bioequivalence studies - advanced biopharmaceutics

bioequivalence studies biopharm -advanced biopharmaceutics

1. Bioequivalence studies Prepared By, Sujitha Mary II Sem M.Pharm St Joseph College Of Pharmacy

2. content 2 BIOEQUIVALENCE STUDIES BIOEQUIVALENCE PROTOCOL DESIGN EVALUATION OF THE DATA STUDY SUBMISSION AND DRUG REVIEW PROCESS CONCLUSION REFERENCE

3. 1.BIOEQUIVALENCE STUDIES 3 To compare the bioavailability of the generic drug product to the brand-name product. Bioequivalence may be defined as the bioavailability of the generic drug is compared with the measured parameter of from that of the reference drug hen administered at the same molar dose of active moiety either in single or multiple doses.

4. . 4 Chemical equivalence indicates that two or more dosage forms contain the labelled quantities of drug Therapeutic equivalence implies that one structurally different chemical can yield the same clinical result as another chemical Pharmaceutical equivalents : Drug products in identical dosage forms that contain same active ingredient(s),the same salt or ester, are of the same dosage form, use the same route of administration, and are identical in strength or concentration.

5. Necessity to Establish Bioequivalence 5 Marketed drug products do not give comparable therapeutic effects. 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.

6. 2. BIOEQUIVALENCE PROTOCOL Title A Principal investigator (study director) B. Project/protocol number and date Study objective Study design Design Drug products Test product(s) Reference product Dosage regime n Sample collection schedule Housing/confinement Fasting/meals schedule Analytical methods Study population Subjects Subject selection Medical history Physical examination Laboratory tests . 6

7. . 7 C. Inclusion/exclusion criteria Inclusion criteria Exclusion criteria D. Restrictions/prohibitions Clinical procedures Dosage and drug administration Biological sampling schedule and handling procedures Activity of subjects Ethical considerations Basic principles Institutional review board Informed consent Indications for subject withdrawal Adverse reactions and emergency procedures Facilities Data analysis A. Analytical validation procedure B. Statistical treatment of data Drug accountability Appendix

8. 1.TITLE 8 Name of the principle investigator, other person responsible for conducting the study. Name of the laboratory and clinical pharmacology where the study will be conduct. Complete official address of the premises of the lab and contact number of the person in charge of the study, with time for contact Name of the sponsor and other person responsible for monitoring the study should be mentioned along with complete official as well as residential addresses and phone number with contact times

9. 2. Study Objective 9 : The objective for a bioequivalence study is that the drug bio availability from test and reference products are not statically different when administered to patients are subjects at same molar dose under similar experimental conditions

10. 3.Study design 10 A. 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 concentration—time profile. Subjects should be in fasting condition—at least 10 hrs. before drug administration and 4 hrs. after administration.

11. . 11 B. 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 bioavailability is affected by food (e.g.. Ibuprofen, naproxen).

12. cross over design . 1. 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. 12

13. . 2.BALANCE INCOMPLETE BLOCK DESIGN: More than 3 formulations Latin square design will not be used because each volunteer may required drawing of too many blood samples If each volunteer expected to receive at least 2 formulations then such study can be carried out using BIBD. Volunteer no Period 1 Period 2 1 A B 2 A C 3 A D 4 B C 5 B D 6 B A 7 C A 8 C B 9 C D 10 D A 11 D B 12 D C 13

14. . 14 SUBJECT PERIOD 1 2 1 A B 2 B A 3 A B 4 B A 3 . PARALLEL GROUP DESIGN: The subjects are divided randomly into groups, each group receiving one treatment randomly. Here number of groups is same as number of treatments to be compared. Each subject receives only one treatment .

15. . 15 SEQUENCE PERIOD 1 2 3 4 1 T R T R 2 R T R T 4. REPLICATED CROSS OVER DESIGN Used for the determination of individual bioequivalence. Allows comparison of within-subject variance and to provide an estimate of the subject-by-formulation interaction variance. Four-period, two-sequence, two-formulation design is recommended. Where R = reference T = treatment

16. DIFFERENCE BETWEEN PARALLEL GROUP AND CROSS OVER GROUP 16 PARALLEL GROUP CROSS OVER Group assigned different treatment Each patient receive both treatment Shorter duration Larger treatment Larger sample size Smaller sample size No Carry Over Effect Carry Over Effect

17. 4.Evaluation of the data 17 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 different results. Data presented in both tabulated and graphic form for evaluation. Plasma drug concentration–time curve should be available.

18. . 18 2. Pharmacokinetic Evaluation of the Data Area under the curve to the last quantifiable concentration (AUC 0–t ) Area under the curve to infinity (AUC 0–∞ ) T max C max elimination rate constant, k elimination half-life, t 1/2

19. . 19 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%

20. 5.Study Submission And Drug Review Process 20 Brand–Name Drug NDA Requirements Generic Drug ANDA Requirements 1. Chemistry 1. Chemistry 2. Manufacturing 2. Manufacturing 3. Controls 3. Controls 4. Labelling 4. Labelling 5. Testing 5. Testing 6. Animal studies 6. Bioequivalence 7. Clinical studies   8. Bioavailability   The contents of New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) are similar in terms of the quality of manufacture.

21. . 21 The study has been properly designed, the objectives are clearly defined, Validated both statistically and pharmacokinetic analysis and case reports and various data are included in the submission. The FDA review (inspect both the clinical and analytical facilities used in the study and audit the raw data used in support of the bioavailability study. If the application is incomplete, the FDA will not review the submission and the sponsor will receive a Refusal to file letter.

22. 6.CONCLUSION 22 Both bioavailability and bioequivalence focus on measuring the absorption of the drug into systemic circulation 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

23. 7 . REFERENCE 23 Leon Shargel and Andrew BC Yu; Applied Biopharmaceutical and Pharmacokinetics; Drug Product Performance, In vivo: Bioavailability and Bioequivalence; 7 th Edition; MC Graw Hill Publication ; 2016; page no: 482-502 DM. Brahmankar and Sunil B Jaiswal; textbook Biopharmaceutical and Pharmacokinetics ; bioavailability and bioequivalence ;3 rd Edition; Vallabh Prakashan publication, Delhi; 2015; page no: 329-360 www.slideshare.com

24. Thankyou….. .