- RE nº 894, of May 29, 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
provided in Article
111, clause II, item “a” of paragraph 3 of the Bylaws approved
by Administrative Order 593, of August 25, 2000, re-published 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 protocol and technical report of
bioequivalence study”, attached.
Article 2 - Resolution
RE n. 479, of March 19, 2002, is hereby revoked.
Article 3 - This Resolution
enters into force on the date of its publication.
GUIDE FOR PROTOCOL
DESIGN OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE STUDY
1. Title of the project
(must contain the name of the drug, strength, dosage form and name of
manufacturer of the test and the reference drug products).
2. Number and date of the protocol.
3. Main investigator (researcher in charge).
4. Clinical investigator (must necessarily be a physician).
5. Person in charge of the analytical phase.
6. Person in charge of the statistical phase.
7. Facility (name and address):
7.1. clinical phase;
7.2. analytical phase;
7.3. statistical phase;
7.4. clinical assessment;
7.5. clinical laboratory tests.
8. Study objective.
9. Study design:
9.2. identification of test and reference drug products: name of the drug,
name of the brand (when applicable), dosage form, dose per unit, name
and address of the manufacturer, batch number, date of manufacture and
date of expiry (when available);
9.3. posology: dose, schedule and volume of liquid for administration;
9.4. housing of subjects;
9.5. fasting and feeding time table;
9.6. sampling schedule;
9.7. sample manipulation procedures.
10. Study population:
10.1. detailed description
(sex, age, weight, height);
10.2. subject selection:
10.3. clinical assessment (medical history and physical exam);
10.4. clinical laboratory exams: electrocardiogram, hematological and
biochemical exams (including proofs of hepatic and renal function), serological
exams (Hepatitis B, Hepatitis C, HIV), beta HCG (for women) and urine
10.5. inclusion criteria;
10.6. exclusion criteria;
10.7. restrictions and prohibitions: before, during and after study;
10.8. criteria for subject discontinuation or withdrawal from the study.
11. Adverse reactions
(including classification method) and emergency procedures.
12. Ethical considerations:
12.1. basic principles
- must follow the resolutions in force of the National Health Council-Ministry
of Health (CNS/MS), which regulate research norms on human beings.
13. Analytical method:
13.2. validation protocol.
14. Statistical treatment:
14.1. present study
design, according to "GUIDE FOR PLANNING AND EXECUTION OF STATISTICAL
STAGE OF RELATIVE BIOAVAILABILITY / BIOEQUIVALENCE STUDIES";
14.2. justify sample size in the study;
14.3. definition of the acceptance interval of the pharmacokinetic parameters
to be tested in the study, in compliance with the "GUIDE FOR RELATIVE
BIOAVAILABILITY / BIOEQUIVALENCE TESTS";
14.4. specify outlier detection method.
15. Criteria of protocol
deviation acceptance (for example: deviation from sampling schedule, etc.).
16.1. form for retention samples (the number of units of the test and
the reference drug products that are to be retained (enough to repeat
the study) must be informed. These samples must be stored in proper conditions
to preserve the original characteristics of the products up to their expiry
16.2. form for inventory of the drug products used in the study (the number
of units of test and reference drug products used in the study, as well
as any occurring loss, must be informed);
16.3. model of informed consent form;
16.4. form for registration of adverse events;
16.5. randomization list.
OBS.: All the pages
of the document must contain: name of the center, protocol number and