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WHAT IS IT???. HOW IS IT???. WHY IS IT???. REGULATION VERSUS PHARMACEUTICAL COMP.. Facts. Generic drugs are safe and effective alternatives to brand name prescriptionsGeneric drugs can help both consumers and the government reduce the cost of prescription drugs. NDA vs. ANDA Review Process. Original DrugNDA RequirementsChemistryManufacturingControlsLabelingTestingAnimal StudiesClinical Studies(Bioavailability/Bioequivalence).
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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 2×2 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