Bioequivalence studies, design and
evaluation of bioequivalence studies
SUBMITTED TO SUBMITTED BY
ASSISTANT PROFESSOR M.PHARM 1 YEAR
(PHARMACEUTICS) SEM II
COLLEGE OF PHARMACY COLLEGE OF PHARMACY
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contents
• Introduction to Bioequivalence
• Need of Bioequivalence
• Design of Bioequivalence
• Evaluation of Bioequivalence
• Reference
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Introduction to Bioequivalence
• Bioequivalence studies are drug product performance tests that
compare the bioavailability of the same active pharmaceutical
ingredient from one drug product (test) to a second drug product
(reference). Bioavailability and bioequivalence can be considered
as measures of the drug product performance in vivo.
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Need of Bioequivalence
• During drug development, bioequivalence studies are used to compare,
(a) early and late clinical trial formulations;
(b) formulations used in clinical trials and stability studies, if different;
(c) clinical trial formulations and to-be-marketed drug products, if different; and
(d) product strength equivalence, as appropriate.
• Bioequivalence study designs are used to support new formulations of
previously approved products, such as a new fixed-dose combination version of
two products approved for coadministration, or modified-release versions of
immediate-release products.
• Bioequivalence studies may be needed to support regulatory approval of major
changes in formulation, manufacturing, or site, in comparison to reference
formulation.
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Design of Bioequivalence
• The main objective for a bioequivalence study is that the drug bioavailability from test
and reference products is not statistically different when administered to patients or
subjects at the same molar dose from pharmaceutically equivalent drug products
through the same route of administration under similar experimental conditions.
• The basic design for a bioequivalence study is determined by
(1) the scientific questions and objectives to be answered,
(2) the nature of the reference material and the dosage form to be tested,
(3) the availability of analytical methods,
(4) the pharmacokinetics and pharmacodynamics of the drug substance,
(5) the route of drug administration, and
(6) benefit–risk and ethical considerations with regard to testing in humans.
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Bioequivalence study protocol
• I. Title
A. Principal investigator (study director).
B. Project/protocol number and date
• I. Study objective
• III. Study design
A. Design
B. Drug products
1. Test product(s)
2. Reference product
C. Dosage regimen
D. Sample collection schedule
E. Housing/confinement
F. Fasting/meals schedule
G. Analytical methods
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• IV. Study population • VI. Ethical considerations
A. Subjects A. Basic principles
B. Subject selection
B. Institutional review board
1. Medical history
2. Physical examination C. Informed consent
3. Laboratory tests D. Indications for subject withdrawal
C. Inclusion/exclusion criteria E. Adverse reactions and emergency
1. Inclusion criteria procedures
2. Exclusion criteria • VII. Facilities
D. Restrictions/prohibitions
• VIII. Data analysis
• V. Clinical procedures
A. Dosage and drug administration A. Analytical validation procedure
B. Biological sampling schedule and B. Statistical treatment of data
handling procedures • IX. Drug accountability
C. Activity of subjects
• X. Appendix
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Study design
• The FDA provides the guidance for the performance of: In vitro dissolution
and In vivo bioequivalence studies which include(solid oral dosage form)
1. Fasting study
2. Food intervention study
3. Sprinkle BE study (extended release capsules having beads)
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Fasting studies
1. This study is required for all immediate release and modified release oral
dosage forms.
2. Both male and female subjects are included.
3. Overnight fasting is required(at least 10 hrs).
4. After administration of drug fasting continued up to 4 more hrs.
5. Blood sampling is performed before dose and at different intervals after
dose.
6. Plasma drug concentration-time profile is obtained.
7. No other medication given at least 1 week prior to study.
8. In some cases, a parallel design may be more appropriate for certain drug
products, containing a drug with a very long elimination half-life.
9. A replicate design may be used for a drug product containing a drug that has
high intrasubject variability.
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Food intervention study
1. It uses single dose, randomized, 2 treatment, 2 period crossover study.
2. Conducted using meal conditions that have greatest effect on GI physiology.
3. Meal containing high calories(50% of total caloric content) and fat (800-1000
cal) is taken.
4. After a overnight fast of 10 hrs, meal is given 30min prior to dosing.
5. The meal is consumed over 30min with administration of drug(with 240ml of
water) immediately after meal.
6. No food is allowed 4hrs after dosing.
7. Study on drugs like ibuprofen and naproxen which is affected by food.
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EVALUATION OF bioequivalence studies
Analytical Method:-
• Must be validated for accuracy, precision, sensitivity,& specificity.
• Using more than one analytical method for a study is not valid—different
methods may yield different results.
• Data presented in both tabulated and graphic form for evaluation.
• Plasma drug concentration–time curve should be available.
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PHARMACOKINETIC EVALUATION OF THE DATA
• Area under the curve to the last quantifiable concentration (AUC0–t)
• Area under the curve to infinity (AUC0–∞)
• T max
• C max
• Elimination rate constant, k
• Elimination half-life, t 1/2
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STATISTICAL EVALUATION OF THE DATA
(a) Analysis Of Variance (ANOVA) When p ≤ 0.05, the difference b/w 2 drug products is
not “statistically significant”.
(b) Two One-Sided Tests Procedure Demonstrate if bioavailability of the drug from Test
formulation is too low or high in comparison to reference drug.
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WAIVERS OF IN VIVO BIOEQUIVALENCE STUDIES
• Done when 2 drug products are:
• In same dosage form.
• Proportionally similar in active & inactive ingredients.
• Differ only in strengths of the medication.
• Bioequivalence study of lower strength(s) can be waived.
• Only in vitro dissolution test is required to establish bio-equivalency.
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1) Applied Biopharmaceutics arned Pfhearrmeacnokcineetics, 7th Edition by Leon
Shargel , Andrew B.C YU ; page no: 482 -488
2) Basic pharmacokinetics 2nd edition: by Sunil S Jambekar and Philip J Breen
page no:- 141 – 155
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Thank you
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