bioequivalance studies protocol study

1. BIOEQUIVALENCE
STUDIES
PRESENTED BY: Arun Agarwal
Mpharm (2015-2017)
Invertis Institute of Pharmacy, Invertis University, Bareilly

2. CONTENT
• Introduction.
• Assessment of bioavailability and
Bioequivalence.
• Design and Evaluation of
Bioequivalence Studies.
• Design.
• Important points to be consider while
start studies.
• Analytical Methods.
• Reference Standard.
• Extended-Release Formulations.
• Combination Drug Products.
• Study designs.
• Fasting Study.
• Food Intervention Study.
• Multiple-Dose (Steady-State) Study.
• Evaluation of the Data.
• Analytical method.
• Pharmacokinetic Evaluation of the
Data.
• Statistical Evaluation of the Data.
• Analysis ofVariance (ANOVA).

3. INTRODUCTION
Bioequivalence is established if
the in-vivo bioavailability of a
test drug product (usually the
generic product) does not differ
significantly in the product's
rate and extent of drug
absorption.

4. Drug products with possible bioavailability and
bioequivalence problems
Lack of bioavailability or bioequivalence may be suspected when
evidence from well-controlled clinical trials or controlled
observations in patients of various marketed drug products do
not give comparable therapeutic effects.

5. Biopharmaceutical properties
• Low solubility in water (e.g., less than 5 mg/ml).
• The dissolution rate of one or more such products is slow (e.g., less than 50% in 30
minutes).
• The particle size and/or surface area of the active drug ingredient.
• Drug products that have a high ratio of excipients to active ingredients (e.g., greater than
5:1).
• The therapeutic moiety is rapidly metabolized or excreted.
• The active drug ingredient or therapeutic moiety is unstable in specific portions of the GI
tract.

6. Assessment of bioavailability and
Bioequivalence
• The in-vivo bioavailability of a drug product is demonstrated by the rate and
extent of drug absorption, as determined by comparison of measured
parameters, e.g., concentration of the active drug ingredient in the blood,
cumulative urinary excretion rates, or pharmacological effects.
• The design of the bioavailability study depends on :
oThe objectives of the study.
oThe ability to analyze the drug (and metabolites) in biological fluids.
othe pharmacodynamics of the drug substance.
oThe route of drug administration.
oThe nature of the drug product.

7. Methods for Assessing Bioavailability and
Bioequivalence
• Plasma drug concentration
• Urinary drug excretion
• Acute pharmacodynamic effect
• Clinical observations
• In-vitro studies

8. Plasma drug concentration
Where:
• F = fraction of dose absorbed,
•D 0 = dose,
• k = elimination rate constant,
•V D = volume of distribution.

9. Cont..

10. Urinary drug excretion data
• This method of assessing bioavailability is based on the principle that the
urinary excretion of unchanged drug is directly proportional to the plasma
concentration of drug.
• As the rule of Thumb, determination of bioavailability using urinary
excretion data should be conducted only if at least 20% of administered
drug is excreted unchanged in the urine.
• This study useful for those drugs which are extensively excreted in urine and
also those drugs which have urine as a site of action.
• E.g.Thiazide, sulphonamides, nitrofurantoin and hexamine.

11. Cont..

12. Cont..

13. Cont..

14. Acute Pharmacodynamic Effect
• The acute pharmacodynamic effect is measured over a period of time after
administration of the drug product.
• This approach may be particularly applicable to dosage forms that are not
intended to deliver the active moiety to the bloodstream for systemic
distribution.
• Measurements of the pharmacodynamic effect should be made with
sufficient frequency to permit a reasonable estimate for a time period at
least three times the half-life of the drug.

15. Clinical Observations
• Well-controlled clinical trials in humans establish the safety and
effectiveness of drug products and may be used to determine
bioavailability.
• However, the clinical trials approach is the least accurate, least sensitive,
and least reproducible of the general approaches for determining in-vivo
bioavailability.
• The FDA considers this approach only when analytical methods and
pharmacodynamic methods are not available to permit use of one of the
approaches described above.

16. Design and Evaluation of Bioequivalence
Studies
Bioequivalence studies are performed to compare the
bioavailability of the generic drug product to the brand-name
product.

17. Design
• The basic design for a bioequivalence study is determined by :
1. The scientific questions to be answered,
2. The nature of the reference material and the dosage form to be tested,
3. The availability of analytical methods..
4. Benefit–risk and ethical considerations with regard to testing in humans.
For some generic drugs.

18. Important points to be consider while start studies
• For bioequivalence studies, the test and reference drug formulations must
contain the pharmaceutical equivalent drug in the same dose strength.
• Both a single-dose and/or a multiple-dose (steady-state) study may be
required.
• the Institutional Review Board (IRB) of the clinical facility in which the study
is to be performed must approve the study.

19. • The study is performed in normal, healthy male and female volunteers who
have given informed consent to be in the study.
• The number of subjects in the study will depend on the expected
intersubject and intrasubject variability.
• Smokers are often included in these studies.
• The subjects are generally fasted for 10 to 12 hours (overnight) prior to drug
administration and may continue to fast for a 2 to 4hour period after dosing.

20. Analytical Methods
• The analytical method used in an in-vivo bioavailability or bioequivalence study to
measure the concentration of the active drug ingredient or therapeutic moiety, or
its active metabolite(s), in body fluids or excretory products.

21. Reference Standard
For bioequivalence studies on a proposed generic drug product the
reference standard is the reference listed drug (RLD), which is listed in
Approved Drug Products with Therapeutic Equivalence Evaluations—the
Orange Book (www.fda.gov/cder/orange/default.htm), and the proposed
generic drug product is often referred to as the "Test" drug product.

22. Extended-Release Formulations
• A comparison bioavailability study is used for the development of a new
extended release drug product in which the reference drug product may be
either a solution or suspension of the active ingredient or a currently
marketed non-controlled release drug product such as a tablet or capsule.
• For example, the bioavailability of a non-controlled-release (immediate-
release) drug product given at a dose of 25 mg every 8 hours is compared to
an extended-release product containing 75 mg of the same drug given once
daily.

23. Combination Drug Products
• Generally, the purpose of an in-vivo bioavailability study involving a
combination drug product containing more than one active drug substance
is to determine if the rate and extent of absorption of each active drug
ingredient or therapeutic moiety in the combination drug product is
equivalent to the rate and extent of absorption of each active drug
ingredient or therapeutic moiety administered concurrently in separate
single-ingredient preparations.

24. STUDY DESIGNS
• For many drug products, the FDA, Similar guidelines appear in the United
States Pharmacopeia NF. Currently, three different studies may be required
for solid oral dosage forms.
(1) Fasting study,
(2) A food intervention study, and/or
(3) A multiple-dose (steady-state) study.

25. Fasting Study
• Bioequivalence studies are usually evaluated by a single-dose, two-period,
two-treatment, two-sequence, open-label, randomized crossover design
comparing equal doses of the test and reference products in fasted, adult,
healthy subjects.
• Blood sampling is performed just before (zero time) the dose and at
appropriate intervals after the dose to obtain an adequate description of the
plasma drug concentration–time profile.
• The subjects should be in the fasting state (overnight fast of at least 10
hours) before drug administration and should continue to fast for up to 4
hours after dosing. No other medication is normally given to the subject for
at least 1 week prior to the study.

26. Food Intervention Study
• Food intervention or food effect studies are generally conducted using meal
conditions that are expected to provide the greatest effects on GI
physiology so that systemic drug availability is maximally affected.
• A typical test meal is two eggs fried in butter, two strips of bacon, two slices
of toast with butter, 4 ounces of brown potatoes, and 8 ounces of milk.
• fast of at least 10 hours, subjects are given the recommended meal 30
minutes before dosing. The meal is consumed over 30 minutes, with
administration of the drug product immediately after the meal.
• The drug product is given with 240 mL (8 fluid ounces) of water. No food is
allowed for at least 4 hours post dose.

27. Multiple-Dose (Steady-State) Study
• For these studies, three consecutive trough concentrations (C min) on three
consecutive days should be determined to ascertain that the subjects are at
steady state.
• The last morning dose is given to the subject after an overnight fast, with
continual fasting for at least 2 hours following dose administration. Blood
sampling is performed similarly to the single-dose study.

28. Evaluation of the Data
Analytical Method
• Analytical method for measurement of the drug must be validated for
accuracy, precision, sensitivity, and specificity.
• The plasma drug concentration–time curve for each drug product and each
subject should be available.

29. Pharmacokinetic Evaluation of the Data
• For single-dose studies, including a fasting study or a food intervention
study, the pharmacokinetic analyses include calculation for each subject
• For multiple-dose studies, pharmacokinetic analysis includes calculation for
each subject of the steady-state area under the curve, (AUC0–t), T max, C min,
C max, and
• The percent fluctuation [100 x (C max – C min)/C min].

30. Statistical Evaluation of the Data
• To prove bioequivalence, there must be no statistical difference between
the bioavailability of theTest product and the Reference product.
• Many statistical approaches (parametric tests) assume that the data are
distributed according to a normal distribution or "bell-shaped curve".
• The distribution of many biological parameters such as C max and AUC have a
longer right tail than would be observed in a normal distribution .

31. Analysis ofVariance (ANOVA)
• An analysis of variance (ANOVA) is a statistical procedure () used to test the data
for differences within and between treatment and control groups.
• A bioequivalent product should produce no significant difference in all
pharmacokinetic parameters tested.
• The parameters tested usually include AUC0–t, AUC0–∞, t max, and C max obtained for
each treatment or dosage form.
• The ANOVA may evaluate variability in subjects, treatment groups, study period,
formulation, and other variables, depending on the study design.

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