Highly Variable Drugs – Highly Variable Drugs – Bioequivalence Issues:Bioequivalence Issues:FDA Proposal Under FDA Proposal Under

ConsiderationConsiderationBarbara M. Davit, J.D., Ph.D.Barbara M. Davit, J.D., Ph.D.

Deputy Director, Division of Bioequivalence (DBE)Deputy Director, Division of Bioequivalence (DBE)Office of Generic Drugs (OGD)Office of Generic Drugs (OGD)

Office of Pharmaceutical Sciences (OPS)/CDEROffice of Pharmaceutical Sciences (OPS)/CDER

Advisory Committee for Pharmaceutical ScienceAdvisory Committee for Pharmaceutical ScienceOctober 6, 2006October 6, 2006

Discussion topicsDiscussion topics

Characteristics of highly variable (HV) Characteristics of highly variable (HV) drugsdrugs

Present bioequivalence (BE) study Present bioequivalence (BE) study approach used by the OGD for all drugsapproach used by the OGD for all drugs● Disadvantages of using current approach for Disadvantages of using current approach for

HV drugsHV drugs Reference-scaled average BE approach Reference-scaled average BE approach

under consideration by FDAunder consideration by FDA● Advantages/concernsAdvantages/concerns

Questions for committeeQuestions for committee

HV Drug CharacteristicsHV Drug Characteristics

Within-subject variability (CVWithin-subject variability (CVWRWR) in BE ) in BE parameters AUC and/or Cparameters AUC and/or Cmaxmax >> 30% 30%

Non-narrow therapeutic indexNon-narrow therapeutic index Represent about 10% of drugs Represent about 10% of drugs

studied in vivo and reviewed by OGDstudied in vivo and reviewed by OGD

Some reasons for high Some reasons for high variability in BE parametersvariability in BE parameters

Drug substanceDrug substance● Variable absorption rateVariable absorption rate● Low extent of absorptionLow extent of absorption● Extensive presystemic metabolismExtensive presystemic metabolism

Drug productDrug product● Inactive ingredient effectsInactive ingredient effects● Manufacturing effectsManufacturing effects● Bioanalytical assay sensitivityBioanalytical assay sensitivity● Suboptimal PK samplingSuboptimal PK sampling

Impractical to identify mechanism in each Impractical to identify mechanism in each casecase

Characteristics of HV drugs Characteristics of HV drugs evaluated by OGDevaluated by OGD

Can use Root Mean Square Error (RSME) to Can use Root Mean Square Error (RSME) to estimate within-subject variability in two-estimate within-subject variability in two-way crossover studiesway crossover studies● Conclude drug is HV if RMSE Conclude drug is HV if RMSE >> 0.3 0.3

Using this criterion, about 10% of drugs Using this criterion, about 10% of drugs evaluated by OGD are HV drugs; of theseevaluated by OGD are HV drugs; of these● 55% are consistently HV55% are consistently HV● 20% are “borderline” cases20% are “borderline” cases● For the remaining 25%, high variability occurs For the remaining 25%, high variability occurs

sporadically (not HV in most BE studies)sporadically (not HV in most BE studies)

BE issues with HV DrugsBE issues with HV Drugs

High probability that BE parameters High probability that BE parameters will differ when same subject will differ when same subject receives a HV drug on more than one receives a HV drug on more than one occasionoccasion

Because of the high variability, a HV Because of the high variability, a HV drug that is truly therapeutically drug that is truly therapeutically equivalent to the reference may not equivalent to the reference may not meet BE acceptance criteriameet BE acceptance criteria

Present FDA approach used for Present FDA approach used for BE studies of HV drugsBE studies of HV drugs

Generally, firms submitting ANDAs for HV Generally, firms submitting ANDAs for HV drugs use the same study design as for drugs use the same study design as for drugs with lower variabilitydrugs with lower variability● Two-way crossover studyTwo-way crossover study● Replicate-design studyReplicate-design study

HV drugs must meet same acceptance HV drugs must meet same acceptance criteria as drugs with lower variabilitycriteria as drugs with lower variability● 90% CI of AUC and C90% CI of AUC and Cmaxmax test/reference ratios test/reference ratios

must fall between limits of 0.8 to 1.25 (80-must fall between limits of 0.8 to 1.25 (80-125%)125%)

Disadvantages of present FDA Disadvantages of present FDA approach for HV drugsapproach for HV drugs

ApproachApproach DisadvantagesDisadvantages

Enroll adequate # of Enroll adequate # of subjects (N) to show subjects (N) to show BE in 2-way crossover BE in 2-way crossover studystudy

Study may require larger NStudy may require larger N● avg. N = 47 for HV drugs *avg. N = 47 for HV drugs *● avg. N = 33 for other drugs *avg. N = 33 for other drugs *

If study underpowered, must If study underpowered, must do new studydo new study

Replicate-design (4-Replicate-design (4-period) studyperiod) study

High dropout rate; may need to High dropout rate; may need to enroll larger Nenroll larger N

Group sequential-Group sequential-design studydesign study

Must have protocol in place Must have protocol in place a a prioripriori;; Statistical adjustmentStatistical adjustment

* Based on BE studies submitted to OGD in 2003-2005

Evolution of new proposal for Evolution of new proposal for BE studies of HV drugsBE studies of HV drugs

Pharmaceutical Sciences Advisory Pharmaceutical Sciences Advisory Committee in 2004 suggested Committee in 2004 suggested reference-scaled average BE reference-scaled average BE approachapproach

OGD Science Team studied approach OGD Science Team studied approach by simulating outcome of BE studies by simulating outcome of BE studies of HV drugsof HV drugs

FDA is considering using this FDA is considering using this approach for BE studies of HV drugsapproach for BE studies of HV drugs

New FDA proposal: scaled New FDA proposal: scaled average BE for HV drugsaverage BE for HV drugs

Three-period BE studyThree-period BE study● Provide reference product (R) twiceProvide reference product (R) twice● Provide test product (T) onceProvide test product (T) once● Sequences = TRR, RRT, RTRSequences = TRR, RRT, RTR

BE criteria scaled to reference BE criteria scaled to reference variabilityvariability● ((µµTT - µ - µRR))22 - - ӨӨσσ22

WRWR << 0 ; 0 ; ӨӨ = upper BE limit = upper BE limit Both AUC and CBoth AUC and Cmaxmax should meet BE should meet BE

acceptance criteriaacceptance criteria

Advantages of reference-scaled Advantages of reference-scaled average BEaverage BE

If T variability < R variability, will If T variability < R variability, will benefit test productbenefit test product

If T variability > R variability, no If T variability > R variability, no benefit for test productbenefit for test product

Use of scaled average BE for Use of scaled average BE for borderline HV drugsborderline HV drugs

Our simulations confirmed that, for a true Our simulations confirmed that, for a true “borderline” HV drug*, either scaled or “borderline” HV drug*, either scaled or unscaled average BE approach is suitableunscaled average BE approach is suitable● Outcome of a 3-way crossover BE study will be Outcome of a 3-way crossover BE study will be

similar whether a reference-scaled average BE similar whether a reference-scaled average BE analysis or unscaled average BE analysis is analysis or unscaled average BE analysis is conductedconducted

* We define a borderline HV drug as one for which, in * We define a borderline HV drug as one for which, in individual studies, within-subject variability in BE individual studies, within-subject variability in BE parameters is generally slightly > or < 30%, and the parameters is generally slightly > or < 30%, and the average within-subject variability is about 30%average within-subject variability is about 30%

When scaled average BE When scaled average BE approach is unsuitableapproach is unsuitable

HV due to generic product or study HV due to generic product or study conductconduct

If due to effects of generic formulation, will If due to effects of generic formulation, will not benefit from scaled average BE not benefit from scaled average BE approachapproach● If T variability > R variability

Studies poorly performedStudies poorly performed● Burden on applicant to prove to OGD that drug Burden on applicant to prove to OGD that drug

substance is HVsubstance is HV● OGD can conclude that scaled average BE OGD can conclude that scaled average BE

approach is unacceptableapproach is unacceptable

Concerns about reference-Concerns about reference-scaled average BEscaled average BE

ConcernConcern Proposed solutionProposed solution

Firms will conduct Firms will conduct a replicate-design a replicate-design study, then submit study, then submit results with both results with both scaled and unscaled scaled and unscaled BE analysesBE analyses

If CVIf CVWRWR >> 30%, FDA 30%, FDA will use the will use the reference-scaled reference-scaled average BE approachaverage BE approachIf CVIf CVWRWR < 30%, FDA < 30%, FDA will use the unscaled will use the unscaled average BE approachaverage BE approach

Concerns about reference-Concerns about reference-scaled average BEscaled average BE

ConcernConcern Proposed solutionProposed solution

Scaling can allow Scaling can allow the resulting AUC the resulting AUC and Cand Cmaxmax geometric geometric mean ratios to be mean ratios to be either unacceptably either unacceptably low or highlow or high

Acceptance criteria Acceptance criteria can include a point can include a point estimate constraintestimate constraint

Concerns about reference-Concerns about reference-scaled average BEscaled average BE

ConcernConcern Proposed solutionProposed solution

What should be an What should be an appropriate number appropriate number of subjects for a BE of subjects for a BE study that uses this study that uses this approach?approach?

Should the FDA Should the FDA recommend a recommend a minimum number of minimum number of subjects?subjects?

AcknowledgementsAcknowledgements

OGD Working OGD Working GroupGroup● Mei-Ling ChenMei-Ling Chen● Dale ConnerDale Conner● Sam HaidarSam Haidar● Lai Ming LeeLai Ming Lee● Rob LionbergerRob Lionberger● Fairouz MakhloufFairouz Makhlouf● Devvrat PatelDevvrat Patel● Don SchuirmannDon Schuirmann● Lawrence YuLawrence Yu

DBE Research DBE Research GroupGroup● Beth Fabian-FritschBeth Fabian-Fritsch● Sheryl GuntherSheryl Gunther● Xiaojian JiangXiaojian Jiang● Devvrat PatelDevvrat Patel● Keri SuhKeri Suh● Christina ThompsonChristina Thompson