中美仿制药研发申报流程

中美仿制药研发和申报流程涂家生，Ph.D.中国药科大学药剂学教授Tel:025-83271305Email:[e-mail]2011.11郑州我国仿制药申报、审评和研发对策主要内容中美关于原研药和仿制药的背景美国仿制药：申报、基于问题的审评和研发对策展望1234CompanyLogo3药物经济学催生美国仿制药制度美国社会安全制度导致政府赤字严重SSA已经破产：如何破局？降低医疗费用成为必然Hatch-Waxman法案出台美国FDA药品注册申请：新药（两类）、仿制药和非处方药申请1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)•“FullReports”ofSafetyandEfficacyInvestigations•Applicanthasrightofreferencetoessentialinvestigations?•Duplicateofanalreadyapprovedproduct•Nosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)NDA的研发和申报505(b)(1)新药申报资料内容1.Index2.Summary3.Chemistry,ManufacturingandControl4.Samples,MethodsValidationPackageandLabeling5.NonclinicalPharmacologyandToxicology6.HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification505(b)(2):历史过程HatchWaxman法案：1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizen’sPetition(2003)可以降低研发的费用和审评力量的浪费505(b)(2)的关键:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?505(b)(2)的意义介于全创新药物和仿制药之间具有专利保护，且不存在产权纠纷和仿制药不同，无替换的要求应有突破505(b)(2)范围NewChemicalEntity(rarely)：我国1.1-1.3Newdosageform：我国5类Newdosingregimen：我国补充申请Newstrength：我国补充申请Newrouteofadministration：我国2类Newindication：我国1.6505(b)(2)情形Newactiveingredient(differentsalt,ester,complex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRxOTCswitchNewCombinationProducts“Genericbiologics”505(b)(2)排他性Exclusivitiesavailablefor505(b)(2)productsNCEExclusivity(5years)NewProductExclusivity(3years)OrphanDrugExclusivity(7years)Pediatricexclusivityextensions(6months)PatentIssues505(b)(2)drugscanhaveOrangeBook-listedpatents,andenjoy30-monthstayprotectionagainstgenericcompetitorsBut,505(b)(2)NDAsmayalsobeblockedbypatentsonReferenceDrugs505(b)(2)新药的成功例子NCEThalomid®(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine(2000)Guaifenesinextendedrelease(2002)Quininesulfate(2005)NewDosageFormTramadolorallydisintegratingtablets(2005)Ondansetronoralspray(filed2006)505(b)(2)新药的例子NewDosingRegimenTramadolextendedreleasetablets(2005)NewStrength/FormulationAntara(micronizedfenofibratecaps)(2004)(130mgisBEtoTricor200mg)NewFormulation/InactiveIngredientAvita(tretinoingel)(newemollient)(1998)Abraxane(cremaphor-freepaclitaxel)(2005)Oxy-ADF(oxycodoneformulatedtoreducedrugabuse)(indevelopment)505(b)(2)新药的例子NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)(2003)NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)RxOTCSwitchAlavert(loratadine)(2002)505(b)(2)新药的例子“GenericBiologics”Omnitrope(rHGH)(2006)Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals2004-05)Fortical(calcitoninsalmonrecombinant)(2005)*ExamplesbasedonpubliclyavailableinformationFDANDA审评过程FDA可以使用已有数据用于审评NDA吗？Hatch-Waxman之前,国会限制FDA在审评NDAX时应用NDAY的数据：“NodatainanNDAcanbeutilizedtosupportanotherNDAwithoutexpresspermissionoftheoriginalNDAholder.”[FDA“FinkelMemorandum”(1978,1981)]Hatch-Waxman解除只适合ANDAs：ANDAprocessallows“genericproducerofthefullytesteddrugtorelyonthesafetyandefficacydataofapriorapplicant....”505(b)(2)doesnotauthorizesuchdatarelianceMerelysetsconditionsforcertainNDAsRequires“fullreportsofinvestigations”establishingsafetyandeffectiveness[21USC§§355(b)(1)(A),(d)(1)]美国仿制药Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.Genericdrugapplicationsaretermed“abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.FDA审评仿制药程序二、美国仿制药的申报、审评和研发对策由FDA的OGD审评审评方式采用QbR申报资料采用CTD资料内容也针对问题ComparisonofReceiptsandApprovalsofANDAApplications273261335346326335449563766213230306249266294310373413467307361364010020030040050060070080090019951996199719981999200020012002200320042005FiscalYearNumberofSubmissionsReceiptsApprovals(Full&Tentative)OfficeofGenericDrugsMEDIANApprovalTimesANDAORIGINALS28.224.719.618.717.318.918.418.317.316.316.305101520253019951996199719981999200020012002200320042005FiscalYearMonthsOfficeofGenericDrugsPendingOriginalApplications417427422374395564615780010020030040050060070080090019981999200020012002200320042005atFiscalYearendSubmissionsinQueueOfficeofGenericDrugsControlledCorrespondenceDocumentsReceived457511631685111615029520200400600800100012001400160019992000200120022003