Pdf equivalence testing is the natural approach to many statistical problems. In the present article, this power approach which in practice usually consists of testing the hypothesis of no difference at level 0. Sample sizes computed in the usual manner from an analysis of variance are shown to be too small to assure a declaration of bioequivalence except under favorable conditions. They presented a study of the power of bioequivalence hypothesis test, in which the use of extended. Second, a widely held view is embraced that the timedependent drug. Many models, including normal, poisson, binomial, matched pairs, testing means and variances or both simultaneously are considered. Bioavailability and bioequivalence studies intechopen.
For example, such hypotheses occur in bioequivalence studies where one may wish to show two. Keywords equivalence hypothesis testing bioequivalence analysis program. Pdf on equivalence and bioequivalence testing researchgate. Before approaching to the sample size estimation procedure, we will take a quick look on tost procedure of bioequivalence testing. Abstract when the aim of the randomized controlled trial rct is to show that one treatment is superior to another, a statistical test is employed and the trial test is called a superiority trial test. Samples statistically different to the control were considered toxic p mar 14, 2014 the bioequivalence is typically demonstrated by testing the differences between specific responses measurements of a specific endpoint of interest produced by the two drugs. Citeseerx bioequivalence trials, intersectionunion tests. Schuirmann office of biostatistics, office of translational sciencescenter for drug evaluation and researchus food and drug administration, silver spring, maryland, usa. Step 2 find the critical values from the appropriate table. In addition, the investigators should follow the procedures of 21 cfr 58 and ich e6, good clinical practice. If the computed pvalue is greater than the previously stated signi. The classical approach to analyze pharmacokinetic pk data in bioequivalence studies aiming to compare two different formulations is to perform noncompartmental analysis nca followed by.
Equivalence hypothesis testing in experimental software. Experimental design and statistical analysis issues pertinent to both classical and bioequivalence testing on. A bioequivalence study was carried out on two formulations of doxepin containing 15% of the active cis isomer and 85% of the less active trans isomerthe 90% confidence intervals in auclast, in cmax and in cmaxauclast for ndesmethyldoxepin fell entirely within bioequivalence li whether stereoselective or nonstereoselective data were analyzed. Little optimal theory is available for such testing problems, and it is the purpose of. If one assumes the boundary hypothesis 0, the second row of. Under the normality of the response variable, the most common approach to testing for bioequivalence is the two onesided tests procedure. Jan 21, 2019 on bayesian analysis and hypothesis testing in the determination of bioequivalence donald j. The conventional method of testing equivalence hypotheses is to perform two, onesided tests tost of hypotheses. The null hypothesis is typically stated as that the true population mean responses of the two drugs are different, whereas the alternative hypothesis is stated as. Sample size and power analysis in bioequivalence studies. If a second sample is taken, the combined sample can then be used for inference purposes regarding bioequivalence. Bertoletti and others published selection of relevant effect levels for using bioequivalence hypothesis testing find. Western michigan university, 2009 applicants submitting a new drug application nda or new animal drug application nada under the federal food, drug, and cosmetic act fdc act are required to document bioavailability ba.
Guideline for bioequivalence studies of generic products. Project director center for bioequivalence studies and bioassay research international center for chemical and biological sciences university of karachi pakistan. The food and drug administration fda is announcing the. Why should we introduce another approach to equivalence testing. Statistical approaches for bioequivalence the general structure of a be criterion is that a function. Test and reference are bioequivalent if the entire population distribution mean. In this paper we consider the construction of optimal tests of equivalence hypotheses. Statistical procedures for bioequivalence analysis srinand ponnathapura nandakumar, ph. Pdf optimal testing of equivalence hypotheses semantic. Bioequivalence studies for nasal aerosols and nasal sprays for local. The current practice is to carry out two onesided tests tost procedure with the null hypothesis h0 of nonbioequivalence at 5% level of significance. Optimal confidence sets for testing average bioequivalence. Power of the two onesided tests procedure in bioequivalence.
The concept of intersectionunion tests will be shown to clarify, simplify, and unify bioequivalence testing. Experimental design and statistical methods for classical. Statistical tests for population bioequivalence 541 from the reference formulation, where y t, y r and y r are independentobservations from di. Draft guidance on podofilox food and drug administration. Power computations illustrated in this paper seem to indicate that experiment sizes may need to be greater for bioequivalence testing as opposed to classical hypothesis testing. Step 4 make the decision to reject or not reject the null hypothesis. The null hypothesis of nonequivalence is rejected in favor of the alternative hypothesis of. Hypothesis testing for equivalence based on symmetric open intervals. Bioavailability and bioequivalence studies are required to ensure therapeutic equivalence between a pharmaceutically equivalent test drug and a generic drug or reference drug.
Singlesource drug products are drug products for which the patent has not yet. On bayesian analysis and hypothesis testing in the determination of bioequivalence donald j. Our alternative hypothesis the one we wish to demonstrate is that the ratio is within the indicated range. The value of testing two onesided null hypotheses of nonequivalence at a significance level of 0. For the method of interval hypotheses testing, we would reject the null hypothesis of bioinequivalence in favor of the alternative of bioequivalence. Statistical approaches to establishing bioequivalence fda. Handbook of bioequivalence testing crc press book as the generic pharmaceutical industry continues to grow and thrive, so does the need to conduct adequate, efficient bioequivalence studies. Traditional statistical approach is often designed to test the null hypothesis of equality. This setup arises when trying to demonstrate equivalence or sometimes called bioequivalence of treatments. On bayesian analysis and hypothesis testing in the. Efficient modelbased bioequivalence testing deepai. Assessment of bioequivalence 1 bioequivalence range, parameters, data transformation and statistical analysis 2 acceptance criteria iii. The hypothesis testing problem for assessing average bioequivalence is stated as. Samples statistically different to the control were considered toxic p bioequivalence tests in plant pathology k.
Oct 06, 2009 the conduct of a study that can truly attest to the bioequivalence of two drug products requires some prior knowledge of the performance of the products in the human body so that an appropriate number of test subjects can be enrolled and provide adequate power to test the hypothesis with a reasonable likelihood i. Review on bioavailability and bioequivalence studies. In recent years, there have been significant changes to the statistical models for evaluating bioequivalence. Bioequivalence trials, intersectionunion tests, and. Using the terminology of statistical hypothesis testing, this is. Hypothesis testing santorico page 290 hypothesis test procedure traditional method step 1 state the hypotheses and identify the claim.
Pdf selection of relevant effect levels for using bioequivalence. Ensuring uniformity in standards of quality, efficacy, and safety of pharmaceutical products is the fundamental responsibility of central drugs standard control. Bioequivalence bioequivalence is defined to the class using the terms provided in section 505j7b of the federal food, drug, and cosmetic act. Bioequivalence hypothesis testing was used to compare responses for each sample and the control bertoletti et al. In a hypothesis test of 1 or 2, the type i error rate is the probability of declaring the drugs to be bioequivalent, when in fact they are not. Statistical approaches to establishing bioequivalence february 2001. Comprehension sideeffect free programs crossover design experimental. We claim bioequivalence if the estimated 90% confidence interval is in % entirely within the bioequivalence limits of 80% and 125%. Experimental design and analysis for bioequivalence trials. To establish bioequivalence, the 90% confidence interval of the difference in therapeutic cure rates between the test product and rld treatment groups at the testofcure visit study day 3846 must be within 0. Easy multiplicity control in equivalence testing using two. Statistical approaches to establishing bioequivalence. The second part of the thesis is concerned with multiple testing of bioequivalence. For example, such hypotheses occur in bioequivalence studies where one may wish to show two drugs, a brand name and a proposed generic version, have the same therapeutic effect.
The foundation is set, first, through evidence that a specified, approved, reference drug product e. A multisource drug product is a drug product that contains the same active drug substance in the same dosage form and is marketed by more than one pharmaceutical manufacturer. Tasneem ahmad, cbsbr, university of karachi 1 selection of be study design estimation of sample size number of volunteers 800 calculation of bioavailability ba. Superiority, equivalence, and noninferiority trials.
We endorse the proposal by 4 to define a hierarchy of bioequivalence models. We develop the exact analytical formula for the probability of rejection in the two onesided tests procedure for crossover bioequivalence studies. Pargal abstract bioequivalence be means the absence of a greaterthanallowable difference between the systemic bioavailability of a test product and that of a reference product. Bioequivalence and bioequivalency testing joseph p. Communications in statistics theory and methods, 38 11, 17921803 used an open interval to define equivalence and provided exact and approximate methods for testing a null hypothesis of nonequivalence. Balthasar1 department of pharmaceutics and pharmaceutical chemistry, 421 wakara way, suite 318, university of utah, salt lake city ut 84108 prologue this lecture material is covered in one and onehalf fifty.
The main focus of this lecture is to instruct students in process and requirements needed to attain the ab rating. Bioequivalence trials, intersectionunion tests and. The problem is theoretically interesting because it has been recognized as one for which the desired inference, instead of the usual significant difference, is practical equivalence. Use of statistical tests of equivalence bioequivalence tests in plant pathology k.
Sample size estimation for bioequivalence testing between. Statistical methods for bioequivalence testing have been well developed and extensively applied in pharmaceutical research fda, 2001. A good example of concise bioequivalence testing and reporting is provided in miles et al. The power of the two onesided tests procedure for testing bioequivalence is derived from the bivariate noncentral tdistribution. Experimental design and statistical methods for classical and. The bioequivalence is typically demonstrated by testing the differences between specific responses measurements of a specific endpoint of interest produced by the two drugs. A comparison of the two onesided tests procedure and the. Use of statistical tests of equivalence bioequivalence tests. Samples statistically different to the control were considered toxic p bioequivalence studies evolved, being statistical procedures for comparing whether the generic and brand name drugs are similar in treating patients for various diseases. Two proportions noninferiority, superiority, equivalence. Note that this is basically the reverse of a standard hypothesis test in which the null hypothesis rather than the alternative hypothesis would indicate no difference between the 2 means. Experimental design and statistical methods for classical and bioequivalence hypothesis testing with an application to dairy nutrition studies 1. Usual hypothesis testing for equality are not appropriate for.
It should be noted that existing fda guidelines fda, 2001 for drug testing advocate that equivalence limits be, respectively, 80% and 125% of the reference means i. Bioequivalence and related hypothesis testing aaron zeng. In determining bioequivalence, for example, between two products such as a commercially available brand product and a potential tobemarketed generic product, pharmacokinetic studies are conducted whereby each of the preparations are administered in a crossover study to volunteer subjects, generally healthy individuals but occasionally in patients. Ba and be testing samples, regarding retention of study drug samples and 21 cfr 320.
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