Bioequivalence study

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 of Variance (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 : The objectives of the study. The ability to analyze the drug (and metabolites) in biological fluids. the pharmacodynamics of the drug substance. The route of drug administration. The 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 = dose, k = elimination rate constant, V D = volume of distribution.

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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.

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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 : The scientific questions to be answered, The nature of the reference material and the dosage form to be tested, The availability of analytical methods.. 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. Fasting study, A food intervention study, and/or 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, (AUC 0–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 the Test 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 of Variance (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 AUC 0–t , AUC 0–∞ , 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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