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BIOEQUIVALANCE prepared by tarun kumar mishra:

BIOEQUIVALANCE prepared by tarun kumar mishra


CONTENTS Introduction Need for bioequivalence studies Importance Criteria Types of bioequivalence studies Design of bioequivalence studies Evaluation of bioequivalence studies Clinical Signifaicance Advantages Dusadvantages


INTRODUCTION Bioequivalence Is defined as “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study There are several types of equivalences . Chemical equivalence Therapeutic equivalence CHEMICAL EQUIVALENCE It indicates that two or more drug product contain the same label chemical substance as an active ingredient in the same amount.


THERAPEUTIC EQUIVALENCE Two pharmaceutical products are therapeutically equivalent if they are pharmaceutically equivalent and after administration in the same molar dose their effects, with respect to both efficacy and safety, will be essentially the same as can be derived from appropriate studies (bioequivalence, pharmacodynamic , clinical or in-vitro studies). Therapeutically equivalent drug products are interchangeable.


NEED FOR BIOAVAIIBILITY STUDIES New product is intended to be a substitute for an approved medicinal product as a pharmaceutical equivalent or alternative To ensure clinical performance of such drug products  Bioequivalence studies are conducted if there is: A risk of bio-in equivalence and/or A risk of pharmacotherapeutics failure or diminished clinical safety In vivo bioavailability / bioequivalence studies and in vitro dissolution testing recommended to applicants intending to submit Investigational new drug application (INDs)New drug applications (NDAs)Abbreviated new drug applications (ANDAs) for conventional and extended release dosage forms administered orally.


IMPORTANCE  To evaluate the absolute bioavailability of dosage form compared with reference dosage forms.  Dose proportionality study to determine if bioavailability parameters are linear over proposed dosage range.  Intra/inter subject variability Intervention study to examine effect of e.g. Food and concomitant medication. Dosage form proportionality study to determine if equipotent drug treatments administered at different dose strength of the market form produce equivalent drug bioavailability. Bioequivalence study needed as a result of changes in the formulation or manufacturing processes.


CRITERIA OF B,S Evidence from well-controlled clinical trials, or controlled observations in patients and bioequivalence studies : Various drug products do not give comparable therapeutic effects are not bioequivalent drug products . Narrow therapeutic ratio and minimum effective concentration in the blood . Serious adverse effects Physicochemical:  Low solubility in water . Dissolution rate slow Particle size and surface area of the active drug ingredient Structural forms dissolves poorly . High ratio of excipients . Hydrophilic or hydrophobic excipients and lubricants• Pharmacokinetic:  GI tract or localized site. Degree of absorption poor


TYPES OF B.S In vivo : 1 . Oral immediate-release products with systemic action Indicated for serious conditions requiring assured response . Narrow therapeutic margin . Absorption <70%  Unfavorable physiochemical properties . Bioavailability problems . 2 . Non-oral immediate-release products . 3 . Modified-release products with systemic action.

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 In vitro : Dissolution study can be used in lieu of in vivo bioequivalence under certain circumstance, called as biowaivers . 1 . The drug product differs only in strength of the active substance it contains, provided all of the conditions hold- Pharmacokinetics linear . Qualitative composition same. Ratio between active substance and the excipients are same. Same manufacturer and same production site . Bioavailability or bioequivalence study performed with the original product . 2 . Slightly reformulated or manufacturing method slightly modified by the original manufacturer.


DESIGN OF B.S The design and evaluation of well-controlled bioequivalence studies require cooperative input from pharmacokineticists , statisticians, clinicians, bioanalytical chemists, and others . 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, and Benefit–risk and ethical considerations with regard to testing in humans. For some generic drugs, the FDA offers general guidelines for conducting these studies.


BIOEQUIVALENCE STUDY PROTOCOL 1.Title c.Dosage regimen a.principal investigator d.Sampling b.project number& date e.Housing 2.Study objective F.Fasting /meals shedule 3.Study design g.Analytical method a.Design b.Drug product 4.Subject selection -Test product -Medical history -Reference product - Physical examination - Labrotory 5.Inclusion/Exclusion criteria

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5 .Clinical procedures e.Adverse reactions & emergency a.Dosage &drug procedures administration 7.Facilities b.Biological sampling 8.Data analysis shedule 9.Analytical validation project c.Activity of subjects 10.Appendix 6.ETHICAL CONSIDERATIONS a.basic principles b.instituional review board c.informed consent d.indication for subject withdrawl


STUDY DESIGN OF B.S :Fasting study • Single dose, two-period, two-treatment, two sequence, open label, randomized cross over designs . • Fasted, adult, healthy subjects .• All immediate release and modified release oral dosage forms • Both male and female subjects • Overnight fast and 4 hour after dosing Food intervention study • Co-administration of food with an oral drug product may affect the bioavailability of the drug.

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. Multiple dose • Multiple dose, steady state, randomized, two-treatment, two- way, crossover study .• Adult and healthy subject • Three consecutive trough concentration on three consecutive days Types of test designs 1.Completely randomized designs All treatments( factor levels) are randomly allocated among all Experimental subjects . Method of randomization : label all subjects with the same number digits. Randomly select non-repeating numbers . Advantages :-  Easy to construct.

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 Any number of treatments & subjects . Easy & simple to analyses . Disadvantages:- Best suited for relatively few treatments. All subjects must be as homogenous 2 . Randomized block designs Subjects are sorted into homogenous groups called blocks . Method of randomization: Subjects having similar background characteristics are formed as blocks.

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Then treatments are randomized within each block, just like the simple randomization . Advantages:- Effective & systemic way of grouping . Any number of treatments or replications . Different treatments need not have equal sample size. Statistical analysis simple & easy to construct . Spoiled results, the design is easy to construct . Disadvantages :- More complex analysis Degrees of freedom of experimental error are not as large as with a completely randomised design.

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 Repeated measures, cross-over & carry-over designs :- • Same subject serves as a block . • Repeated measures on each subject we get the design name “repeated measures design ” • The administration of two or more treatments one after the other in a specified or random order to the same group of patients is called a crossover design or change-over design • Carry over effects • Wash out period Advantages :  Good precision for comparing treatments  Economic on subjects

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 Disadvantages :  Order-effect .  Carry over effect . Latin Square designs : • Each Subject receives each treatment during the course of the experiment . • A Latin square design is a two factor design with one observation in each cell . • Rows represent subjects & columns represent treatments .• Standard: the first row & the first column consist r letters in alphabetical order.

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. Advantages : Minimizes inter-subject variability, Intra-subject variability & time effect. Formulation variables . Disadvantages:- Degrees of freedom for experiments error larger than necessary . More complex. Wash out period very long


EVALUATION OF B.S Analytical method • Accuracy, precision and specificity . • More than one analytical method not be valid . • Data presented in both tabulated and graphical form • Plasma drug concentration versus time curve for each drug product and each subject . Pharmacokinetic evaluation of the data • Single dose study:AUC0-t ,AUC0-∞, Tmax and Tmax . • Multiple dose studies:AUC0-t,Tmax,Cmax,Cmin and percent fluctuation[100*( Cmax-Cmin )/ Cmin ]

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 Statistical evaluation of the data • No statistical difference between the bioavailability of the test product & the reference product . • Bell- shaped curve • Log values resembles more closely a normal distributionAnalysis of variance(ANOVA ) • No significance difference . • AUC0-24,AUC0-∞, Tmax & Cmax • Evaluate variability in subjects , treatment groups, study period, formulation & other variables .• Variability in the data is large then two drug products are bioequivalent . • Statistically significant, If p≤ 0.05 P- level of Statistical significance.

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 If p> 0.05 the difference between the two drug products are not statistically significant .• To detect small differences between the test products, a power test is performed . • Sample size, variability of the data & desired level of significance . • Power is set at 0.80 with an α=0.2 & a level of significance of 0.05 .

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 Two one-sided tests procedure • Confidence interval approach . • Greater 20 %. • 90% confidence limits . • Student’s t-distribution of the data . • within 20 %. • Lower 90% confidence interval for the ratio of means cannot be less than 0.80 & the upper 90% confidence interval for the ratio of the means cannot be greater than 1.20 . • Log transformed data , 90% confidence interval is set at 80 to 125%

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 Confidence limits termed the bioequivalence interval .• No-statistical differences between the mean AUC & Cmax parameters .• 90% confidence intervals for AUC & Cmax values of the test drug product should not be less than 0.80(80%) nor greater than 1.25(125%) of the reference product based on log- transformed data.


CLINICAL SIGNIFICANCE  Clinical interpretation is important in evaluating the results of a bioequivalence study . Differences of less than 20% in AUC & Cmax between drug products are unlikely to be clinically significant in patients . A small, statistically significant difference if the study well controlled & the number of subjects is sufficiently large . Above MEC & do not reach the MTC . Elderly or patients . Normal healthy volunteers . Minimize product to product variability by different manufactures & lot to lot variability with a single manufacture.


ADVANTAGES Minimises the effect of inter subject variabilty Minimises the carry over effect Requires less number of subjects to get meanigful results .


DISADVANTAGES Requires longer time to complete studies Completion of studie depends on number of formulation evaluated in the studies. Incease in study period leads to high subject dropouts. Medical ethics does not allow too many trials on a subject continously for a longer time.

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