Anvisa Ba-be Guidelines

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Anvisa - Page 1 of 5 Destaques do governo Português Español   The Institution Anvisa Informs Services Areas of Action Legislation Search    Resolution - RE nº 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 nº 238, dated 31 March 2003, Whereas disposed in Article111, item II, line a Paragraph 3 of the Internal Regulation approved b
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  Destaques do governo PortuguêsEspañolThe InstitutionAnvisa InformsServicesAreas of ActionLegislationSearch Resolution-RE nº896 of 29 May 2003 D.O.U. 06/02/2003 The Substitute Chairman of the Collegiate Directorate of the National SanitarySurveillance Agency in the use of the attributions vested in him under PresidentialDecree nº238, dated 31 March 2003,Whereas disposed in Article111, item II, line a Paragraph 3 of the InternalRegulation approved by Presidential Decree nº593, dated 25 August 2000,republished in the DOU of 22 December 2000,Whereas the contents were submitted to the Collegiate Directorate that approvedthem in meeting held on 6 March 2003, resolves: Article 1 To determine the publication for the attached“GUIDE FOR RELATIVEBIOAVAILABILITY/BIOEQUIVALENCE TESTS . Article 2 This resolution enters into force on the date of its publication. DAVI RUMEL ANNEX GUIDE FOR RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE TESTS OFMEDICINESRelative bioavailability/bioequivalence studies shall observe three stages: clinical,analytical and statistical, and shall be planned and submitted in compliance with theGUIDE FOR THE ELABORATION OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE STUDY PROTOCOL and the GUIDE FOR PROTOCOL ANDTECHNICAL REPORT OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCESTUDY, respectively.1. Clinical Stagea) The test and Reference Drugs to be submitted to the relativebioavailability/bioequivalence study shall initially be analyzed according to their inscription in the Brazilian Pharmacopoeia or, in its absence, in other codesauthorized by the legislation in force, in compliance with the GUIDE FOR THEUNDERTAKING OF THE STUDY AND PREPARATION OF PHARMACEUTICALEQUIVALENCE REPORT. The difference in the amount of the active ingredientpresent 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 itsquantification in the urine, whenever justified. As an alternative, the study can be Page 1 of 5Anvisa -3/19/2012    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 thequantification of the unchanged active ingredient or whenever they are active,contributing significantly to the efficacy and safety of the product, having been in largepart 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 criteriaestablished to the determine bioequivalence.d) The conventional study is open, randomized and crossed. Subjectsreceive the testand 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 200ml of water) in fasting subjects.f) The number of periods and sequences of the study shall be determined by thenumber of drug products analyzed in order to ensure the statistical validity, incompliance with the GUIDE FOR THE PLANNING AND UNDERTAKING OF THESTATISTICAL STAGE OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCESTUDIES. The interval between the periods shall be of at least seven half-lives of theactive 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 toguarantee the reliability of the bioequivalence study. The number of subjects iscalculated by means of the variation coefficient and power of the test (see the GUIDEFOR THE PLANNING AND UNDERTAKING OF THE STATISTICAL STAGE OFRELATIVE BIOAVAILABILITY/ BIOEQUIVALENCE STUDIES). The use of less than12 subjects is forbidden. The protocol shall determine the existence of enoughsubjects to compensate for eventual dropouts.i) depending on the drug product, the studies may be conducted in subjects agedanywhere 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 womenshall 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 considerednormal 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 thepathology for which the drug product is indicated with their free and informed consentor 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 than24h), an alternative collection schedule of up to 72 hours that makes it possible todetermine the area under the truncated curve in its primary packaging, in bulk or afinished product (ASCO-72) or a parallel study may be used.o) multiple dose studies are not usually recommended since single dose studies aremore sensitive to differences in the formulas. However, multiple dose studies may beused in cases in which they recognizably reduce the inter-individual variability in theabsorption of the active ingredient.p) studies with food shall be undertaken for forms of modified release (in addition to Page 2 of 5Anvisa -3/19/2012  the study performed in fasting subjects) and for immediate release drug products withknown food interaction.q) studies that involve a measure of pharmacodynamic effect are indicated in thosecases in which it is not possible to quantify the active ingredient in circulation in aprecise 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 theprocedures adopted to control or treat them.s) the research project, the experimental protocol and the free and informed consentterm 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 shallinclude the name of the active ingredient, the dose per unit, the dosage form and thename of the manufacturer of the test and Reference Drugs. This title shall be includedin the experimental protocol and in the free and informed consent term as well as inthe report prepared by the Committee for Ethics in Research.t) any subjects participating in the clinical studies that require confinement shallremain in appropriate location that meets the Good Clinic Practices (GCP) standardsunder 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 thecharacteristics of the material to be analyzed. Appropriate (certified) storage andtransportation packaging shall be used. The temperature of the biological sample shallbe registered with a calibrated device to ensure the maintenance of stability duringtransportation.v) any deviations from standard procedure shall be reported and justified.2. Analytical stagea) all the stages of the study shall be undertaken according to the international GoodLaboratory Practices (GLP) norms;b) The bioanalytical, chromatographic or other method used to quantify the activeingredient in biological liquid shall be detailed in the form of a protocol or StandardOperating Procedure (SOP) and shall be validated for its application in compliancewith the GUIDE FOR THE VALIDATION OF ANALYTICAL AND BIOANALYTICALMETHODS. The use of chromatographic methods is recommended;c) the proportion between the concentration of the analyte and the response resultingform the bioanalytical method shall present reproducibility and be adequately definedusing enough standards for the building of a calibration curve;d) the analytes of biological liquids (active ingredient or metabolite) shall undergostability 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: withoutreplication, 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 beconsidered equal to zero for the statistical calculations; Page 3 of 5Anvisa -3/19/2012  i) the analytical protocol shall contain the sample’s data reintegration criteria; j) any deviations from the protocol shall be reported and justified.3. Statistical stage3.1. General methodology3.1.1. the pharmacokinetic parameters are obtained from the blood concentration timecurve of the active ingredient, statistically analyzed for the determination of bioequivalence;3.1.2. the following pharmacokinetic parameters shall be determined: the area under the blood concentration time curve, calculated using themethod of the trapezoids, from time zero to time t (ASC0-t), where t is the time relatedto the last concentration determined through experimentation; the area under the blood concentration time curve, calculated from time zeroto time infinite (ASC0-inf), where ASC0-inf = ASC0-t + Ct/lz, where Ct is the lastconcentration of the active ingredient determined through experimentation and lz isthe 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: 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 withoutinterpolation of values; the depuration (D), the apparent volume of distribution (Vd) and theelimination half-life (t1/2) of the active ingredient and/or the metabolite shall also bedetermined, although there is no need for statistical treatment; for studies employing multiple doses the following parameters shall bedetermined: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 ingredientconcentration (Cmin) determined at the end of each interval of the dose in steadystate;c) average concentration of the active ingredient in steady state(C* = ASC0-t /t);d) Fluctuation rate in steady state3.1.2.6. for the evaluation of bioequivalence the ASC0-t, Cmax and Tmax parametersshall be used; in case of multiple dose studies it is necessary to prove that the equilibriumstate was reached after the administration of the test and Reference Drugs;3.1.3. neither the exclusion of more than 5% of the study’s subjects nor the lack of over 10% of the values for blood concentration of the active ingredient fromadministration of each drug product per volunteer shall be accepted.3.2. Statistical Analysis (see the GUIDE FOR THE PLANNING AND UDERTAKINGOF THE STATISTICAL STAGE OF RELATIVE BIOAVAILABILTY/BIOEQUIVALENCESTUDIES)a) a chart shall be submitted, containing individual values, average (arithmetic andgeometric), standard deviation and variation coefficient of all the pharmacokineticparameters related to the administration of the test and Reference Drugs; Page 4 of 5Anvisa -3/19/2012
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