Legislation
Resolution

Resolution - RE nº 478, of March 19, 2002
(Official Journal of 20/03/2002)

The Director of the Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in him under Administrative Rule 724, issued by the Director-Chairman, on October 10, 2000,

WHEREAS

paragraph 3 of article 111, of the Bylaws approved by Administrative Rule 593, of August 25, 2000, re-published in the Official Journal of the Union of December 22, 2000;
that the matter was submitted to the examination of the Collegiate Board of Directors, which approved the matter in a meeting held on March 13, 2002, decides:

Article 1 - To determine the publication of the "Guide for Proof of Bioequivalence of Generic Drugs", attached.

Article 2 - This Resolution enters into force on the date of its publication.

GONZALO VECINA NETO

GUIDE FOR BIOEQUIVALENCE STUDIES OF GENERIC DRUGS - 1/2002

The bioequivalence studies of generic drugs must observe three stages: clinical, analytical and statistical, and must be presented in compliance with the GUIDE FOR PROTOCOL AND TECHNICAL REPORT OF BIOEQUIVALENCE STUDY.

1. Clinical stage

a) the test and the reference drug products to be submitted to the bioequivalence study must, at first, be analyzed according to their monograph registered in the Brazilian Pharmacopoeia and, for lack of it, in other codes authorized by the legislation in force, according to the GUIDE FOR UNDERTAKING PHARMACEUTICAL EQUIVALENCE STUDY. The difference in the drug proportions between the test and the reference drug products must not be greater than 5% (five per cent);

b) the bioequivalence study is generally undertaken through the quantification of the drug or the active metabolite in the circulation (frequently in plasma or serum), or through its quantification in the urine, whenever justified. Alternatively, the study may be undertaken through the comparison of pharmacodynamic measurements.

c) the bioequivalence study is of the open, random, crossed type. The subjects receive the test and the reference drug products on separate occasions (periods), under a scheme of single or multiple doses. The drug products must be administrated with a standard (usually 200mL) liquid (generally water) volume.

d) The number of periods and the study sequences will be determined by the number of drug products analyzed, in order to ensure the statistical validity. The interval between the periods must be, at least, of seven half-lives of the drug or the metabolite elimination, whenever it is active;

e) In general, the quantification of the drug in samples of blood, plasma or serum is employed. The sample collection schedule must observe a length of time equal or greater than 3-5 times the half-life of elimination of the drug, or the metabolite, whenever it is active;

f) The number of healthy subjects must always ensure sufficient statistical power in order to guarantee the reliability of the results of the bioequivalence study. The minimum number of subjects is generally 24, between 18 and 50 years of age and capable of expressing their free and informed consent.

g) Depending on the drug product, subjects taking part in the studies may be male, female or both, noting that in the last case, the number of men and women must be the same.

h) the weight of the subjects must be within a limit of ± 15% of the weight considered normal for men and women, considering height and physical structure;

i) smokers and subjects with a history of alcohol and drug abuse must be avoided. In case smokers are included, these subjects must be identified;

j) in the case of studies requiring subjects with different characteristics from those previously mentioned, their inclusion must be scientifically justified;

k) cytotoxic drug products must be tested on 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;

l) in the case of drugs presenting long elimination half life (over 24 hours), the previously mentioned aspects may undergo changes, provided they are scientifically justified, in such a way as to ensure the achievement of reliable results;

m) the investigator must fill out a registration form of adverse events and list the adopted procedures for the control or treatment of the adverse effects;

n) the research project, the experimental protocol and the free and informed consent term must be submitted to a Committee of Ethics in Research accredited by the National Committee of Ethics in Research (CONEP) of the National Council of Health/Ministry of Health (CNS/MS). The title of the project must include the drug name, the dosage, the dosage form and name of the manufacturers of the test and the reference drug products. This title must also be included in the experimental report, in the free and informed consent term, as well as in the report prepared by the Committee of Ethics in Research.

o) the subjects taking part in clinical studies requiring confinement, must stay in an appropriate place that meets the Good Clinic Practices (GCP), under the responsibility of a doctor.

2. Analytical stage

a) all stages of the study must be carried out in compliance with international norms of Good Laboratory Practices (GLP);

b) analytical methods must be validated according to the GUIDE FOR VALIDATION OF ANALYTICAL METHODS;

c) stability studies of the drug in biological liquids must be carried out in compliance with item 3 of the GUIDE FOR VALIDATION OF ANALYTICAL METHODS;

d) the analytical protocol must contain criteria for the samples re-analysis. No more that 20% of the samples can be re-analyzed;

e) any loss of samples must be justified;

f) the analysis of the samples may be carried out in the following conditions: without replication, in duplicate or triplicate. For the analysis of samples in duplicate, the average value must be considered, and for triplicate, the average of the nearest two values;

g) all determinations with values lower than the Quantification Limit (QL), must be considered equal to zero for the statistical calculations.

3. Statistical Stage

3.1. General Methodology

3.1.1. the pharmacokinetic parameters are obtained from the blood concentration curves of the drug versus time, statistically analyzed for the determination of the bioequivalence;

3.1.2. the following pharmacokinetics parameters must 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 drug determined through experimentation and lz is the elimination constant of the terminal stage. The ASC0-t must be equal or greater than 80% of the ASC0-inf;

3.1.2.3. the peak of maximum concentration (Cmax) of the drug and/or metabolite and the timing to reach this peak (Tmax) must be directly obtained without interpolation of values;

3.1.2.4. the depuration (D), the apparent volume of distribution (Vd) and the half-life of elimination (t1/2) of the drug and/or the metabolite must also be determined, although there is no need for statistical treatment;

3.1.2.5. for studies employing multiple doses the following parameters must 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 drug concentration (Cmin) determined at the end of each interval of the dose in steady state;

c) average concentration of the drug in steady state(C* = ASC0-t /t);;

d) Fluctuation rate in steady state
3.1.2.6. for the bioequivalence assessment the parameters ASC0-t, Cmax and Tmax must be employed;

3.1.2.7. in the case of studies with multiple doses it must be proved that the steady state was obtained after the administration of the test and the reference drug products.

3.1.3. the exclusion of outliers must be justified;

3.1.4. the lack of over 10% of the values for blood concentration of the drug resulting from administration of each drug product will not be accepted.

3.2 Statistical Analysis

a) a chart must be presented, 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 drug products;

b) the ASC0-t e Cmax parameters must be transformed into logarithm. The distribution of the transformed data is closer to a normal distribution in relation to the data not transformed;

c) analysis of variance (ANOVA) of the pharmacokinetics parameters ASC0-t and Cmax must be carried out in order to evaluate the effects of sequence (group), of subjects, of period and of treatment. In addition, the ANOVA chart must be presented, 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 drug products, for the ASC0-t- and Cmax parameters. The CI antilogarithm obtained constitutes the CI of 90% for the ratio of the geometrical averages of the parameters (Inserir Parâmetro RE 478.EPS). -The construction of this CI must 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 bioequivalents when the 90% CI for the ratio between the means of ASC0-t and of Cmax 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 one-sided tests with no hypothesis of bioequivalence, with a level of significance of 5% (µ=0,05);

h) for drugs presenting low therapeutical range, such as carmazepine, valproic acid, clindamycin, and others, a 95% CI must be adopted;

i) validated statistical programs must be used;

j) whenever necessary, appropriate statistical models, depending on the kind of bioequivalence study (for exemple, of multiple doses), must be employed;

k) in cases of subjects presenting different behavior on the absorption parameters, in relation to the remaining subjects, their exclusion from the study must be justified. The results of the study must be presented with and without the inclusion of their data;

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