USP体内生物等效性试验指南GuidanceSelectionComparatorPharmaceu

161©WorldHealthOrganizationWHOTechnicalReportSeries,No.902,2002Annex11Guidanceontheselectionofcomparatorpharmaceuticalproductsforequivalenceassessmentofinterchangeablemultisource(generic)productsIntroductionThisannexprovidesalistofcomparatorproductsforequivalenceassessmentofinterchangeablemultisource(generic)products.TheinformationoncomparatorpharmaceuticalproductswascollectedbytheSecretariatfromdrugregulatoryauthoritiesandpharmaceuticalcompanies.Thelisthasbeendrawnuptoassistregulatoryauthoritiesandpharmaceuticalcompaniesindecidingonappropriatecompara-torproductsinthecontextofmultisource(generic)marketingautho-rization.Theinformationcouldalsobeusedfordrugprocurementpurposes.Wherethecomparatorpharmaceuticalproductisnotclearlydefined,criteriaaresuggestedthatareprovidedinadecision-treeformat(seeFigure1).Thispermitstheselectionofacomparatorpharmaceuticalproduct.Theguidelinesonregistrationrequirementstoestablishinterchange-abilityofmultisource(generic)pharmaceuticalproductspublishedbyWHO(1)statethatmultisourceproductsmustsatisfythesamestand-ardsofquality,safetyandefficacyasthoseapplicabletothecorre-spondinginnovatorproduct.Theyrecommendthatqualityattributesofamultisourceproductshouldbetestedagainsttheinnovatorprod-uctforwhichinterchangeisintended.Theinnovatorproductisusuallythemostlogicalcomparatorproductbecauseitsquality,safetyandefficacyshouldhavebeenwellassessedinpre-andpost-marketingstudiesand,inaddition,thedataonitssafetyandefficacyareusuallylinkedtoapharmaceuticalproductwithdefinedspecificationsforqualityandperformance.Despiteac-ceptanceofthegeneralobjective,thereisnoagreementonthecrite-riaforselectingalistofinternationalcomparatorproducts,nordoesalistofsuchproductsexist.Thecomparatorproductchoseniseitherthemostwidelyused“leading”productonthemarketortheproductthatwasfirstintroducedinthatmarket.Forthisreason,amongothers,significantdifferencesmayexistbetweenthecomparatorproductsusedindifferentcountries.162Inthelightofthevariousapproachescurrentlyunderscientificandregulatorydiscussion,thefeasibilityofdevelopingasystemofinter-nationalcomparatorproductswasconsidered.Thisinitiativeledtotherecommendationsgivenhere,whichreplacethoseofPartSevenofthepreviouslypublishedWHOguidelinesonmultisourcepharma-ceuticalproducts(1).Alistofinternationalcomparatorpharmaceuticalproductsforequivalenceassessmentofinterchangeablemultisource(generic)products1isgiveninTable1.Figure1Decision-treeforuseinidentifyingacomparatorpharmaceuticalproduct1ThelistisbasedoninformationcollectedbyWHOfromdrugregulatoryauthoritiesandsupplementedwiththatfrompharmaceuticalcompanies.Itwillbeperiodicallyupdated.Comparatorpharmaceuticalproduct(CPP)ofknownquality,safetyandefficacyInnovatorproductknown?YesNoAvailableonlocalmarket?PresentonListB?YesNoYesNoConsiderinnovatorproductasCPPConsiderobtaininginnovatorproduct:ListAFollowcompendialstandardsapproachConsidermarketleaderproductInnovatorproductavailable?Qualityofmarketleaderproductknownandwelldocumented?YesNoYesNoConsiderinnovatorproductasCPPConsidermarketleaderproductConsidermarketleaderproductasCPPConductcomparativecompendialtestsonmultisourceandmarketleaderproductsAcceptabletestresults?YesNoConsidermarketleaderproductasCPPConsidersecondmarketleaderproduct163Instructionsontheuseofthelist1.NationalregulatoryauthoritiesmayissuethisguidancetogetherwithListsAandB,whichshouldbeavailabletoapplicants/phar-maceuticalcompaniesthatplantodevelopmultisourcepharma-ceuticalproductsintendedtobeinterchangeablewithinnovatororotherpharmaceuticalproductsofestablishedquality,safetyandefficacy.2.ListAprovidesinformationaboutpharmaceuticalproductsfromtheWHOModelListofEssentialDrugs(2),andincludestheinnovatorproducts(columnheaded“Trademark”)andthenationalmarketswherethemanufacturersinquestionconsiderthattheirproducts’quality,safetyandefficacyarebestdocu-mented(columnheaded“Primarymarket”).3.PharmaceuticalcompaniesplanningtodevelopaninterchangeablemultisourcepharmaceuticalproductshoulddeterminewhethertheinnovatorpharmaceuticalproductappearinginListAisavailableonthelocalmarket.4.Iftheinnovatorpharmaceuticalproductisavailableonthelocalmarket,pharmaceuticalcompaniesshouldusethisproductinequivalenceassessmentwiththeirmultisourceproduct.5.Iftheinnovatorproductisnotavailableonthelocalmarket,phar-maceuticalcompaniesshouldobtainfromthemarketaproductthatisthebestrepresentativeinnovatorproductfromthepointofviewofitsquality,safetyandefficacy(seecolumnheaded“Primarymarket”ofListA).6.Thetypeofequivalenceassessmentofthecomparatorpharmaceu-ticalproductandthemultisourceproductunderinvestigationmayvary,dependingonlocalrequirementsandtheavailabilityofresources.RecommendationsonthetypeofequivalencestudiestobecarriedoutwhensuchstudiesarenecessaryaregivenintheWHOguidelinesonmultisourcepharmaceuticalproducts(1).7.Forsomepharmaceuticalproducts,aninnovatorproductcannotbeidentified.ExamplesoftheseproductsfromtheWHOModelListofEssentialDrugs(2)appearinListB.Fortheseproducts,alocal,nationalorregionalpharmacopoeiaorTheinternationalpharmacopoeia(3)forboththedrugsubstanc