Legislation
Resolution
Resolution
 RE nº 896, of May 29, 2003
(D.O.U
of 02/06/2003)
The Deputy of the Collegiate
Board of Directors of the Brazilian Sanitary Surveillance Agency, in the
use of the attribution vested in him by Administrative Order n. 238, of
March 31, 2003,
WHEREAS
provided in Article
111, clause II, item “a” of paragraph 3 of the Bylaws approved
by Administrative Order 593, of August 25, 2000, republished in the Federal
Official Journal 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 6, 2003, decides:
Article 1  To determine
the publication of the "Guide for relative bioavailability/bioequivalence
tests”, attached.
Article 2  This Resolution
enters into force on the date of its publication.
DAVI
RUMEL
ANNEX
GUIDE FOR RELATIVE
BIOAVAILABILITY/BIOEQUIVALENCE TESTS OF DRUG PRODUCTS
The relative bioavailability/bioequivalence
studies must observe three stages: clinical, analytical and statistical,
and must be planned and presented according to the GUIDE FOR PROTOCOL
DESIGN OF RELATIVE BIOAVAILABILITY / BIOEQUIVALENCE STUDY and the GUIDE
FOR TECHNICAL REPORT OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE STUDY,
respectively.
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 CARRYING OUT PHARMACEUTICAL
EQUIVALENCE STUDY AND DESIGN OF REPORT. 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 (blood, 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) in general, the
unaltered drug must always be quantified. The metabolites must be quantified
in the cases of analytical limitations for quantification of the unaltered
drug, or when the unaltered drugs are active, significantly contributing
to the effectiveness and safety of the product, having been formed, significantly,
by presystemic metabolism. In the cases where the quantification of the
drug and metabolite(s) is necessary, both must comply with the criteria
established for bioequivalence determination.
d) the conventional
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. A parallel design may be used whenever
necessary.
e) the drug products
must be administrated with a standard (usually 200mL) liquid (generally
water) volume to the fasting volunteers.
f) 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, according to the
GUIDE FOR PLANNING AND CARRYING OUT THE STATISTICAL STAGE OF RELATIVE
BIOAVAILABILITY/BIOEQUIVALENCE STUDIES. The interval between the periods
must be, at least, of seven halflives of the drug or the metabolite elimination.
g) the sample collection
schedule must observe a length of time equal or greater than 35 times
the halflife of elimination of the drug or the metabolite.
h) 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 number
of volunteers is calculated through the variation coefficient and power
of the test (see GUIDE FOR PLANNING AND CARRYING OUT STATISTICAL STAGE
OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE STUDIES), and a number less
than 12 is not allowed. The protocol must establish a sufficient number
of subjects in the study, foreseeing possible dropouts.
i) according to the drug product, the studies may be conducted in volunteers
aged between 18 and 50 and capable of providing their free and informed
consent, male, female or both, in which case the number of men and women
must be the same and distributed equally between the sequences.
j) 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.
k) smokers and subjects
with a history of alcohol and drug abuse must be avoided. In case smokers
are included, these subjects must be identified.
l) in the case of
studies requiring subjects with different characteristics from those previously
mentioned, their inclusion must be scientifically justified.
m) 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.
n) in the case of
drugs presenting long elimination half life (over 24 hours), an alternative
collection schedule may be used, of up to 72 hours, allowing the determination
of the area under the fragmented curve (ASC072), or a parallel study.
o) multiple dose studies
are not generally recommended, since single dose studies are more sensitive
to differences in formulations. However, multiple dose studies can be
used in cases where, admittedly, they educe the interindividual variability
in the absorption process of the drug.
p) studies with feeding
must be carried out for modified release forms (in addition to the fasting
study) and for immediate release drug products with known interaction
with foods.
q) studies that involve
pharmacodynamic effect measurement are indicated in the cases where it
is not possible to quantify the drug in circulation precisely and accurately,
since its concentration is very low (for example: ophthalmic suspensions,
local action creams, local action inhalants, etc).
r) the researcher
must fill out a registration form of adverse events and list the adopted
procedures for the control or treatment of the adverse effects.
s) 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 Health Council/Ministry
of Health (CNS/MS). The title of the project must include the drug name,
the dose per unit, the pharmaceutical form and name of the manufacturers
of the test and the reference drug products. This title must also be included
in the experimental protocol, in the free and informed consent term, as
well as in the report prepared by the Committee of Ethics in Research.
t) the subjects taking
part in clinical studies requiring confinement, must stay in an appropriate
place that meets the Good Clinical Practices (GCP), under the responsibility
of a doctor.
u) in cases where
it is necessary to transport the biological samples (plasma, serum or
urine) the procedure for good laboratory practice must be followed in
order to preserve the characteristics of the material to be analyzed.
Use appropriate packing (certified) for preservation and transport. The
temperature of the biological sample must be recorded with calibrated
device to ensure maintenance of stability during the period of transport.
v) any protocol deviations
must be reported.
2. Analytical stage
a) all the stages
of the study must be carried out in compliance with international norms
of Good Laboratory Practices (GLP);
b) the bioanalytical,
chromatographic or other method, used for quantification of the drug in
biological liquid, must be described in detail in the form of protocol
or standard operational procedure (SOP) and must be validated for its
application, according to the GUIDE FOR VALIDATION OF ANALYTICAL AND BIOANALYTICAL
METHODS. The use of chromatographic methods is recommended;
c) the relation enters
the concentration of the analyte and the response from the bioanalytical
method must be reproducible and adequately defined, using a sufficient
number of standards for the construction of the calibration curve;
d) analyte stability
studies (drug or metabolite) must be carried out in the biological liquids,
according to the GUIDE FOR VALIDATION OF ANALYTICAL AND BIOANALYTICAL
METHODS;
e) the analytical
protocol must contain criteria for the samples reanalysis. No more than
20% of the samples can be reanalyzed;
f) any loss of samples
must be justified;
g) 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 or
triplicate, the acceptance criteria of the results must be described in
the SOP;
h) all determinations
with values lower than the Quantification Limit (QL), must be considered
equal to zero for the statistical calculations;
i) the analytical
protocol must contain the criteria for reintegration of the sample data;
j) any protocol deviations
must be reported and justified.
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:
3.2.1 the following
pharmacokinetic parameters must be determined:
3.1.2.1. the area
under the blood concentration versus time, calculated using the method
of the trapezoids, from time zero to time t (ASC0t), where t is the time
related to the last concentration determined through experimentation;
3.1.2.2. the area
under the blood concentration versus time, calculated from time zero to
time infinite (ASC0inf), where ASC0inf = ASC0t + 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 ASC0t must
be equal or greater than 80% of the ASC0inf, except in the cases where
the fragmented ASC is used;
3.1.2.3. the peak
of maximum concentration (Cmax) of the drug and/or metabolite and the
time 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 halflife 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:
ASC0t 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* = ASC0t /t);
d) fluctuation rate
in steady state.
3.1.2.6. for the bioequivalence
assessment the parameters ASC0t, 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 more than 5% of the subjects from the study or 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
(to see GUIDE FOR PLANNING CARRYING OUT STATISTICAL STAGE OF RELATIVE
BIOAVAILABILITY / BIOEQUIVALENCE STUDIES)
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) it is recommended
that the ASC0t e 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 data not transformed. Justifications
must be presented in the cases where it was chosen to carry out the statistical
analysis in original scale data;
c) analysis of variance
(ANOVA) of the pharmacokinetics parameters ASC0t and Cmax must be carried
out in order to evaluate the effects of sequence, 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 ASC0t and Cmax parameters. The CI antilogarithm obtained constitutes
the CI of 90% for the ratio of the geometrical averages of the parameters
(ASC0t teste/ ASC0t
referência e Cmax teste/ Cmax referência)
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 following ratios:
ASC0t test/ASC0ref and Cmax test/Cmax ref between the means the pharmacokinetic
parameters of test and reference are between 80 and 125%. Other limits
of the 90% CI for Cmax, previously established in the protocol, may be
accepted with scientific justifications. When clinically relevant, Tmax
is also to be considered;
e) 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% (µ=0,05);
f) for drugs presenting low therapeutic range, such as carbamazepine,
ASC0t, Cmax and Tmax parameters must be employed in bioequivalence assessment;
for valproic acid, clindamycin and others, a 95% CI must be adopted;
g) validated statistical
programs must be used;
h) whenever necessary,
appropriate statistical models, depending on the kind of bioequivalence
study (for example, of multiple doses), must be employed;
i) in cases of subjects
presenting different behavior on the absorption parameters, in relation
to the other 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.
j) inform software
programs used for the statistical analysis of the data.
