欧盟关于生物等效性和生物利用度的指导原则

1、European Medicines AgencyLondon,24May2007Doc.Ref.EMEA/CHMP/EWP/200943/2007COMMITTEEFORMEDICINALPRODUCTSFORHUMANUSE(CHMP)RECOMMENDATIONONTHENEEDFORREVISIONOF(CHMP)CPMP/EWP/QWP/1401/98AGREEDBYEFFICACYWORKINGPARTYMay2007ADOPTIONBYCHMPFORRELEASEFORCONSULTATION24May2007ENDOFCONSULTATION(DEADLINEFORCOMMEN

2、TS)31August2007Commentsshouldbeprovidedto HYPERLINK mailto:EWPSecretariatemea.europa.eu EWPSecretariatemea.europa.euFax:+442074188613KEYWORDSBioavailability,bioequivalence,guidance7WestferryCircus,CanaryWharf,London,E144HB,UKTel.(44-20)74188400Fax(44-20)74188613E-mail: HYPERLINK mailto:mailemea.euro

3、pa.eu mailemea.europa.eu HYPERLINK http:/www.emea.europa.eu http:/www.emea.europa.euEMEA2007Reproductionand/ordistributionofthisdocumentisauthorisedfornoncommercialpurposesonlyprovidedtheEMEAisacknowledgedINTRODUCTIONTheNoteforguidance(NfG) The term NfG has been replaced bythis document.ontheinvesti

4、gationofbioavailability(BA)andbioequivalence(BE),forproductswithasystemiceffect,definesrequirementsforbioavailabilityandbioequivalencestudiesregardingnecessity,design,conduct,evaluation,andreporting.Discussionduringmutualrecognitionprocedures(MRP)anddecentralised(DC)proceduresrevealedthatseveralissu

5、esintheNfGmaybedifferentlyinterpretedbyMemberStates.BetterclarityontheseissuesshouldimprovetheunderstandingoftheGuideline,andasaresultmayincreasetheconsensusbetweenMemberStatesduringtheMRPandDCprocedures.PROBLEMSTATEMENTFirstly,theNfGisoutdatedinsomeaspects,sincethecomingintoforceofthenewpharmaceuti

6、callegislationwiththenewamendmentofDirective2001/83/EC.Furthermore,bioavailabilityandbioequivalencearetwodifferenttopicsthatneedtobedistinguishedandeachdeservesspecificattentionbecauserequirementsforbioavailabilityandbioequivalencemaydiffer.GuidanceonbioavailabilityintheNfGislimited.Thisshouldbeimpr

7、ovedandextended.Ontheotherhand,regulatoryexperiencehasshownthatguidanceonbioequivalenceneedsfurtherharmonisationwithintheEuropeanUnion.ThiswasalreadyrecognisedandaQ&Adocumenthasbeenreleasedrecently( HYPERLINK http:/www.emea.europa.eu/pdfs/human/ewp/4032606en.pdf http:/www.emea.europa.eu/pdfs/human/e

8、wp/4032606en.pdf).Inaddition,inthelastdecadetheanalyticalmethodshavebeenimprovedinsuchawaythattheguidanceandrequirementsontheanalytestobemeasuredneedtobeupdated.Similarly,experiencegainedintheBiopharmaceuticsClassificationSystem(BCS)allowsfurtherrecommendationsonbiowaivers.DISCUSSION(ONTHEPROBLEMSTA

9、TEMENT)ThefollowingdiscussionpointshavebeendefinedwhenreviewingthecurrentNfGontheInvestigationofBioavailabilityandBioequivalenceinordertoimprovetheharmonisation:?SpecificrecommendationsonBAwillbegiven.RequirementsonexploratoryandconfirmatoryBAandBEstudieswillbedifferentiatedinseparatesectionsofthegu

10、idancedocument?RecommendationsonBEinthecurrentguidancewillbeupdatedwithregardto:otheconceptofessentialsimilaritywhichhaschangedsincethenewlegislationwithreferencetotherecentDirectiveamendment(Directive2004/27/EC)andrelevantguidelinesounderwhichcircumstancesaparalleldesignmaybeusedounderwhichcircumst

11、ancesasequentialdesignmaybeusedothestudydesignfordrugswithdoseandtimedependentpharmacokineticsotheacceptabilityofsteadystatedesignsotheanalytestobemeasuredandtobetakenintoaccountintheassessmentofbioequivalenceotheneedofenantiomericbioanalyticalmethodsorequirementsforpotencycorrectionofTestandReferen

12、ceproductsostudydesign/dosinginstructionsforparticulardosageforms(e.g.,orodispersibletablets)a Guideline ” . The latter term will be applied in the revision process ofodissolutiontestconditionsoproportionalityofcompositions?IncorporationandadaptationofothertopicsdiscussedintherecentQuestionandAnswer

13、document:otheassessmentofCmaxinbioequivalencestudiesowhethertheacceptancerangeofBElimits(90%CIs)canbeextendedorequirementsonhowtohandleoutliersoinclusionofthebordersofthe90%CIotheuseofanon-parametricstatisticalmethodoinwhichcasesmetaboliteshavetobemeasuredandtobetakenintoaccountinthebioequivalentass

14、essmentothedefinitionofhighlyvariabledrugsotheselectionofthestrengthtobemeasuredostandardisationwithregardtofoodintakeforstudiesunderfedconditionsotheuseofurinarydataforbioequivalenceassessment?BCSconceptsandbiowaiverrequirementswillberevisedandexpandedinaseparateAnnex/sectionRECOMMENDATIONItispropo

15、sedtorevisethecurrentNoteforGuidanceontheInvestigationofBioavailabilityandBioequivalence(CPMP/EWP/QWP/1401/98)toprovideanupdatedNfGontheabove-mentionedissues.PROPOSEDTIMETABLEItisanticipatedthatadraftCHMPdocumentmaybereleased12monthsafteradoptionoftheConceptPaper.Itwillbelaterreleasedfor6monthsofext

16、ernalconsultationandfinalisedwithin6months.RESOURCEREQUIREMENTSFORPREPARATIONThepreparationofthisdocumentwillinvolvetheEWPTherapeuticSubgrouponPharmacokineticsandtheQWP.IMPACTASSESSMENT(ANTICIPATED)AnticipatedBenefittoIndustryandOtherInterestedPartiesRevisionoftheNoteforGuidanceontheInvestigationofB

17、ioavailabilityandBioequivalenceshouldimproveunderstandingoftheGuidelineandleadtoamoreconsistentinterpretationofregulatoryrequirements,whichcanresultinimproveddesignandsuccessofbioequivalencestudies.AnticipatedBenefittoRegulatoryAuthoritiesRevisionoftheNoteforGuidanceontheInvestigationofBioavailabilityandBioequivalenceshouldimproveconsist