that already exist to develop new brand biologics, no incentives exist to develop generic biologics.Generic biologics legislation should include an incentive, just as Hatch-Waxman does for small molecule drugs, for the developme

36、nt of generic biologics.Abbreviated Generic Pathway Under PHSAEffective generic biologics legislation will include a mechanism for expeditious resolution of patent disputes.Hatch-Waxman has shown that patent mechanisms can be abused to delay generic market entry.Abbreviated Generic Pathway Under PHS

37、AOnly those patent disputes that would cause the generic company to delay launch should be litigated simultaneously with the FDA approval process.Disputes over any other patent that the brand owns should wait until the generic company actually launches.Abbreviated Generic Pathway Under PHSASuch a pr

38、ocess ensures that brand companies cannot use weak or suspect patents to delay generic market entry.At the same time, the process protects all legitimate patent rights it allows litigation over all patents, but controls when that litigation can start so that generic marketing isnt unduly delayed.Neg

39、otiations Are OngoingMuch Momentum Gained in DebateOptimistic for Ultimate ResolutionRegulatory IssuesU.S. Proposed LegislationSummaryGeneric Biologics in USSignificant Momentum in US CongressFailed to Pass in 2007-08 Session; Likely to Be On Legislative Agenda in 2021Strong Consensus for Generic Biologics Among Payers, Consumer GroupsDebate Centers On Three IssuesMechanics of PathwayHow to Resolve IP IssuesExclusivity IssueState Governors Broad, Bipartisan Support for a Wor