Seminar on

BIOEQUIVALENCE STUDIES

Presented by: Muhammed Fahad 1st M.Pharm Dept. of Pharmaceutics Al-Shifa College of Pharmacy

BIOEQUIVALENCE STUDIES

• To compare the bioavailability of the generic drug product to the brand-name product.

• Bioequivalent drugs that have same systemic bioavailability will have same predictable drug response.

• Still, variable response may occur due to age, drug tolerance, drug interactions or disease states.

2

Determining Bioequivalence

• Test drug is bioequivalent if in vivo bioavailability of test (generic drug) do not differ significantly (statistically insignificant) compared to reference (brand drug).

• Done by measuring plasma drug concn, urinary excretion rates, pharmacodynamic effects, etc.

3

Neccessity to Establish Bioequivalence

• Marketed drug products do not give comparable therapeutic effects.

• Narrow therapeutic ratio; requires careful dosing.• Serious adverse effect on the treatment (if not

bioequivalent).• Low water solubility of active drug.• Slow dissolution rate.• High ratio of excipients to active ingredients (>5:1).

4

Neccessity to Establish Bioequivalence

Contd…• Active drug absorbed in particular segment of the GI

tract .• Absorption is less than 50%.• Rapid first-pass metabolism.• Drug is subject to dose-dependent kinetics.• Drug is rapidly metabolized or excreted.• Drug requires special coatings such as enteric

coating.

5

DESIGN OF BIOEQUIVALENCE STUDIES

The test and reference drug formulations must contain:

pharmaceutically equivalent drug, in the same dose strength, in similar dosage forms (eg, immediate release or

controlled release), and given by the same route of administration. Approval from Institutional Review Board (IRB) of the

testing unit. Consists of both single dose & multiple dose studies.

6

I. Title A. Principal investigator

(study director)

B. Project/protocol number and date

II. Study objectiveIII. 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 methodsIV. Study population A. Subjects B. Subject selection 1. Medical history 2. Physical examination 3. Laboratory tests

Elements of a Bioavailability Study Protocol

7

C. Inclusion/exclusion criteria 1. Inclusion criteria 2. Exclusion criteria D. Restrictions/prohibitionsV. Clinical procedures A. Dosage and drug

administration B. Biological sampling

schedule and handling procedures

C. Activity of subjectsVI. Ethical considerations A. Basic principles B. Institutional review board

C. Informed consent D. Indications for subject

withdrawal E. Adverse reactions and

emergency proceduresVII. FacilitiesVIII. Data analysis A. Analytical validation

procedure B. Statistical treatment of

dataIX. Drug accountabilityX. Appendix

8

Analytical Methods

• Must be accurate.• Of sufficient sensitivity to measure small changes.• Should be with appropriate precision.• Measure the actual concentration of the active drug

or active metabolite(s), achieved in the body.

9

Reference Standard• One formulation of the drug is chosen as reference

standard against which all other formulations of the drug are compared.

• Reference drug should be administered by the same route as other drug formulations.

• Reference standard is generally a formulation currently marketed with a fully approved NDA for which there are valid scientific safety and efficacy data.

• Usually innovator’s or brand drug.10

Extended-Release Formulations

• Done in order to ensure that:

1. Product has claimed controlled-release characters.

2. No occurrence of dose-dumping.

3. Steady state is equivalent to currently marketed extended release formulation.

4. Consistent pharmacokinetic performance b/w units.

New extended-release product compared with existing non-controlled release products.

11

Combination drug products

• To determine the rate & extend of absorption of each active ingredient.

• And to determine if it is equivalent to the rate and extent of absorption of each active ingredient administered concurrently as separate single-ingredient preparations.

12

Study Designs

1. Fasting study

2. Food intervention study

3. Multiple-dose (steady-state) study

13

Fasting Study

• Done for immediate-release and modified-release oral dosage forms.

• Male and female subjects may be used.• Blood sampling is done at appropriate intervals to

obtain plasma drug concn—time profile.• Subjects should be in fasting condition—at least 10

hrs before drug administration and 4 hrs after administration.

14

Food Intervention Study

• Studies are conducted after high-fat and high-calorie meal.

• Subjects should be in fasting condition at least 10 hrs before drug administration.

• Meal is given 30 minutes before dosing.• No food given for at least 4 hrs after administration.• Done for modified-release dosage forms.• And for immediate-release forms if bioavailabilty is

affected by food (e.g.. Ibuprofen, naproxen).

15

Multiple-Dose (Steady-State) Study

• Done for oral extended-release (controlled-release) drug products.

• Done in addition to the fasting & food intervention study.

• Three consecutive Cmin measured on three consec:

days to determine steady state.• Sampling done similar to fasting study.

16

Crossover Designs

• Each subject receives the test & reference drug product.

• Eg. Latin-square crossover designs.• Each subject receives each drug product only once.• Adequate wash-out period is provided b/w drugs.

Advantages: Subject-to-subject variation is reduced. All patients do not receive same drug product on the

same day.

17

18

19

• Period—time period in which a study is performed.• Two-period study – performed on 2 diff. days separated

by a washout period—generally about 10 elimination half-lives.

• Sequence—no. of diff orders in the treatment groups in a study.

• For e.g., a two-sequence, two-period study would be designed as follows:

20

EVALUATION OF DATA

1. 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 diff. results.

• Data presented in both tabulated and graphic form for evaluation.

• Plasma drug concentration–time curve should be available.

21

EVALUATION OF DATA

2. 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

22

EVALUATION OF DATA

3. Statistical Evaluation of the Data

• (a) Analysis Of Variance (ANOVA) When p ≤ 0.05, the diff 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.

Evaluation of confidence limits—90% ± 20%

23

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 bioequivalency.

24

REFERENCES• Shargel. L, Applied Biopharmaceutics and

Pharmacokinetics, 5th edition, Mc Graw Hill, Singapore, 2005, pp 460-475

• Madan. P. L, Biopharmaceutics and Pharmacokinetics, 1st edition, Jaypee, New Delhi, 2000, pp 141-155

• Chatwal. G. R, Biopharmaceutics and Pharmacokinetics, 1st edition, Himalaya, new Delhi, 2003, pp 201-215

• Brahmankar. D. M, Biopharmaceutics and Pharmacokinetics—A Treatise, 1st editon, Vallabh Prakashan, 2006, pp290-296

25

26

THANK YOU