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    1. Bioavailability and Bioequivalence: General concepts and overview Ariya Khunvichai, Ph.D. 20 April 2007

    3. Facts Generic drugs are safe and effective alternatives to brand name prescriptions Generic drugs can help both consumers and the government reduce the cost of prescription drugs

    4. NDA vs. ANDA Review Process Original Drug NDA Requirements Chemistry Manufacturing Controls Labeling Testing Animal Studies Clinical Studies (Bioavailability/Bioequivalence) Generic Drug ANDA Requirements Chemistry Manufacturing Controls Labeling Testing Bioequivalence Study (In Vivo, In vitro)

    5. Generic Drug: Definition Same active ingredient (s) Same route of administration Same dosage form Same strength Same indications Compares to reference listed drug (RLD)

    6. Bioequivalence (BE): Definition the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

    7. Bioequivalence

    8. Goals of BE Ultimate: Bioequivalence studies impact of changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the efficacy is based Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product. Important for linking the commercial drug product to clinical trial material at time of NDA Important for post-approval changes in the marketed drug formulation

    9. Scheme of Oral Dosage Form

    10. Bioavailability The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation

    13. Bioavailability IV??? Bench mark for bioequivalence How to calculate?

    14. Clinical/PD Dose-Response

    17. Approaches to Determining BE (21 CFR 320.24) In vivo measurement of active moiety in biologic fluid In vivo pharmacodynamic comparison (Topical Corticosteroid) In vivo clinical comparison (Nasal suspensions) In vitro comparison (Nasal Solution, Topical solution, Oral solution)

    18. Study Design: Basic design consideration Minimize variability not attributable to formulations Minimize bias To compare performance of two products!!!

    19. Study Designs Single-dose, two-way crossover, fasted Single-dose, two-way crossover, fed Alternative Single-dose, parallel, fasted (Long half-life) Single-dose, replicate design (Highly Variable Drugs) Multiple-dose, two-way crossover, fasted (Less Sensitive, non-linear kinetic)

    20. Duration of washout period for cross-over design should be approximately > 5 times the plasma apparent terminal half-life However, should be adjusted accordingly for drugs with complex kinetic model Study Designs

    21. Sample size determination significant level (a = 0.05) 20% deviation from the reference product power > 80% Sample time determination adequate data points around tmax 3 or more time of t1/2 to around AUC0-t = at least 80% AUC0-inf Study Designs

    22. Subjects? (Inclusion/exclusion criteria) LABEL Study Designs

    23. Study Design: Case 1

    24. Statistical Analysis (Two one-sided Tests Procedure) AUC (Extent) and Cmax (Rate) Log transformation - 90% Confidence Intervals (CI) of the difference in Log (AUCt) Log (AUCR) must fit between 80%-125%

    25. Statistical Analysis 80%-125% What does this mean? Can there be a 46% difference? What is a point estimate? What is a confidence interval?

    26. Statistical analysis BE criteria -Two one-sides tests procedure Test (T) is not significantly less than reference Reference (R) is not significantly less than test Significant difference is 20% (a = 0.05 significance level) T/R = 80/100 = 80%, or 100/80 =125%

    27. BE Results (90% CI)

    28. Problems of 22 Crossover Design Overparameterization Carry-over effect is confounded If carryover effect exists, the drug effect cannot be estimated correctly

    30. In vivo BE Inspections Covers clinical and analytical components Study design Issues Analytical method

    31. Bioanalytical Method Validation Method Validation should include Accuracy Precision Sensitivity Specificity Recovery Stability

    32. Accuracy Closeness of determined value to the true Value The acceptance criteria is mean value < 15% deviation from the true value. At LOQ, 20% deviation is acceptable Bioanalytical Method Validation

    33. Precision The closeness of replicate determinations of a sample by an assay The acceptance criteria is < 15% CV, at 20% LOQ Bioanalytical Method Validation

    34. Sensitivity The limit of quantitation is the lowest concentration which can be measured with acceptable accuracy and precision Bioanalytical Method Validation

    35. Selectivity Ability of the method to measure only what it is intended to measure in the presence of other components in the sample. Blank samples of the biological matrix should be tested for the interfering peak. Bioanalytical Method Validation

    36. Recovery The extraction efficiency of an analytical process, reported as an percentage of the known amount of an analyte. Recovery does not have to be 100% but the extent of recovery of internal standard and analyte should be consistent. Bioanalytical Method Validation

    37. Stability During, sample collection , sample storage and sample analysis process, the stability of drug in matrix should be conducted Bioanalytical Method Validation

    38. Thank you and Questions??

    39. Back up slides

    40. Statistical Method: Case 1

    42. Crossover Design 2x2 Crossover design A single-dose bioequivalence study is performed in normal, healthy, adult volunteers. 18 subjects are hired (Male or Female?). The subjects are randomly selected for each group and the sequence of drug administration is randomly assigned. One-week washout periods Fasted or Fed? Study Design: Case 1