高特异性药物的生物等效性研究

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1、Why Bioequivalence of Highly Variable Drugs is an IssueCharles E.DiLibertiVice President,Scientific AffairsBarr Laboratories,Inc.Presentation to the Advisory Committee for Pharmaceutical Sciences April 14,2004April 14,20041Definition of Highly Variable Drugs(HVDs)Any drug whose rate and extent of ab

2、sorption shows large dose-to-dose variability within the same patientCommonly understood to include those drugs whose intrapatient coefficient of variation(Cmax and/or AUC)is approximately 30%or moreApril 14,20042Current Bioequivalence CriteriaComparison between test and reference productUse natural

3、 log transformation of Cmax and AUCCriterion:90%confidence intervals about geometric mean test/reference ratios for both Cmax and AUC must fall within 80 125%Applies to all systemically acting drugs(i.e.,not locally acting)with measurable blood or urine levels without regard to the drugs inherent va

4、riabilitySame criteria used by pioneer firms to support formulation changesApril 14,20043April 14,20044Why Alternative Acceptance Criteria Are Needed for HVDsReduce human experimentation(number of participants)in BE studiesProhibitive size of BE studies for some HVDs means no generic is available ma

5、ny American patients go untreated/undertreatedChanging criteria to reduce number of participants in BE studies on HVDs can be accomplished without compromising safety/efficacy80 125%BE criteria not universally implemented worldwideApril 14,20045Foreign BE CriteriaCountry/RegionAUC 90%CI CriteriaCmax

6、 90%CICriteriaCanada(most drugs)80 125%none (point estimate only)Europe(some drugs)80 125%75 133%South Africa(most drugs)80 125%75 133%(or broader if justified)Japan(some drugs)80 125%Some drugs wider than 80 125%Worldwide(WHO)80 125%“acceptance range for Cmax may be wider than for AUC”April 14,2004

7、6Types of Drugs That Are Highly VariableIncludes many therapeutic classesIncludes both newer and older productsPotential savings to patients in the billions of dollars if generics are approvedExamples:atorvastatin,esomeprazole,pantoprazole,clarithromycin,paroxetine(CR),risedronate,metaxalone,itracon

8、azole,balsalazide,acitretin,verapamil,atovaquone,disulfiram,erythromycin,sulfasalazine,etc.April 14,20047Fed BE StudiesConfidence interval criteria now required for BE studies under fed conditionsGeneral paucity of information on variability under fed conditionsSome drugs show much more variability

9、under fed conditions than fasting conditions,making them HVDs(e.g.,esomeprazole,pantoprazole,tizanidine)May be more HVDs than generally appreciatedApril 14,20048Why Current 80-125%Criteria Are Not Appropriate For HVDsCurrent criteria are appropriate for drugs with low to moderate variability because

10、 dose-to-dose variability within a patient is comparable to the width of the criteriaCurrent criteria are not appropriate for HVDs because dose-to-dose variability within a patient is much larger than the width of the criteriaHVDs are“wide therapeutic index”drugs i.e.,have shallow dose response curv

11、es,and wide safety marginsModifying BE acceptance criteria for HVDs to reduce the number of participants in BE studies can be accomplished while maintaining assurance of safety and efficacyApril 14,20049Different HVDs May Require Different Approaches One Size Does Not Fit AllApril 14,200410Example 1

12、:HVDs Not Subject to Significant Accumulation at Steady StateHalf-life short with respect to dosing intervalExamples:omeprazole,tizanidine,azathioprineConsider reference-scaled criteria for both Cmax and AUCDose-to-dose variability within a patient not smoothed out at steady state for either Cmax or

13、 AUC Drug exhibits wide dose-to-dose variations in blood levels irrespective of chronic dosingSame logic applies to HVDs not dosed chronicallyApril 14,200411Example 2:HVDs Subject to Significant Accumulation at Steady StateChronically used and with half-life long with respect to dosing intervalExamp

14、les:itraconazole,metaxalone,acitretinConsider reference scaling criteria for Cmax onlySteady state T/R for AUC same as under single dose conditions(assuming linear kinetics)but variability in AUC will be reduced at steady state drug may not have highly variable AUC at steady stateT/R for Cmax will b

15、e closer to unity at steady state than under single dose conditions,so adjusting criteria for Cmax could be accomplished without impacting assurance of safety/efficacyApril 14,200412Example 2:HVDs Subject to Significant Accumulation at Steady State(contd)Alternatively,could permit demonstration of b

16、ioequivalence with multiple dose steady state studyNot suitable for all drugs due to safety concerns,e.g.,toxic drugs,inclusion of females,etc.April 14,200413April 14,200414April 14,200415April 14,200416April 14,200417Special ConsiderationsApril 14,200418Parallel Studies for Long Half-Life DrugsFor

17、long half-life drugs,crossover studies may not be feasible,necessitating parallel designsPowering parallel studies depends on between-subject variability,not within-subject variabilityBetween-subject variability is often large,necessitating large BE studies on such products,as for HVDsHigh between-s

18、ubject variability does not necessarily imply high within-subject variability(HVD)instead it may be due to interindividual differences in absorption/metabolism(e.g.,genetic polymorphism)Multiple dose steady state studies generally not feasibleConsider reference-scaled criteriaApril 14,200419Pooling

19、Data from Multiple Dosing GroupsLarge n required for HVDs often requires two or more dosing groupsFDA currently requires a statistical test for poolability of data from multiple dosing groups(group x treatment interaction)If interaction term is significant,then the groups may not be pooledIf the gro

20、ups may not be pooled,each group is evaluated on its own for confidence interval criteria,and is likely to fail due to underpoweringThis procedure results in discarding(and having to repeat)about 5%of studies based on random chance aloneEven if there were some underlying explanation for the statisti

21、cal significance(e.g.,differences in demographics among the dosing groups),there is no reason not to use the data from all dosing groups(they would be useable if the same subjects had been dosed in a single group)April 14,200420ConclusionsWhile current BE acceptance criteria are appropriate for drug

22、s with ordinary variability,they are not appropriate for HVDsCurrent BE acceptance criteria make it difficult or impossible to develop generic equivalents to some HVDs,effectively denying treatment to many patientsPractical,scientifically sound,alternative BE acceptance criteria could be implemented

23、 for HVDs to reduce BE study size while maintaining assurance of safety and efficacyDifferent approaches may be needed for different types of drugs,depending particularly on accumulation following multiple dosingOther,related situations(e.g.,parallel studies,multiple dosing groups)should be considered in conjunction with any changes to acceptance criteria for HVDsApril 14,200421