Results from Replicate Design Studies in ANDAs

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Results from Replicate Design Studies in ANDAs

• Rabi Patnaik, Ph.D.
• Division of Bioequivalence
• Office of Generic Drugs
• Office of Pharmaceutical Science, CDER

Advisory Committee for Pharmaceutical Science
Meeting CDER Advisory Committee Conference
Room 5630 Fishers Lane, Rockville, MD November
29, 2001.
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ABE IBE Criteria and Parameters
ABE
Lower BE Limit lt Test Mean - Ref. Mean lt Upper
BE Limit
IBE
(Test Mean - Ref. Mean)2 (SubjForm)2 (Test
within-subj. SD2 - Ref. within-subj. SD2)
lt
Upper BE Limit
(Ref. within-subj. SD)2 or (Regulatory
within-subj. SD)2
use Ref. within-subj. SD if Ref. within-subj.
SD gt 0.2 (Reference-scaled) use Regulatory
within-subj SD (0.20) if Ref. within-subj SD lt
0.2 (Constant-scaled)
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Summary of Studies
Purpose of Submission Approval of generic
drugs Number of Studies 13 Study Design
2-treatment, 2-sequence, 4-period
Crossover Sequence Designs ABAB/BABA and
ABBA/BAAB Number of Subjects 16 - 59 Demography
Controlled population (mostly young healthy male
subjects) Dosage Forms IR, MR (solid oral
products), Suspension, Suppository Analyte
Parent Drug BE Measures AUC(0-T), AUC(0-inf),
CMAX
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Summary of Results
Number of Data Sets Passing/Failing by IBE and
ABE Criteria
Individual Bioequivalence (IBE)
Pass
Fail
11/13 (AUCT) 12/13 (AUCI) 12/13 (CMAX)
2/13 (AUCT) 1/13 (AUCI)
Pass
Average Bioequivalence (ABE)
Fail
1/13 (CMAX)
NONE
Summary of IBE Parameters
Within-subj. Std. Dev. Range - Ref. Drug
Within-subj. Std. Dev. Test/Ref. Ratio - Range
Subj.X Form. - Range
Test/Ref G. Mean Ratio. - Range
BE Measure
AUC(0-T)
89.3 - 103.6
0.06 - 0.39
0.88 - 1.56
0 - 0.2
AUC(0-inf)
89.3 - 103.9
0.08 - 0.38
0.77 - 1.54
0 - 0.12
CMAX
88.5 - 115.1
0.11 - 0.45
0.69 - 1.34
0 - 0.2
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Performance of the IBE Criterion - Some Examples
1. Failing ABE Passing IBE Drug 2 - IR
(CMAX) - N55
2. Passing IBE (Drug 1 - IR , N29) Failing
IBE (Drug 4 - IR, N59) - AUC(0-T)
3. Passing IBE (Drug 3 - SUP., N57) Failing
IBE (Drug 6 - ER, N27) - AUC(0-T)
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Subject-by-Formulation Interaction (Drug 4) -
AUC(0-T)
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Subject-by-Formulation Interaction - CMAX (Drug
2)
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Concluding Remarks
1. IBE approach is an aggregate criterion. The
combination of all three parameters
(differences in means, differences in
within-subject variances, and
subjectformulation) determines the outcome. 2.
Scaling approach is particularly helpful for
highly variable drugs with large
within-subject variances. 3. Analysis of showed
that important subject-by-formulation
interactions occurred due to a few subjects.
The reliability and the possible cause of such
observed interactions need to be carefully
investigated. 4. The studies received thus far
during the interim period, have utilized
controlled populations. The frequency of
occurrence of important subject-by-formulation
interactions and the utility of this approach
will be better evaluated as BE studies
using heterogeneous general populations become
available to the Agency.