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Legislation
Resolution

Resolution - RE nº 895, 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, 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 design of technical report of relative bioavailability/bioequivalence study”, attached.

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

DAVI RUMEL

ANNEX

GUIDE FOR DESIGN OF TECHNICAL REPORT OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE STUDY

1. General considerations.

1.1. All the pages of the report must contain: name of the center, identification code of the study and sequential numbering.

1.2. The report must be docketed in two copies together with diskette or CD-ROM containing spreadsheet in MS-Excel with the results of the pharmacokinetic parameters calculated separately (ASC0-t, ASC0-inf, Cmax and Tmax), and the individual values of the plasmatic drug concentrations, for all the phases of the study (model table annex I);

2. General information.

2.1. Cover page:

2.1.1. identification code of the study;
2.1.2. title: name of the drug, dose per unit, dosage form and name of the manufacturers of the test and reference drug products;
2.1.3. name of main researcher;
2.1.4. name and address of the bioequivalence center responsible for the project;
2.1.5. date.

2.2. Signature page:

2.2.1. identification code of the study;
2.2.2. title, according to item 2.1.2;
2.2.3. name and address of the bioequivalence center responsible for the project;
2.2.4. dated signatures, together with name, title/qualification and function in the study,
2.2.5. of the main researcher and the people responsible for the clinical, analytical and statistical phases.

2.3. Summary:

2.3.1. title, according to item 2.1.2;
2.3.2. sponsor: name and address;
2.3.3. main researcher;
2.3.4. site(s): name and address of the site(is) where the clinical, analytical and statistical phases were carried out;
2.3.5. clinical analyses laboratory: name and address;
2.3.6. objective;
2.3.7. design;
2.3.8. subjects: description, sex, initial and final number;
2.3.9. drug products:

2.3.9.1. test: brand name (if applicable), generic name, dose per unit, dosage form, batch number, date of manufacture, expiry date, name and address of the manufacturer;
2.3.9.2. reference: brand name, dose per unit, dosage form, batch number, date of manufacture, expiry date, name and address of the manufacturer;

2.3.10. posology: dose, schedule and volume of liquid for administration;
2.3.11 confinement of the subjects: dates and time of entrance and exit in each period;
2.3.12 administration of drug products: dates and time of the beginning and end in each period;
2.3.13 washout period;
2.3.14 fasting and feeding time table;
2.3.15 sampling schedule;
2.3.16 sample manipulation procedures: collection, separation and storage of the biological material;
2.3.17 dropout/withdrawal of subjects in each period;
2.3.18 bioanaytical method:

2.3.18.1. bioanaytical technique;
2.3.18.2. detection;
2.3.18.3. internal standard;
2.3.18.4. biological matrix;
2.3.18.5. anticoagulant;
2.3.18.6. type of extraction;
2.3.18.7. linearity range;
2.3.18.8. quantification parameter;
2.3.18.9. detection parameter;

2.3.19. dates of beginning and end of the analytical phase;
2.3.20. statistical analysis: brief summary of the methodology used, with identification of the programs employed;
2.3.21. summary of protocol deviations;
2.3.22. adverse events: summary (example: number of events, classification, number of subjects involved, related or not to the drug product, consequences for the project, etc.);
2.3.23. results: table containing the ratio of the geometric averages (or difference of the arithmetic averages), confidence intervals (CI), intra-subject variation coefficients (CV) and strength of the test, referring to Cmax and ASC0-t parameters of the test and reference products;
2.3.24. discussion and conclusion;
2.3.25. date and signature of the main researcher.

2.4. Annexes:

2.4.1. study protocol and its respective annexes, in compliance with the GUIDE FOR PROTOCOL DESIGN OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE STUDY;
2.4.2. approval by Committee of Ethics in Research;
2.4.3. brief resumes of the main researcher and of the people responsible for the clinical, analytical and statistical phases.

3. Clinical report.

3.1. Cover page:

3.1.1. identification code of the study;
3.1.2. title, according to item 2.1.2;
3,1,3. the term: clinical report;
3.1.4. name and address of the bioequivalence center of the clinical phase.

3.2. Content index.

33. Signature page.

Must contain: dated signatures together with name, title/qualification and function in the study, of the main researcher and the people responsible for the clinical phase.

3.4. Glossary.

3.5. Introduction.

Information on the drug, such as: description, synthesis, physical and chemical data, pharmacokinetics, pharmacodynamics, action mechanism, interactions, therapeutic use, bioequivalence data, etc.

3.6. Objective.
3.7. Design.
3.8. Randomization list.
3.9. Drug products:

3.9.1. test: brand name (if applicable), generic name, dose per unit, dosage form, batch number, date of manufacture, expiry date, name and address of the manufacturer;
3.9.2. reference: brand name, dose per unit, dosage form, batch number, date of manufacture, expiry date, name and address of the manufacturer;
3.9.3. analytical certificates of the drug products;
3.9.4. retention samples of the drug products of the study;
3.9.5. inventory of drug products of the study.

3.10. Study population:

3.10.1. individual data (sex, age, weight, height, body mass index): table with data and descriptive statistics of all the subjects.
3.10.2. selection:

3.10.2.1. clinical assessment (medical history and physical exam): tables with individual data;
3.10.2.2. clinical laboratory tests: tables with individual results;
3.10.2.3. inclusion criteria;
3.10.2.4. exclusion criteria.

3.10.3. restrictions and prohibitions: before, during and after the study;
3.10.4. criteria for discontinuation or removal of subjects from the study;
3.10.5. report on cases of withdrawal or dropout.

3.11. Confinement of the subjects:

3.11.1. place: detailed description;
3.11.2. form: report on conditions, restrictions, exercises, etc.;
3.11.3. periods: date and time of entrance and exit in each period.

3.12. Fasting and feeding timetables.
3.13. Standard diet and ingestion of liquids.

3.14. Administration of the drug products:

3.14.1. posology: dose, schedule and volume of liquid per administration;
3.14.2. washout period;
3.14.3. table with dates and schedules of administration for all individuals.

3.15. Sampling schedule.

Table reporting planned times and actual times of sample collection for all the subjects.

3.16. Vital signs.

May be presented as table.

3.17. Collection, manipulation, storage and transport of the samples.

3.18. Adverse events and emergency procedures.

Detailed report of the cases, subjects involved, classification, relation or not with the drug, date, time, duration, measurements taken, use of medication use, etc.

3.19. Standard operational procedures (SOP) of the clinical phase: instructions to the subjects, identification of the samples, procedures for blood collection, procedures for administration of drug products, and others.

3.20. Protocol deviations and their respective degrees of impact in the clinical and pharmacokinetic results.

4. Analytical report.

4.1. Cover page:

4.1.1. identification code of the study;
4.1.2. title, according to item 2.1.2;
4.1.3. the term: analytical report;
4.1.4. name and address of the bioequivalence center of the analytical phase.

4.2. Content index.

4.3. Signature page.

Must contain: dated signatures together with name, title/qualification and function in the study, of the main researcher and the people responsible for the analytical phase.

4.4. Glossary.
4.5. Bioanaytical method:
4.5.1. bioanaytical technique;
4.5.2. detection;
4.5.3. internal standard;
4.5.4. biological matrix;
4.5.5. anticoagulant;
4.5.6. type of extraction;
4.5.7. linearity band;
4.5.8. quantification parameter;
4.5.9. detection parameter.

4.6. Reference standards: identification, batch number, validity, name and address of the manufacturer.

4.7. Preparation of the calibration standards, quality controls and dilution standard.

Report compliance with or deviations from SOP, date of preparation, storage conditions (if applicable), tests carried out, etc.

4.8. Receipt, labeling and storage of the samples.
4.9. Concentration calculation of the samples.
4.10. Protocol deviations and their respective degrees of impact on the results of the study, including justifications for loss of samples.
4.11. Tables:

4.11.1. individual plasmatic concentrations of the test and reference products;
4.11.2. summary of the sample assay: listing per subject, identification of the analytical run, reanalyzes, identification of the reanalysis run, values of the first analysis and of the reanalyzes, reported value and decision criterion;
4.11.3. calibration curves: identification, dates and initial and final hour, study samples, coefficients (linear, angular and correlation);
4.11.4. calibration curves: quantified values obtained from calibration standards with respective percentages of nominal deviations;
4.11.5. analytical runs validation quantified values obtained from quality controls and their respective nominal deviations;
4.11.6. sample reanalysis: causes, number and percentage for each cause in relation to the total number of samples in the study;
4.11.7. reintegration: identification of the sample and run, initial and reintegrated value, reason for reintegration and method used.

4.12. Annexes:

4.12.1. method validation: report on the assays recommended in the GUIDE FOR VALIDATION OF BIOANALYTICAL METHOD;
4.12.2. analyses certificates of the standards of the analyte standards and internal standard;
4.12.3. Standard Operational Procedures (SOPs):

4.12.3.1. of the analytical method: must describe the methodology in detail, addressing the following topics, among others: reagents; materials; equipment; chromatographic instrumentation; sample treatment (includes all the procedures to which the samples are submitted); chromatographic conditions (mobile phase, column, flow speed, column temperature, temperature of the autosampler, volume of injection, retention times of the analyte and internal standard (in the case of mass spectrometry, specify monitored ions), detector, etc.); detection parameters; integration parameters; construction parameters of the calibration curve;
4.12.3.2. for preparation, stock and acceptance criteria of the stock--solutions, calibration standards, quality control samples, dilution standards and reference solutions;
4.12.3.3. for carrying out the validation assays and acceptance criteria of the results;
4.12.3.4. for carrying out the analytical runs and acceptance criteria;
4.12.3.5. of sample reanalysis and reporting of final concentrations;
4.12.3.6. of chromatographic analysis;
4.12.3.7. of sample reanalysis for anomalous values;
4.12.3.8. of reintegration of sample data;
4.12.3.9. others;

4.12.4. complete series of the chromatograms of at least 20% of the subjects, with data: identification of the run, identification of the sample, calculated concentration, parameters (analyte and internal standard), list of parameters (analyte and internal standard), retention times (analyte and internal standard), date and hour.

5. Statistical report.

5.1. Cover page:

5.1.1. identification code of the study;
5.1.2. title, according to item 2.1.2;
5.1.3. the term: statistical report;
5.1.4. name and address of the bioequivalence center of the statistical phase.

5.2. Content index.
5.3. Signature page:

dated signatures together with name, title/qualification and function in the study, of the main researcher and the people responsible for the statistical phase.

5.4. Glossary.
5.5. Pharmacokinetic and statistical analysis:

5.5.1. calculation of the sample size;
5.5.2. ANOVA table for the pharmacokinetic parameters;
5.5.3. construction of the confidence interval (CI) for the Cmax and ASC0-t parameters.

5.6. Conclusion.
5.7. Bibliographical references.
5.8. Tables:

5.8.1. individual plasmatic concentrations of the test product, with identification of the sequence of each subject and the following data for each time of collection: average, minimum and maximum concentration, standard deviation and CV (%);
5.8.2. individual plasmatic concentrations of the reference product, with identification of the sequence of each subject and the following data for each time of collection: average, minimum and maximum concentration, standard deviation and CV (%);
5.8.3. pharmacokinetic parameters (listed in item 3.1.2 of the GUIDE FOR RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE TESTS OF DRUG PRODUCTS) of the test product (including the ASC0-t/ASC0-inf ratio), with individual values, averages, standard deviations, variation coefficients, minimum and maximum values;
5.8.4. pharmacokinetic parameters (listed in item 3.1.2 of the GUIDE FOR RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE TESTS OF DRUG PRODUCTS) of the reference product (including the ASC0-t/ASC0-inf ratio), with individual values, averages, standard deviations, variation coefficients, minimum and maximum values;

5.9. Annexes:

5.9.1. model table containing plasmatic concentration data;
5.9.2. listing of the output of the statistical program used.

ANNEX I

Test formulation

MODEL OF Tale of plasmatic concentrations

Time (hours)

Vol. 1

Vol. 2

Vol. 3

Vol. 4

Vol. 5

Vol. 6

Vol. 7

0

0,5

1

1,5

2

4

8

24

32


Reference formulation

Time (hours)

Vol. 1

Vol. 2

Vol. 3

Vol. 4

Vol. 5

Vol. 6

Vol. 7

 

0

               

0,5

               

1

               

1,5

               

2

               

4

               

8

               

24

               

32

               

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