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Resolution - RE n 896 of 29 May 2003


D.O.U. 06/02/2003

The Substitute Chairman of the Collegiate Directorate of the National Sanitary Surveillance Agency in the use of the attributions vested in him under Presidential Decree n 238, dated 31 March 2003, Whereas disposed in Article111, item II, line "a" Paragraph 3 of the Internal Regulation approved by Presidential Decree n 593, dated 25 August 2000, republished in the DOU of 22 December 2000, Whereas the contents were submitted to the Collegiate Directorate that approved them in meeting held on 6 March 2003, resolves: Article 1 To determine the publication for the attached GUIDE FOR RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE TESTS". Article 2 This resolution enters into force on the date of its publication.

DAVI RUMEL

ANNEX GUIDE FOR RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE TESTS OF MEDICINES Relative bioavailability/bioequivalence studies shall observe three stages: clinical, analytical and statistical, and shall be planned and submitted in compliance with the GUIDE FOR THE ELABORATION OF RELATIVE BIOAVAILABILITY/ BIOEQUIVALENCE STUDY PROTOCOL and the GUIDE FOR PROTOCOL AND TECHNICAL REPORT OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE STUDY, respectively. 1. Clinical Stage a) The test and Reference Drugs to be submitted to the relative bioavailability/bioequivalence study shall initially be analyzed according to their inscription in the Brazilian Pharmacopoeia or, in its absence, in other codes authorized by the legislation in force, in compliance with the GUIDE FOR THE UNDERTAKING OF THE STUDY AND PREPARATION OF PHARMACEUTICAL EQUIVALENCE REPORT. The difference in the amount of the active ingredient present in the test and Reference Drugs shall not be greater than 5% (five per cent). b) The study is undertaken through the quantification of the active ingredient and/or active metabolite in the circulation (blood, plasma or serum), or through its quantification in the urine, whenever justified. As an alternative, the study can be

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undertaken by comparing pharmacodynamic measurements. c) On the whole, the unchanged active ingredient shall always be quantified. Metabolites shall be quantified whenever there are analytical limitations for the quantification of the unchanged active ingredient or whenever they are active, contributing significantly to the efficacy and safety of the product, having been in large part made by pre-systemic metabolism. In those cases in which the quantification of the active ingredient and metabolite(s) is necessary, both shall comply with the criteria established to the determine bioequivalence. d) The conventional study is open, randomized and crossed. Subjects receive the test and Reference Drugs on separate occasions (periods), under a scheme of simple or multiple doses. A parallel design can be used whenever necessary. e) All drug products shall be administered with a standard liquid volume (usually 200 ml of water) in fasting subjects. f) The number of periods and sequences of the study shall be determined by the number of drug products analyzed in order to ensure the statistical validity, in compliance with the GUIDE FOR THE PLANNING AND UNDERTAKING OF THE STATISTICAL STAGE OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE STUDIES. The interval between the periods shall be of at least seven half-lives of the active ingredient and/or metabolite elimination. g) the schedule for the collection of samples shall contemplate a time equal to or greater than 3-5 times the elimination half-life of the active ingredient or metabolite. h) the number of healthy subjects shall always ensure enough statistical power to guarantee the reliability of the bioequivalence study. The number of subjects is calculated by means of the variation coefficient and power of the test (see the GUIDE FOR THE PLANNING AND UNDERTAKING OF THE STATISTICAL STAGE OF RELATIVE BIOAVAILABILITY/ BIOEQUIVALENCE STUDIES). The use of less than 12 subjects is forbidden. The protocol shall determine the existence of enough subjects to compensate for eventual dropouts. i) depending on the drug product, the studies may be conducted in subjects aged anywhere between 18 and 50 capable of expressing their free and informed consent, of the male or female gender or both. In this last case the number of men and women shall be the same and distributed equally between the sequences. j) the weight of the subjects shall be within a limit of +/- 15% of the weight considered normal for men and women, taking into account height and physical structure. k) smokers or subjects who have a history of alcohol or drug abuse shall be avoided. In case smokers are included, these subjects shall be identified. l) In studies that require subjects with other characteristics than those specified above, their inclusion shall be justified scientifically. m) cytotoxic drug products shall be tested in voluntary patients suffering from the pathology for which the drug product is indicated with their free and informed consent or that of their legal representative, in case of incapability of the patient. n) in case of active ingredients that present a long elimination half-life (greater than 24h), an alternative collection schedule of up to 72 hours that makes it possible to determine the area under the truncated curve in its primary packaging, in bulk or a finished product (ASCO-72) or a parallel study may be used. o) multiple dose studies are not usually recommended since single dose studies are more sensitive to differences in the formulas. However, multiple dose studies may be used in cases in which they recognizably reduce the inter-individual variability in the absorption of the active ingredient. p) studies with food shall be undertaken for forms of modified release (in addition to

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the study performed in fasting subjects) and for immediate release drug products with known food interaction. q) studies that involve a measure of pharmacodynamic effect are indicated in those cases in which it is not possible to quantify the active ingredient in circulation in a precise and exact manner due to an extremely reduced concentration (for example: ophthalmic suspensions, local action lotions, local action inhalants, etc.). r) the investigator shall fill in a form for the registration of adverse events and list the procedures adopted to control or treat them. s) the research project, the experimental protocol and the free and informed consent term shall be submitted to and approved by a Committee for Ethics in Research (ERC) that is licensed in the National Committee for Ethics in Research (CONEP) of the National Health Council of the Ministry of Health. The title of the project shall include the name of the active ingredient, the dose per unit, the dosage form and the name of the manufacturer of the test and Reference Drugs. This title shall be included in the experimental protocol and in the free and informed consent term as well as in the report prepared by the Committee for Ethics in Research. t) any subjects participating in the clinical studies that require confinement shall remain in appropriate location that meets the Good Clinic Practices (GCP) standards under the responsibility of a doctor. u) whenever it is necessary to transport biological samples (plasma, serum or urine), procedures shall comply with the good laboratory practices in order to preserve the characteristics of the material to be analyzed. Appropriate (certified) storage and transportation packaging shall be used. The temperature of the biological sample shall be registered with a calibrated device to ensure the maintenance of stability during transportation. v) any deviations from standard procedure shall be reported and justified. 2. Analytical stage a) all the stages of the study shall be undertaken according to the international Good Laboratory Practices (GLP) norms; b) The bioanalytical, chromatographic or other method used to quantify the active ingredient in biological liquid shall be detailed in the form of a protocol or Standard Operating Procedure (SOP) and shall be validated for its application in compliance with the GUIDE FOR THE VALIDATION OF ANALYTICAL AND BIOANALYTICAL METHODS. The use of chromatographic methods is recommended; c) the proportion between the concentration of the analyte and the response resulting form the bioanalytical method shall present reproducibility and be adequately defined using enough standards for the building of a calibration curve; d) the analytes of biological liquids (active ingredient or metabolite) shall undergo stability studies in compliance with the GUIDE FOR THE VALIDATION OF ANALYTICAL AND BIOANALYTICAL METHODS; e) the analytical protocol shall contain the criteria for the re-analysis of the samples; no more than 20% of the samples may be re-analyzed; f) any loss of samples shall be justified; g) the analysis of the samples may be carried out in the following conditions: without replication, in duplicate or in triplicate. In order to analyze the samples in duplicate or triplicate, the acceptance criteria for the samples shall be described in the SOP; h) all determinations with values below the Lower Quantification Limit (LQL) shall be considered equal to zero for the statistical calculations;

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i) the analytical protocol shall contain the samples data reintegration criteria; j) any deviations from the protocol shall be reported and justified. 3. Statistical stage 3.1. General methodology 3.1.1. the pharmacokinetic parameters are obtained from the blood concentration time curve of the active ingredient, statistically analyzed for the determination of bioequivalence; 3.1.2. the following pharmacokinetic parameters shall be determined: 3.1.2.1. the area under the blood concentration time curve, calculated using the method of the trapezoids, from time zero to time t (ASC0-t), where t is the time related to the last concentration determined through experimentation; 3.1.2.2. the area under the blood concentration time curve, calculated from time zero to time infinite (ASC0-inf), where ASC0-inf = ASC0-t + Ct/lz, where Ct is the last concentration of the active ingredient determined through experimentation and lz is the elimination constant of the terminal stage. The ASC0-t shall be equal or greater than 80% of the ASC0-inf; except when the truncated ASCO is being used: 3.1.2.3. the peak of maximum concentration (Cmax) of the active ingredient and/or metabolite and the timing to reach this peak (Tmax) shall be directly obtained without interpolation of values; 3.1.2.4. the depuration (D), the apparent volume of distribution (Vd) and the elimination half-life (t1/2) of the active ingredient and/or the metabolite shall also be determined, although there is no need for statistical treatment; 3.1.2.5. for studies employing multiple doses the following parameters shall be determined: a) ASC0-t calculated in the interval of the dose (t) in steady state; b) Cmax e Tmax, obtained without interpolation of data; minimum active ingredient concentration (Cmin) determined at the end of each interval of the dose in steady state; c) average concentration of the active ingredient in steady state(C* = ASC0-t /t); d) Fluctuation rate in steady state 3.1.2.6. for the evaluation of bioequivalence the ASC0-t, Cmax and Tmax parameters shall be used; 3.1.2.7. in case of multiple dose studies it is necessary to prove that the equilibrium state was reached after the administration of the test and Reference Drugs; 3.1.3. neither the exclusion of more than 5% of the studys subjects nor the lack of over 10% of the values for blood concentration of the active ingredient from administration of each drug product per volunteer shall be accepted. 3.2. Statistical Analysis (see the GUIDE FOR THE PLANNING AND UDERTAKING OF THE STATISTICAL STAGE OF RELATIVE BIOAVAILABILTY/BIOEQUIVALENCE STUDIES) a) a chart shall be submitted, containing individual values, average (arithmetic and geometric), standard deviation and variation coefficient of all the pharmacokinetic parameters related to the administration of the test and Reference Drugs;

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b) it is recommended that the ASC0-t and Cmax parameters be transformed into natural logarithm since in general the distribution of the transformed data is closer to a normal distribution in relation to the original data. A justification shall be submitted whenever the original scale is used to undertake the datas statistical analysis; c) analysis of variance (ANOVA) of the pharmacokinetic parameters ASC0-t and Cmax shall be carried out in order to evaluate the effects of sequence (group), of subjects within the sequence, of period and of treatment. In addition, the ANOVA chart shall be submitted, containing source, degree of freedom, sum of squares, average square, F statistic, p figure and the intra and inter individual variation coefficients; d) it is necessary to build a 90 % confidence interval (CI) for the ratio between the means of the values obtained with the test and the Reference Drugs, for the ASC0-tand Cmax parameters. The CI antilogarithm obtained constitutes the CI of 90% for the ratio of the geometric averages of the parameters The construction of this CI shall be based on the residual average square of the ANOVA obtained according to item c; e) Tmax is analyzed as the individual difference: test(-)reference, building a 90% CI, using nonparametric test; f) two drug products are considered bioequivalent when the 90% CI for the following ratios: ASCO-t test/ASCO-tref and Cmax test/Cmax ref between the averages of the pharmacokinetic parameters is included between 80 and 125%. Other limits of the 90% CI for Cmax, previously established in the protocol, may be accepted through scientific justifications. When clinically relevant, Tmax is also to be considered; g) this CI based method is equivalent to the procedure of two corresponding onesided tests with no hypothesis of bioequivalence, with a level of significance of 5% (=0,05); h) Active ingredients presenting low therapeutic range such as carbamazepine, valproic acid, clindamycin and others shall adopt a 95% CI; i) validated statistical programs shall be used; j) whenever necessary, appropriate statistical models shall be used according to the type of study (of multiple dose, for example); l) in cases of subjects presenting different behavior on the absorption parameters, in relation to the remaining subjects, their exclusion from the study shall be justified. The results of the study shall be submitted with and without the inclusion of their data;

m) inform software programs used for the statistical analysis of the data.

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