高变异药物的生物等效性(BE)试验

April 14, 2004
April 14, 2004
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Number of Subjects Required for Crossover BE Study With 80% Power
600
500
Number of Subjects Required
400
300 200
Assumed T/R = 105%
Assumed T/R = 110%
• 80 – 125% BE criteria not universally implemented worldwide
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Foreign BE Criteria
Country/Region Canada (most drugs) Europe (some drugs) South Africa (most drugs) Japan (some drugs) Worldwide (WHO)
Why Bioequivalence of Highly Variable Drugs is an Issue
Charles E. DiLiberti Vice President, Scientific Affairs
Barr Laboratories, Inc. Presentation to the Advisory Committee for Pharmaceutical Sciences
Some drugs wider than 80 – 125%
“acceptance range for Cmax may be wider than
for AUC”
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Types of Drugs That Are Highly Variable
• Includes many therapeutic classes
April 14, 2004
AUC 90% CI Criteria 80 – 125%
80 – 125% 80 – 125%
80 – 125%
80 – 125%
Cmax 90% CI Criteria
none (point estimate only)
75 – 133%
75 – 133% (or broader if justified)
Current Bioequivalence Criteria
• Comparison between test and reference product • Use natural log transformation of Cmax and AUC • Criterion: 90% confidence intervals about geometric mean
• Includes both newer and older products
• Potential savings to patients in the billions of dollars if generics are approved
• Examples: atorvastatin, esomeprazole, pantoprazole, clarithromycin, paroxetine (CR), risedronate, metaxalone, itraconazole, balsalazide, acitretin, verapamil, atovaquone, disulfiram, erythromycin, sulfasalazine, etc.
• Commonly understood to include those drugs whose intrapatient coefficient of variation (Cmax and/or AUC) is approximately 30% or more
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• Prohibitive size of BE studies for some HVDs means no generic is available – many American patients go untreated/undertreated
• Changing criteria to reduce number of participants in BE studies on HVDs can be accomplished without compromising safety/efficacy
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 drug’s inherent variability • Same criteria used by pioneer firms to support formulation changes
April 14, 2004
April 14, 2004
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Definition of Highly Variable Drugs (HVDs)
• Any drug whose rate and extent of absorption shows large dose-to-dose variability within the same patient
100
0 0%

20%
40%
60%
Intrasubject CV
80%
100%
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Why Alternative Acceptance
Criteria Are Needed for HVDs
• Reduce human experimentation (number of participants) in BE studies