Bioequivalence Bioequivalence Methods for Highly Methods for Highly Variable Drugs and Variable Drugs and

Drug ProductsDrug Products

By: Kalpesh PrajapatiGlenmaek Generics Ltd.

Discussion TopicsDiscussion TopicsPresent BE Study ApproachCharacteristics of HVDsDisadvantage of using current

approach for Highly Variable Drugs (HVDs)

Recommended criterion for HVDsNew Approaches Evaluated by FDA Preferred approach for HVD

Introduction – Introduction – As per usual procedure

◦ Comparison between test and reference product

◦ Use natural log transformation of Cmax and AUC

◦ Criterion: 90% confidence intervals about geometric mean test/reference ratios for both Cmax and AUC must fall within 80 – 125%

Highly Variable Drugs Characteristics Highly Variable Drugs Characteristics (HVDs)(HVDs)

Drugs with high within subject variability (CVwr) in bioavailability parameters AUC and/or Cmax ≥ 30% ◦ i.e. Any drug whose rate and extent of absorption shows large

dose-to-dose variability within the same patient.

Recommended criterion for Recommended criterion for HVDsHVDsEnroll adequate no. of subjects to show

bioequivalence in 2 way crossover◦ Disadvantage: Study may require larger sample size

(N) other wise it my underpowered and must go for new study.

◦ Ethically – concern for regulatoryReplicate Design (four period) study

◦ It may lead to high drop out rate◦ Or required to enroll larger sample size◦ Very Expensive

Group Sequential Design◦ By dividing subjects in equal groups & make

conclusion at interim stage and at final stage◦ Required statistical adjustment

New Approaches Evaluated New Approaches Evaluated by FDA by FDA April 2004 – Advisory Committee for

Pharmaceutical Science (ACPS)◦ Different approaches were considered for HVDs ,

e.g. expansion of bioequivalence limits and scaled average bioequivalence

◦ Favored: Scaled average bioequivalence including point estimate constraint.

◦ Minimum sample size of 24

Preferred approach for HVD : Preferred approach for HVD :

scaled average BE for HV scaled average BE for HV drugsdrugsPartial replicate study or reference –

replicated◦ Three period BE study◦ Reference twice and test once◦ Sequences: TRR, RTR, RRT

Evaluation of scaled average BE criteria

◦ where is the BE limit

Cmax and AUC should meet BE criteria

Issues with the SABE Issues with the SABE approachapproachAdvantage

◦Fewer subjects can be used to establish BE for HV drugs

Disadvantage◦What about border line drugs?◦High or Low T/R mean Ratios◦Number of subjects?

ConclusionConclusionMixed scale average BE

◦Normal average bioequivalence for CV < 30

◦Scaled average Bioequivalence for CV>30