Chương V Thông tư 03/2012/TT-BYT: Các giai đoạn thử thuốc trên lâm sàng và tiến hành thử nghiệm

Chapter V

CLINICAL DRUG TRIAL STAGES AND CONDUCTING EXPERIMENT

Article 18. The stages of clinical pharmaceutical drugs, medical biological products trial

1. Stage 1:

a) As the first stage to test new active elements or new formulations of the drugs in humans (usually done in the healthy volunteers).

b) Research purpose of stage 1: to establish a preliminary evaluation of the safety and initial assessment of pharmacokinetics and pharmacodynamics of the active element in humans.

c) Sample size: should be considered carefully based on results of preclinical research, sample sizes of 10-30 subjects.

2. Stage 2:

a) As the test stage to be conducted on a limited number of patients.

b) Research purpose of stage 2: to evaluate the therapeutic effect and safety of active elements in the patients, determine the use dose and appropriate dose regime to provide optimal treatment for clinical trials.

c) Sample size: at least 50 patients.

3. Stage 3:

a) As the test stage to be studied on a larger number of patients. The clinical trial conditions during this period are conducted close to the normal conditions of use. It is often conducted multicenter, randomization, with placebo.

b) Research purpose of stage 3: to determine the stability of the formula, the safety and effectiveness of short and long term of active substance, evaluate the effectiveness of treatment at the overall level. To research the adverse reactions often occurring, detect the special characteristics of researched products.

c) Sample size: at least 200 patients.

4. Stage 4:

a) As the clinical studies to be conducted after the drug has been put into circulation. Study design may vary but the scientific standards and ethical standards are similar to the one before drug is circulated.

b) Research purpose of stage 4: clinical trial of this stage is conducted on the basis of the characteristics of the product allowed for circulation, usually in the form of monitoring after the circulation or evaluation of effect of therapy or evaluation of treatment strategies.

c) Sample size: at least 1,000 patients.

Article 19. The stages of clinical vaccines trial

1. Stage 1:

a) As the first stage of testing new vaccine in the small-scale for preliminary assessment of the safety of the vaccine through the preliminary information collection on drug tolerance. Stage 1 is usually performed on adult healthy volunteers, at risk of infection and low complication before use for the target subjects.

b) Stage 1 is usually open research, non-randomized with a placebo of pharmaceutical fake can be done with some particular age or population groups to determine dose, safety, vaccine schedule, the route of vaccination.

c) The attenuated live vaccines (virus or bacteria) capable of infecting recipients or contacting persons must be evaluated and closely monitored on the dose, clinical signs of infection and response (immediate, early and late). Stage 1 research can provide preliminary information on the dispersion, transmission to contacting persons and the genetic stability of vaccine.

d) Sample size: should be considered carefully based on results of preclinical studies, sample sizes of 30-50 subjects.

2. Stage 2:

a) Is conducted after the completion of Stage 1 with the results approved by the Council of Ethics in biomedical research - Ministry of Health. Purpose of stage 2 is to demonstrate the immunogenicity of the active ingredients, the safety of the vaccines tested on target subjects. Stage 2 research is to evaluate the immune response related to age, race, and gender. Study of design has placebo and randomization.

b) For attenuated live vaccines, in addition to the monitoring of parameters such as stage 1, it needs to pay attention to the presence and existence of antibodies titers: neutralizing antibodies or fixation cross antibodies or cell-mediated immune and interactions affecting the immune system (eg pre-existing antibodies, immunization made at the same time with vaccines or other drugs).

c) Sample size: at least 200 subjects.

3. Stage 3:

a) Stage 3 research is done on a large scale, multi-center to evaluate the protective effect (efficacy) and safety of the active ingredients of immunity in the vaccine on the target subjects.

b) Sample size: at least 500 subjects.

4. Stage 4:

a) Stage 4 research is conducted after the vaccines have been licensed for distribution. Stage 4 is considered as monitoring after granting license or research after granting license for the purpose of determining adverse effects and monitoring protective effect after vaccines are widely used in the population community under conditions of use. Stage 4 can be held to assess:

- The optimal conditions for the use of vaccines (optimal age for vaccination, concomitant use with other vaccine and other conditions).

- Protective effect of risk groups (elderly, immune injury patients, people with certain diseases).

- Maintenance of level of protection and long-term safety.

b) Sample size: at least 10,000 subjects.

Article 20. The stages of testing traditional medicines or drugs from clinical medicinal herbs

1. Stage 1:

a) Research is often conducted on volunteers who meet clinical trial criteria for the purpose of determining safe dose (maximum dose that the dose does not cause serious side effects), as follows:

b) The first dose must be equal to 1/3 - 1/5 of dose expected from preclinical studies. From the first dose to the maximum dose, it may be divided many doses. This stage is ended when the safe dose is determined.

c) Sample size: should be considered carefully based on results of preclinical studies, sample sizes of 10-30 subjects.

2. Stage 2:

a) The study evaluates the safety and efficacy of drugs. Study design has a placebo, randomization, each group has at least 25 patients.

b) Therapeutic dose: dose of drug used in this stage must be based on research results of stage 1.

c) Sample size: at least 50 patients.

3. Stage 3:

a) To confirm the safety and efficacy of drugs in the extended conditions. Study subjects were selected by random method with control or self-control.

b) Sample size: at least 100 patients.

4. Stage 4:

a) Applying as for pharmaceutical drugs.

b) Sample size: at least 200 patients.

Article 21. Clinical drug trial at several different establishments

1. When conducting research in many different establishments, organizations undertaking clinical drug trial need to establish joint steering committee consisting of prime researchers, prime researchers of branches and representatives of the units presiding over research to unify objectives, content, evaluation criteria, plans and research progress.

2. For multinational clinical research, in which Vietnam is a participant, the procedures, dossiers must comply with the provisions of this Circular. Objectives and content of research, trial in Vietnam, and the joint activities to implement the research with other nations must be detailed in the research outline.

Article 22. The objectives, contents and sample sizes of research

Minister of Health specifies objectives, contents and sample sizes of research specified in Article 18, 19, 20 and 21 of this Circular based on the advice of the Council of Ethics in bio-medical research for each case of dossier, research outline.

Article 23. Handling cases of complications during the clinical drug trial

Handling of irregularities in the research process is as follows:

1. In case of dangerous complications threatening the lives of participants in clinical drug trial, the prime researchers and organizations undertaking clinical trials must stop testing on the participants, hold the first aid, recovery and deal with the consequences, make records, and urgently report to the grassroots Council of Ethics, Council of Ethics - Ministry of Health, Department of Science and Training, Ministry of Health.

2. In cases of clinical trial leading to damage the health of participants in clinical drug trial, prime researchers must stop the research for the treatment and monitor the health happening of clinical trial participants and review and decide on continuty or stopping clinical trials.

3. Abnormal cases anticipated and adopted handling measures effectively shall be continued to conduct clinical drug trial.

Article 24. Collection of information and data

1. The information recorded in the course of researching clinical drug trial must be recorded in clinical research files (CRFs). CRF is considered as the original document, preserved, stored in accordance with provisions for used a basis for monitoring, evaluation and acceptance of testing results.

2. The relevant documents required for the clinical assessment process (testing slip, diagnostic imaging results, prescriptions) must be copied from the original writing full name of cross-check examiner, stating clearly the origin and must be managed, stored according to regulations.

Article 25. Data processing

1. The research data of clinical drug trial must be treated by biologic statistical methods and must be processed by an agency or organization independent of the agency or organization undertaking data processing to ensure the objectivity, honesty and trust.

2. Results of statistical analysis must be clearly presented to help identification of differences in clinical outcome; when evaluating treatment effects, it must be based on reliability and the results obtained from statistical analysis. Report on final conclusion of clinical study should be consistent with the results of statistical analysis.

Article 26. Documents archive on clinical drug trial

1. The data, the original document, testing slip, image diagnostic results, the collected documents related to clinical drug trial, minutes of meetings of the boards, supervision records, progress reports, trial registration documents and other trial-related materials must be preserved completely, stored at least 15 years at the research establishments, from the time the study is ended.

2. Prime researcher is responsible for the entire process of preservation and archive of research documentation and for presenting them upon request of the delegations of inspection, supervision and competent state management agencies.

Article 27. Report of research result of clinical drug trial

1. Report of result of clinical drug trial is in compliance with prescribed form (Appendix 7, issued together with this Circular), including full information on the drug, description of the research method, testing process, data analysis, result evaluation, comparison with the research objectives and research tasks; provide honest and objective, accurate conclusions. Contents of report must be consistent with the objectives and content of research in the approved outline.

2. Prime researcher is responsible for the science, accuracy and truthfulness of the data, conclusions, judgment and other contents of the report.

Article 28. Management of drugs of clinical trial

1. The import and export of drugs of clinical trial shall comply with current regulations on import and export of drugs.

2. The management of drugs of clinical trial must comply with current regulations from the stages of sampling, quality testing, packaging, transportation, delivery, storage, labeling, and distribution.

3. It must have a logbook to track the use of drugs of clinical trial together with information on the quantity and quality of drugs.

4. Un-used up drugs and stored drugs must be strictly managed, separated and stored according to the right regulations. Unused up drugs must be handed over to organizations and individuals with drugs of clinical trial.

5. It must be made handling records for the drugs not guaranteed quality in accordance with provisions of the Ministry of Health.

6. Stored drug samples (03 smallest packaging unit) must be preserved at least three years (36 months) in the organizations undertaking clinical drug trial after the end of the research.