BIOEQUIVALENCE STUDIES.pptx

It refers to the drug substance in two or more identical dosage forms , reaches systemic circulation at he same rate and to the same relative extent .
Their plasma concentration –time profile will be identical without significant statistical differences.

1. BIOEQUIVALENCE STUDIES & DESIGN Submitted by:- Shiva Kant Thakur M. Pharm 1 st year ( pharmaceutics ) Submitted To :- Dr .Tejpal Yadav Assistance professor(pharmaceutics)

2. CONTENT Definition Requirement /objectives of BIOEQUIVALENCE Type of bioequivalence in vivo In vitro Study designs

3. Definition It refers to the drug substance in two or more identical dosage forms , reaches systemic circulation at he same rate and to the same relative extent . Their plasma concentration –time profile will be identical without significant statistical differences.

4. Advantages & Disadvantages Minimizes the effect of inter subject variability. It minimizes the carry over effect . Requires less number of subjects to get meaningful results Requires longer time to time to complete the studies. Completion of studies depends of formulations evaluated in the studies. Increase in study period leads to high subject Medical ethics does not allow too many trials on subject continuously for a longer time.

5. Objectives If a new product is intended to be a substitute for an approved medicinal product as a pharmaceutical equivalent or alternative, the equivalence with this product should be shown or justified . In order to ensure clinical performance of such drug products, bioequivalence studies should be performed. Bioequivalence studies are conducted if there is: A risk of pharmacotherapeutic failure or diminished clinical safety.

6. Some of the important terms Equivalence :- it is a relative term that compares drug products with respect to a specific characteristic or function or to a defined set of standards. These are several types of equivalences. Chemical equivalence Pharmaceutical equivalence Bioequivalence Therapeutic equivalence

7. Types of equivalences Chemical Equivalence :- it indicates that two or more drug products contain the same labelled substance as an active ingredient in the same amount . Pharmaceutical Equivalence :-the term implies that two or more drug products are identical in strength , quality ,purity ,content uniformity and disintegration and dissolution characteristics .they may, however, differ in containing different excipients.

8. Types of equivalence C . Bioequivalence :- it is a relative term which denotes that the drug substance in two or more identical dosage forms, reaches the systemic circulation at the same relative rate and to the same relative extent i.e. their plasma concentration –time profiles will be identical without significant statistical differences.. When statistically significant differences are observed in the bioavailability of two or more drug products, bio -inequivalence is indicated. D . Therapeutic :- this term indicates that two or more drug products that contain the same therapeutically active ingredient elicit identical pharmacological effects and can control the disease to the same extent.

9. Types of bioequivalence studies Bioequivalence can be demonstrated either:- In-vivo In -vitro

10. In vivo bioequivalence studies The following sequence of criteria is useful in assessing the need for in vivo studies: Oral immediate – release products with systemic action- Indicated for serious conditions requiring assured response. Narrow therapeutic margin. Pharmacokinetics complicated by absorption < 70% or absorption window ,nonlinear kinetics ,presystemic elimination>70%. Unfavorable physiochemical properties , e.g.low solubility, metastable modification ,instability , etc.

11. In vivo bioequivalence studies Documented evidence for bioavailability problems. No relevant data available , unless justification by applicant that in vivo study is not necessary . 2. Non –oral immediate – release products. 3. Modified – release products with systemic action . In vivo bioequivalence studies are conducted in the usual manner as discussed for bioavailability studies, i.e. the pharmacokinetic and the pharmacodynamics methods.

12. Pharmacokinetic methods Plasma level – time studies Urinary excretion studies Pharmacodynamics methods Acute pharmacological response Therapeutic response

13. In vitro bioequivalence studies If none of above criteria is applicable, comparative in vivo dissolution studies will suffice. In vitro studies, i.e. dissolution studies can be used in lieu of in vivo bioequivalence under certain circumstances , called as bio waivers (exemption). The drug product differs only in strength of the active substance it contains, provided all the following conditions hold- Pharmacokinetics are linear. The qualitative composition is the same .

14. In vitro bioequivalence studies The ratio between active substance and the excipient is the same , or(in the case of small strengths) the ratio between the excipients is the same. Both products are produced by the same manufacture at the same production site. A bioavailability or bioequivalence study has been performed with a original product. Under the same test conditions, the in vitro dissolution rate is the same. 2. The manufacturing method has been slightly modified by the original manufacture in ways that can convincingly be argued to be irrelevant for the bioavailability .

15. In vitro bioequivalence studies 3 . The drug product meets all of the following requirements – The product is in the form of solution or solubilized from(elixir, syrup, tincture, etc ). The product contains active ingredient in the same concentration as the approved drug product. The product contains no excipients known to significantly affect absorption of the active ingredient

16. In vitro bioequivalence studies 4. The in vitro dissolution rate of the new product is equivalent with that of the already approved medicinal product. The product is intended for topical administration ( cream, ointment ,gel , etc.) for local effect . The product is for oral administration but not intended to be absorbed ( antacid or radio- opaque medium ). The product is administered by inhalation as a gas vapor . The criteria for drug products listed above indicate that bioavailability and bioequivalence are self-evident.

17. Bioequivalence protocol Experimental design Wash out period Drug products: ( a) Test product(s ) ( b) Recognized standard Route of administration Dosage regimen Frequency and duration of sampling Randomization of drug administration Single-versus multiple-dose study design

18. Bioequivalence protocol 9. Subjects (a) Healthy subjects versus patients (b) Subject selection ( i ) medical history, (ii) Physical examination, (iii) Laboratory tests (c) Study conditions 10 . Analysis of biological fluids

19. Bioequivalence protocol C. Methods of Assessment of Bioavailability Plasma data Urine data Acute pharmacological effect Clinical response D. Analysis and Presentation of Data 1. Statistical treatment of data-Analysis of variance (AN OVA) 2. Format of data

20. Bioequivalence design study The FDA provides the guidance for the performance of in vitro dissolution and in vivo bioequivalence studies which include ( solid oral dosage form): Fasting study Food intervention study Crossover study designs Sprinkle BE study(extended release capsules having beads)

21. 1. Fasting study The study is required for all immediate and modified release oral dosage forms. Both male and female subjects are included. Overnight fasting is required (at least 10 hrs ). After admn . Of drug fasting continued up to 4 more hours. Blood sampling is performed before dose and at diff. intervals after dose Plasma drug concentation –time profile is obtained. No other medication given at least 1 week prior to study.

22. 2. Food intervention study It uses single dose, randomized ,2 treatment , 2period crossover study. Conducted using meal conditions that have greatest effect on GI physiology. Meal containing high calories (50% of total caloric content) and fat (800-1000cal)is taken. After a overnight fast of 10hrs , meal is given 30min prior to dosing. The meal is consumed over 30min with admn . of drug(with 240ml of water) immediately after meal. No food is allowed 4hrs after dosing. Study on drug like ibuprofen and naproxen which is affected by food.

23. 3.Crossover study designs 1 . Each subject receives the test and reference drug product . 2 . Latin Square Crossover designs are used for BE study in human volunteers . 3 . These Latin Square designs plans the clinical trials so that each subject receives each drug product only once . 4 . Enough time between medications for elimination of drug is given. 5 . Possible crossover effects are minimized by sequence or order in which drug products are given to subject.

24. Crossover study designs Latine –square crossover design for a bioequivalence study of three drug products in six human volunteers . Subject Study period1 Study period2 Study period3 1 A B C 2 B C A 3 C A B 4 A C B 5 C B A 6 B A C

25. Crossover study designs Latine –square crossover design for a bioequivalence study of four drug products in 16 human volunteers .

26. Crossover study designs Subject Study period1 Study period2 Study period3 Study period4 1 A C C D 2 B A D A 3 C D A B 4 D B B C 5 A C D C 6 C D C A 7 B B A B 8 A D B D 9 C C B D 10 B A D A 11 D B A C 12 A A C B 13 C C D A 14 D D B C 15 C B A D 16 B A C A

27. Crossover study designs Period 1 Period 2 Sequence 1 T R Sequence 2 R T Period refers to the time period in which a study is performed. A two-period study is a study that is performed on two different days (time periods) separated by a washout period during which most of the drug is eliminated from the body-generally about 10 elimination half-lives. A sequence refers to the number of different orders in the treatment groups in a study. For example, a two-sequence, two-period study would be designed as above: where R= reference and T = treatment . The same reference and the same test are each given twice to the same subject. Other sequences are possible. In this design, Reference-to-Reference and Test-to-Test comparisons may also be made.

28. Replicated crossover study designs 1 . When the no. of study subjects <80, it is difficult to achieve with highly variable drugs and drug product (%CV> 30 ). 2 . These drugs have wide therapeutic window and despite high variability, have been demonstrated to be safe and effective . 3 . Replicate designs for these drugs require smaller no. of subject and avoid exposure of large no. of healthy subjects . 4 . Used for determining individual BE, to estimate within subject variance for both test and reference . 5 . Provide an estimate of the subject-by- formulation interaction variance.

29. Replicated crossover study designs Period 1 Period 2 Period 3 Period 3 Sequence 1 T R T R Sequence 2 R T R T A four , two sequence ,two formulation design is recommended by FDA Where R = reference and T = treatment T he same reference and the same test are each given twice to the same subject .other sequence are possible . In this design ,Reference –to reference and test to test comparisons may also be made.

30. Sealed average bioequivalence 1 . 3 sequence, 3 period, 2 treatment partially replicated crossover design . 2 . This design allows the estimation of within -subject variance and subject-by- formulation interaction for reference product . 3 . Completion time of this study is shorter than fully replicated four way crossover . \4 . If the test has lower variability than reference product, the study will need smaller no . of subjects . 5 . This is evaluated for both AUC and Cmax.

31. Sealed average bioequivalence Period 1 Period 2 Period 3 Sequence 1 T R R Sequence 2 R T R Sequence 2 R R T

32. Non replicate parallel study design For the drugs having long elimination half life or depot injection in which the drug is slowly released over weeks and month.2 Two separate groups of volunteers are used.3 . One group will have the test product while the other will have the reference product . Blood sample collection time should be adequate to ensure completion of GI transit(2-3days ). Cmax and AUC, 72 hrs after dose admn . can be used to characterize peak and total drug exposure . This design is not for drugs that have high intrasubject variability in distribution and clearance.

33. 4.Multiple dose (steady state) Multiple doses of same drug are given consecutively to reach steady state plasma drug levels. The multiple dose study is designed as steady state, randomized, 2 treatment ,2 way crossover study comparing equal dose of test reference. To ascertain that the subjects are at steady state, three consecutive trough concentrations( Cmin ) are determined. Pharmacokinetic analyses include calculation of following parameters for each subject: AUC Area under the curve during a dosing intervals. t max Time to Cmax during interval.

34. Multiple dose (steady state) Cmax Maximum drug concentration during dosing interval Cmin Drug concentration at end of a dosing interval. Cavg The average drug concentration during a dosing interval Degree of fluctuation = (Cmax- Cmin)/Cmax ; Swing =( Cmax – Cmin)/Cmin

35. Clinical endpoint BE study This consists of randomized double-blind ,placebo –controlled , parallel – designed study comparing test product , reference product, and placebo in patients. The primary analysis for bioequivalence is determined by evaluating the difference between the proportion of patients in the test and reference treatment groups who are considered a “ therapeutics” at the end of study. The superiority of the test and reference products against the placebo is also tested during the same dichotomous end point of “therapeutic cure”.

36. Special Concerns In Bioavailability And Bioequivalence Studies. For certain drug and dosage forms , systemic bioavailability and bioequivalence are difficult to ascertain for eg . Cyclosporine ,verapamil, are considered to be highly variable. The number of subjects required to demonstrate bioequivalence for these drug products may be excessive, requiring more than 60 subjects. The intrasubject variability may be due to the itself or to the drug formulation or to both. The FDA has held public forums to determine whether the current bioequivalence guidelines need to be changed for these highly variable drugs.

37. Thank You