印度2005年生物等效性及生物利用度研究指南

GUIDELINESFORBIOAVAILABILITY&BIOEQUIVALENCESTUDIESCentralDrugsStandardControlOrganization,DirectorateGeneralofHealthServices,MinistryofHealth&FamilyWelfare,GovernmentofIndia,NewDelhi.(March2005)TheseguidelinesshouldbereadinconjunctionwithScheduleYtotheDrugsandCosmeticRules,GCPGuidelinesissuedbyCDSCO,MinistryofHealthandFamilyWelfare,GLPandtheEthicalGuidelinesforBiomedicalresearchonhumansubjectsissuedbyIndianCouncilofMedicalResearch.Allprovisionsdescribedinabovedocumentsshallappropriatelyapplytotheconductofbioavailabilityandbioequivalencestudies.1Contents1.INTRODUCTION2.DEFINITIONS3.SCOPEOFTHEGUIDELINES3.1.Whenbioequivalencestudiesarenecessaryandtypesofstudiesrequired3.1.1.Invivostudies3.1.2.Invitrostudies3.2.Whenbioequivalencestudiesarenotnecessary4.DESIGNANDCONDUCTOFSTUDIES4.1.PharmacokineticStudies4.1.1.Studydesign4.1.2.Studypopulation4.1.3.Studyconditions4.1.4.Characteristicstobeinvestigated4.1.5.Bioanalyticalmethodology4.1.6.Statisticalevaluation4.1.7.SpecialconsiderationsformodifiedreleasedrugproductsiStudyparametersiiStudydesigniiiRequirementsformodifiedreleasedrugproductsunlikelytoaccumulateivRequirementsformodifiedreleasedrugproductslikelytoaccumulate4.2.PharmacodynamicStudies4.3.ComparativeClinicalTrials4.4.In-vitroStudies5.DOCUMENTATION6.FACILITIESFORCONDUCTINGBA/BESTUDIES7.MAINTENANCEOFRECORDSOFBA/BESTUDIES8.RETENTIONOFBA/BESAMPLES9.SPECIALTOPICS9.1.Foodeffectbioavailabilitystudies9.2.Longhalflifedrugs29.3.EarlyExposure9.4.Individualandpopulationbioequivalence31.INTRODUCTIONEnsuringuniformityinstandardsofquality,efficacyandsafetyofpharmaceuticalproductsisthefundamentalresponsibilityofCDSCO.Reasonableassurancehastobeprovidedthatvariousproducts,containingsameactiveingredients,marketedbydifferentlicensees,areclinicallyequivalentandinterchangeable.Accordingly,thebioavailabilityofanactivesubstancefromapharmaceuticalproductshouldbeknownandreproducible.Inmostcases,itiscumbersomeandunnecessarytoassessthisbyclinicalstudies.Bioavailabilityandbioequivalencedataisthereforerequiredtobefurnishedwithapplicationsfornewdrugs,asrequiredunderScheduleY,dependingonthetypeofapplicationbeingsubmitted.Bothbioavailabilityandbioequivalencefocusonthereleaseofadrugsubstancefromitsdosageformandsubsequentabsorptionintothesystemiccirculation.Forthisreason,similarapproachestomeasuringbioavailabilityshouldgenerallybefollowedindemonstratingbioequivalence.Bioavailabilitycanbegenerallydocumentedbyasystemicexposureprofileobtainedbymeasuringdrugand/ormetaboliteconcentrationinthesystemiccirculationovertime.ThesystemicexposureprofiledeterminedduringclinicaltrialsintheearlydrugdevelopmentcanserveasabenchmarkforsubsequentBEstudies.Bioequivalencestudiesshouldbeconductedforthecomparisonoftwomedicinalproductscontainingthesameactivesubstance.Thestudiesshouldprovideanobjectivemeansofcriticallyassessingthepossibilityofalternativeuseofthem.Twoproductsmarketedbydifferentlicensees,containingsameactiveingredient(s),mustbeshowntobetherapeuticallyequivalenttooneanotherinordertobeconsideredinterchangeable.Severaltestmethodsareavailabletoassessequivalence,including:icomparativebioavailability(bioequivalence)studies,inwhichtheactivedrugsubstanceoroneormoremetabolitesismeasuredinanaccessiblebiologicalfluidsuchasplasma,bloodorurineiicomparativepharmacodynamicstudiesinhumansiiicomparativeclinicaltrialsivin-vitrodissolutiontestsTheguidelinesdescribewhenbioavailabilityorbioequivalencestudiesarenecessaryanddescriberequirementsfortheirdesign,conduct,andevaluation.Thepossibilityofusinginvitroinsteadofinvivostudieswithpharmacokineticendpointsisalsoenvisaged.4Forclassesofproducts,includingmanybiologicalssuchasvaccines,animalsera,andproductsderivedfromhumanbloodandplasma,andproductmanufacturedbybiotechnology,theconceptofinterchangeabilityraisescomplexwhichmaybeaddressedbytheapplicantonthebasisofcontemporaryscientificrationale.Invivobioequivalence/bioavailabilitystudiesrecommendedforapprovalofmodifiedreleaseproductsshouldbedesignedtoensurethatitheproductmeetsthemodifiedreleaselabelclaimsiitheproductdoesnotreleasetheactivedrugsubstanceatarateandextentleadingtodosedumpingiiithereisnosignificantdifferencebetweentheperformanceofthemodifiedreleaseproductandthereferenceproduct,whengivenindosageregimestoarriveatthesteadystate.ivtheremustbeasignificantdifferencebetweentheperformanceofmodifiedreleaseproductandtheconventionalreleaseproductwhenusedasreferenceproduct.ItisappreciatedthatpharmacokineticstudiescanbeconductedduringanyphaseofaclinicaltrialforNewChemicalEntities(NCEs).Whiletheseguidelinesdealwithpharmacokinetic/pharmacodynamicstudiesvis-à-visbioavailabilityorbioequivalencestudiesforagenericdrug,theprinciplesdescribedherein,areapplicableforanypharmacokinetic/pharmacodynamicstudy.52.DEFINITIONSBIOAVAILABILITYBioavailabilityreferstotherelativeamountofdrugfromanadministereddosageformwhichentersthesystemiccirculationandtherateatwhichthedrugappearsinthesystemiccirculation.BIOEQUIVALENCEBioequivalenceofadrugproductisachievedifitsextentandrateofabsorptionarenotstatistically