Decision No. 371/BYT-QD on Issuing the "Regulation on Assessing the Safety and Efficacy of Traditional Medicines"

 

 

 

 

 

Pursuant to …;

DECISION NO. 371/BYT-QĐ OF THE MINISTER OF HEALTH ON MARCH 12, 1996, ISSUING THE "REGULATIONS ON THE ASSESSMENT OF SAFETY AND EFFECTIVENESS OF TRADITIONAL MEDICINE DRUGS"

___________________________

THE MINISTER OF HEALTH

- BASED ON THE GOVERNMENT DECREE NO. 68/CP OF OCTOBER 11, 1993, REGULATING THE FUNCTIONS, TASKS, POWERS, AND ORGANIZATIONAL STRUCTURE OF THE MINISTRY OF HEALTH;

- CONSIDERING THE PROPOSAL OF THE DIRECTOR OF THE VIETNAMESE INSTITUTE OF TRADITIONAL MEDICINE AT LETTER NO. 2/YHCT OF MARCH 6, 1995;

- UPON THE PROPOSAL OF THE HEADS OF THE DEPARTMENT OF TRADITIONAL MEDICINE, THE DEPARTMENT OF SCIENCE AND TRAINING, AND THE DEPARTMENT OF PHARMACY;

Pursuant to …;

Article 1:

THIS DECISION ATTACHES THE "REGULATIONS ON THE ASSESSMENT OF SAFETY AND EFFECTIVENESS OF TRADITIONAL MEDICINE DRUGS."

Article 2:

THIS DECISION SHALL TAKE EFFECT FROM THE DATE OF SIGNATURE, ALL PREVIOUS PROVISIONS CONTRARY TO THE PROVISIONS OF THIS DECISION ARE ABOLISHED.

Article 3:

THE DIRECTORS OF THE MINISTRY'S OFFICE, THE INSPECTOR GENERAL, THE HEADS OF THE DEPARTMENT OF TRADITIONAL MEDICINE, THE DEPARTMENT OF SCIENCE AND TECHNOLOGY, THE DEPARTMENT OF TREATMENT, THE DEPARTMENT OF PHARMACY, THE HEADS OF SUBORDINATE UNITS, THE DIRECTORS OF PROVINCE HEALTH SERVICES, AND THE DIRECTORS OF HEALTH SERVICES OF SECTORAL AGENCIES ARE RESPONSIBLE FOR IMPLEMENTING THIS DECISION.

 

 

 

REGULATIONS

REGULATIONS ON THE ASSESSMENT OF SAFETY AND EFFECTIVENESS OF TRADITIONAL MEDICINE DRUGS

(ISSUED ACCOMPANYING DECISION NO. 371/BYT-QĐ OF MARCH 12, 1996)
of the Minister of Health)

TRADITIONAL MEDICINE DRUGS HAVE BEEN USED FOR A LONG TIME IN OUR COUNTRY, IN PRIVATE CLINICS, AND AMONG THE POPULATION. MANY EFFECTIVE REMEDIES AND VALUABLE EXPERIENCES HAVE BEEN TRANSMITTED THROUGH BOOKS OR BY WORD OF MOUTH FROM ONE GENERATION TO ANOTHER. FOLLOWING THE POLICY OF INHERITANCE, DEVELOPMENT, AND ENHANCEMENT OF TRADITIONAL MEDICINE, FROM 1958 TO THE PRESENT, THE HEALTH SECTOR HAS COLLECTED AND COMPILED MANY TRADITIONAL MEDICINE REMEDIES. SOME TRADITIONAL MEDICINE DRUGS HAVE BEEN STUDIED SYSTEMATICALLY AND SCIENTIFICALLY, BUT MANY REMEDIES HAVE NOT BEEN SUMMARIZED AND EVALUATED USING SCIENTIFIC METHODS, THEREFORE, THEIR EFFECTIVENESS IS UNCLEAR.

TO EVALUATE THE EFFECTIVENESS OF DRUGS, ENSURE THE HEALTH AND SAFETY OF USERS, AND PROVIDE A BASIS FOR APPROVING REGISTRATION NUMBERS FOR PRODUCTION AND DISTRIBUTION, THE MINISTRY OF HEALTH ISSUES THE "REGULATIONS ON THE ASSESSMENT OF SAFETY AND EFFECTIVENESS OF TRADITIONAL MEDICINE DRUGS" AS FOLLOWS:

 

PART I

GENERAL PROVISIONS

Article 1. THE TERMS USED IN THESE REGULATIONS ARE UNDERSTOOD AS FOLLOWS:

1. TRADITIONAL MEDICINE DRUGS ARE A RAW OR PROCESSED DRUG OR A FORMULATION PREPARED ACCORDING TO TRADITIONAL MEDICINE METHODS FROM ONE OR MORE PLANT, ANIMAL, OR MINERAL SOURCES WITH THERAPEUTIC OR HEALTH BENEFITS FOR HUMANS.

2. HEREDITARY REMEDIES ARE SPECIFIC REMEDIES FOR CERTAIN DISEASES THAT ARE EFFECTIVE AND FAMOUS IN A REGION OR LOCALITY, PRODUCED AND TRANSMITTED FOR GENERATIONS WITHIN A FAMILY.

3. ANCIENT FORMULAS ARE DRUGS USED EXACTLY AS DESCRIBED IN ANCIENT TEXTS REGARDING THE NUMBER OF INGREDIENTS, QUANTITY OF EACH, PREPARATION METHOD, DOSAGE, USE, AND INDICATIONS.

4. MODIFIED ANCIENT FORMULAS ARE DRUGS WITH A DIFFERENT STRUCTURE THAN ANCIENT FORMULAS REGARDING THE NUMBER OF INGREDIENTS, QUANTITY OF EACH, PREPARATION METHOD, USE, AND DOSAGE, ADAPTED BY DOCTORS WHILE MAINTAINING THE ESSENCE OF THE ANCIENT FORMULA.

5. NEW FORMULAS (MODERN TRADITIONAL MEDICINE DRUGS) ARE DRUGS WITH A COMPLETELY DIFFERENT STRUCTURE THAN ANCIENT FORMULAS REGARDING THE NUMBER OF INGREDIENTS, QUANTITY OF EACH, FORM, USE, AND INDICATIONS.

6. CHARACTERISTIC COMPONENTS ARE NATURAL SUBSTANCES IN TRADITIONAL MEDICINE DRUGS USED AS STANDARDS TO ENSURE THE QUALITY OF TRADITIONAL MEDICINE FORMULATIONS AND ARE NOT NECESSARILY BIOLOGICALLY ACTIVE OR THERAPEUTIC SUBSTANCES.

7. BIOLOGICAL ACTIVITY IS THE FUNCTIONAL CHANGE IN ANIMALS (OR TISSUE SAMPLES) WHEN TRADITIONAL MEDICINE DRUGS ARE TESTED ON THEM.

Article 2.- Applicability:

8. THERAPEUTIC EFFECT IS THE IMPROVEMENT IN PATIENT HEALTH CAUSED BY THE APPLICATION OF TRADITIONAL MEDICINE DRUGS.

1. TRADITIONAL MEDICINE DRUGS SUCH AS MODIFIED ANCIENT FORMULAS, HEREDITARY REMEDIES, AND NEW FORMULAS MUST BE ASSESSED ACCORDING TO THESE REGULATIONS BEFORE PRODUCTION AND DISTRIBUTION.

2. TRADITIONAL MEDICINE DRUGS ALREADY PERMITTED FOR PRODUCTION AND DISTRIBUTION BY THE STATE DO NOT NEED TO BE ASSESSED ACCORDING TO THESE REGULATIONS.

Article 3.- 3. TRADITIONAL MEDICINE DRUGS (MODIFIED ANCIENT FORMULAS, HEREDITARY REMEDIES, AND EXPERIMENTAL FORMULAS NOT YET ASSESSED ACCORDING TO THESE REGULATIONS MAY ONLY BE USED IN TREATMENT AT HEALTH CARE FACILITIES AND NOT WIDELY DISTRIBUTED.

TRADITIONAL MEDICINE DRUGS SUBMITTED FOR ASSESSMENT MUST:

- BE PRODUCED ACCORDING TO A DEFINED PROCESS.

- HAVE QUALITY STANDARDS APPROVED.

- HAVE CLEARLY IDENTIFIED INGREDIENTS.

Article 4.- - HAVE RELATED DOCUMENTATION ON THE FORMULATION SUBMITTED FOR ASSESSMENT.

PRINCIPLES OF APPLICATION:

1. NEW TRADITIONAL MEDICINE FORMULAS (NEW FORMULAS) PROPOSED FOR WIDE DISTRIBUTION MUST BE FULLY ASSESSED ACCORDING TO THE REGULATIONS.

2. TRADITIONAL MEDICINE DRUGS (MODIFIED ANCIENT FORMULAS, HEREDITARY REMEDIES, EXPERIMENTAL FORMULAS) THAT HAVE BEEN USED IN CLINICAL TRIALS AT HOSPITALS AND CLINICS ARE CONSIDERED TO HAVE BEEN ASSESSED IN PHASE 1. IF WIDER PRODUCTION AND APPLICATION ARE SOUGHT, CLINICAL ASSESSMENTS IN PHASES 2 AND 3 MUST BE CONDUCTED (SEE ANNEX 4).

3. TO DETECT ANY TOXIC EFFECTS OF TRADITIONAL MEDICINE DRUGS NOT DISCOVERED IN PHASES 1, 2, AND 3, CLINICAL RESEARCH IN PHASE 4 MUST BE CONDUCTED (SEE ANNEX 4).

Article 5.- 4. TO INTRODUCE NEW INDICATIONS OR USES FOR ANCIENT FORMULAS OR FORMULAS ALREADY REGISTERED FOR WIDE DISTRIBUTION, CLINICAL ASSESSMENTS IN PHASE 5 MUST BE CONDUCTED (SEE ANNEX 4).

ORGANIZATION OF THE ASSESSMENT TEAM AND PLAN:

- THE ASSESSMENT TEAM MUST INCLUDE MULTIPLE MEMBERS INCLUDING SCIENTISTS (CLINICAL, PHARMACOLOGY, PHARMACEUTICAL MATERIALS, FORMULATION, PHYTOCHEMISTRY, TESTING...), COOPERATIVE AGENCIES.

 

PART II

- THE ASSESSMENT PLAN MUST SPECIFY ASPECTS SUCH AS FORM, QUALITY, TOXICITY (ACUTE, SUBACUTE, CHRONIC LD50), PHARMACOLOGICAL EFFECTS, CLINICAL EFFECTS, TIMELINES FOR EACH STEP, INTERIM AND FINAL REPORTS, AND ACCEPTANCE.

Article 6: CONDUCTING THE ASSESSMENT

DEVELOPING THE ASSESSMENT OUTLINE:

1. THE NAME OF THE PROJECT (SPECIFIED CLEARLY).

2. THE OBJECTIVE OF THE PROJECT (SPECIFIED CLEARLY AND CONSISTENT WITH THE PROJECT NAME).

3. REASON FOR SELECTING THE PROJECT.

4. THE FORMULA OF THE DRUG (VIETNAMESE NAME, SCIENTIFIC NAME, FORM, DOSAGE, USE, EFFECT).

5. THE FORMULATION PROCESS.

6. QUALITY STANDARDS FOR RAW MATERIALS AND FINISHED PRODUCTS OF THE DRUGS SUBMITTED FOR ASSESSMENT.

7. DETERMINING THE PHARMACOLOGICAL EFFECTS OF THE DRUGS SUBMITTED FOR ASSESSMENT.

9. Criteria for selecting patients to evaluate the safety and efficacy of the drug under review (based on nationally or internationally recognized diagnostic standards).

10. Evaluation criteria for results.

11. The number of patients included in the evaluation group is determined by statistical probability.

12. The control group for checking treatment outcomes may be:

- A group using an effective drug that has been recognized.

- Or a group using a placebo (dummy drug).

13. Treatment protocols for the evaluation group and the control group must be identical and ensure patient safety.

14. Clinical observation records (daily) and ancillary clinical observations (periodic).

In addition to the points mentioned above in the proposal, the following items are also recorded:

- Research team (qualified personnel).

- Location and means of implementation.

- Plan for reporting to superiors.

- Plan for post-evaluation patient follow-up.

Article 7.- The evaluation proposal must be reviewed and approved by the equivalent Scientific and Technical Council (at the institutional, ministerial, or national level).

- The decision to establish the reviewing council at each level is made by the head of that level according to current regulations.

- The council's responsibilities include reviewing the following contents:

1- Patient rights.

2- Whether the clinical evaluation proposal is complete and feasible.

3- Environmental protection.

- The places receiving traditional medicine evaluations are designated by the Ministry of Health: Institutes; Hospitals; Research Centers with adequate equipment and staff qualifications to conduct evaluation steps and promptly handle any adverse events.

Article 8.- Determine the quality characteristics of traditional medicine (Step 1):

- Establish standards, specifications, and quality of herbal ingredients in the preparation.

- Identify characteristic substances.

- Establish production processes.

(See Appendix 1 attached).

Article 9.- Determine pharmacological effects and toxicity of traditional medicine (Step 2):

1. Identify pharmacodynamic and pharmacological effects of the drug (see Appendix 2 attached).

2. Identify toxicity: acute, subacute, chronic of the drug (see Appendix 3 attached).

3. Experimental methods (must be national or international standard methods) include:

- Basic pharmacodynamic and pharmacological testing methods conducted on animal models or relevant biological experiments closely related to patients.

- Toxicity testing on animals:

+ Systemic toxicity (physiological, biochemical, hematological, anatomical changes...).

+ Acute toxicity (appears within 24-36 hours).

+ Chronic toxicity (appears during prolonged use of the evaluated drug from 3 to 6 months). Subacute toxicity testing can be conducted over a period of 2 months.

+ Local toxicity (irritation and absorption properties of the drug).

+ Special toxicity (generally not tested but must be performed if required).

Article 10.- Clinical effectiveness evaluation stages (Step 3):

Conducted after confirming the quality specifications and determining the toxicity and pharmacological effects of the drug.

1. Stage 1: Preliminary observation of the drug's efficacy to serve as a basis for subsequent evaluation stages.

- Have an appropriate treatment protocol.

- Conducted on a small number (10-30) of healthy individuals (aged 20-30), with normal liver, heart, kidney functions, no history of food or drug allergies (can also be conducted on a few voluntary patients).

- Determine dosage and route of administration.

- Record observations according to the proposal.

- Analyze and evaluate.

- Report results.

2. Stage 2: Determine efficacy and further confirm the safety of the evaluated drug.

- Have an appropriate treatment protocol.

- Conducted on a limited number of patients (30-50) divided into two groups: the drug evaluation group and the control group (or only the group of patients using the evaluated drug). These patients must be monitored inpatient.

- Grouping: If there are two groups, use comparative methods where the patient profiles must be similar in quantity, gender, and duration of illness: the comparison drug must be one with established efficacy or a placebo (dummy drug). If there is only one group using the evaluated drug, use self-comparison methods.

- Daily dosage and treatment duration must be clearly defined and strictly adhere to the protocol.

- Accurately record all clinical changes; check ancillary clinical tests, adverse reactions or side effects of the drug if present.

- Evaluate therapeutic effects in four levels:

+ Complete recovery.

+ Significant improvement.

+ Improvement.

+ No improvement.

- Process data using statistical analysis.

- Report results.

3. Stage 3: Expand clinical evaluation on a larger scale to determine the results of stage 2.

- Evaluation proposal as in stage 2.

- Number of patients approximately 100-150: double-blind method.

- Implementation similar to stage 2: carried out at three centers equipped with technical facilities and qualified personnel.

- Record observations, evaluate therapeutic effects, and report results as in stage 2.

4. Stage 4: When the drug has been widely produced and used, if necessary, proceed to stage 4 to detect harmful cases that were not identified in the previous stages. Approximately 200 patients or more, implemented across multiple centers in various regions nationwide. Implementation similar to stages 2 and 3.

5. Stage 5: When it is found that the drug being used has a new indication, a stage 5 evaluation must be conducted to confirm the new indication of the drug. Implementation similar to stages 2 and 3. Approximately 100 patients or more.

CHAPTER III

RESPONSIBILITIES OF PARTICIPANTS IN THE EVALUATION, REQUESTERS, AND SPONSORS OF TRADITIONAL MEDICINE EVALUATIONS

Article 11.- Responsibilities of evaluation participants:

- Prepare the proposal and necessary materials to submit to the reviewing council.

- Organize the implementation of the proposal; thoroughly understand the evaluated drug; monitor and record observations, promptly handle any adverse events if they occur; regularly report results to the management authority; inform the requester and sponsor.

Article 12.- Responsibilities of requesters and sponsors of traditional medicine evaluations:

- Ensure the integrity (of evaluators and the reviewing council, acceptance council).

- Ensure patient safety.

- Ensure the specifications and quality of the evaluated drug.

- Provide materials about the drug for evaluation to participants before drafting the evaluation outline.

 

PART IV

DATA PROCESSING - STATISTICAL ANALYSIS - EVALUATION OF RESULTS

Article 13.- Data processing:

- After completing the outline and medical records, evaluators must sign and take responsibility.

- Store original medical record data as reference material for subsequent evaluation steps.

- Information recorded in medical records must be transferred accurately and ensure confidentiality.

Article 14.- Statistical analysis:

- The statistical method to be used must be determined beforehand and clearly stated in the outline.

- Statistical results must be presented clearly for easy use in clinical outcome evaluation.

- Results must be published fully, including both positive and negative outcomes (only positive outcomes should not be published).

- Submit a final report to the management authority, the requesting and funding party, and the Evaluation Acceptance Board as decided.

Article 15.- RESULT EVALUATION:

- The Evaluation Acceptance Board designated by the competent authority will evaluate the project's results after members have received the final report and provided comments.

- The Board will evaluate the results of all stages according to the approved outline.

- The Board will report to the competent authority on the accepted results.

 

CHAPTER V

APPLICATION AND ENFORCEMENT PROVISIONS

Article 16.- This regulation applies to scientific research institutions, healthcare facilities, and traditional medicine production units under state and private health authorities nationwide.

Article 17.- This regulation takes effect from the date of issuance - all provisions contrary to this regulation are abolished.

Article 18.- Any complaints regarding the evaluation of the safety and efficacy of traditional medicine by organizations and individuals shall be submitted to the State Management Authority on Traditional Medicine or relevant authorities according to their jurisdiction for study and resolution in accordance with current laws.

 

ANNEX 1

PROCEDURES FOR DETERMINING QUALITY CHARACTERISTICS OF DRUG SUBSTANCES AND VIETNAMESE TRADITIONAL MEDICINE

 

I. INTRODUCTION.

Vietnamese traditional medicine has been used for thousands of years, including herbal medicines and formulations prepared according to traditional principles and folk remedies. Our country has used over two thousand different medicinal herbs, of which more than 80% are plant-based. Vietnamese traditional medicine, like Chinese medicine, includes three types:

1. Raw and processed medicines.

2. Decoctions, which consist of multiple herb pieces and are used in the form of decoctions or alcohol-based preparations.

3. Pills, powders, and other modern forms of medication.

Decoctions are the most commonly used form of medication today. This form is still highly regarded. However, the effectiveness of the entire prescription depends on the quality of each individual herb, from cultivation, harvesting, initial selection, to preparation.

To ensure the safety and efficacy of traditional medicine, it is necessary to establish evaluation procedures for herbal standards in the following areas:

- Authenticity.

- Harvesting time, parts used, preparation methods.

- Active substances or characteristic components selected for both qualitative and quantitative aspects.

When developing evaluation methods, in addition to standardized methods, simple and quick methods that are still reliable (express-methods) should also be considered, especially for locations far from central facilities but close to herbal supply regions.

 

II. SOME CHARACTERISTICS OF VIETNAMESE TRADITIONAL MEDICINE

- Vietnamese traditional medicine, like Chinese medicine, originates from plants, animals, and minerals. In clinical practice, plant-based medicines are the most widely used.

- The same medicinal herb may have different names depending on the region.

- Local people often fail to distinguish between different species when harvesting herbs, although they belong to the same genus. The timing of harvesting is not strictly observed.

- The process of preparing raw and processed medicines for many herbs still varies...

- Through processing, the nature and toxicity of some herbs can change, and the efficacy of processed medicines is usually higher than that of raw ones.

- Sensory evaluation methods are primarily used, and a unified, objective, and scientific method for evaluating the quality of medicines has yet to be established.

- Understanding the relationship between biological effects and therapeutic effects of medicines with active substances or groups of active substances has only recently been addressed.

- Most herbs and prescriptions are still used based on experience.

- The most common forms of medication are decoctions, alcohol-based preparations, or pills.

 

III. RESEARCH OBJECTIVES ON VIETNAMESE TRADITIONAL MEDICINE

Research objectives on Vietnamese traditional medicine include the following issues: - Authenticity of the medicine (authenticity) with sensory, botanical, chemical, and if possible, biological standards.

- Quality assessment of the medicine through determining the levels of impurities, active substances, or groups of active substances in the herbal ingredients.

- Assessment of the effectiveness of traditional preparation processes in terms of physical and chemical changes (and biological changes where applicable) leading to changes in the efficacy, toxicity, and storage duration of the medicine.

For prescriptions containing multiple herbs, the main 2-3 herbs must be selected to determine the presence of active substances or characteristic components. If the levels of certain selected active substances can be determined, especially for expensive herbs (to prevent counterfeiting) and toxic herbs (to ensure user safety), this should be done.

 

IV. GENERAL INTRODUCTION TO RAW MATERIALS USED IN VIETNAMESE TRADITIONAL MEDICINE.

Each raw material used in Vietnamese traditional medicine must be accompanied by a complete scientific dossier recording the following characteristics:

1. Name and general characteristics:

Names include:

- The name of the herb in Vietnamese, Latin, and English (for export).

- The name of the plant in scientific terms, including family, genus, species, variety, and authorship related to the determination of the scientific name.

Additionally, it is necessary to:

- Clearly specify the part used for medicine, the condition of the raw material (for example, leaves, flowers, branches, roots, rootstocks, etc., fresh or processed, in original form or sliced...).

- Briefly describe the distribution of medicinal plants in different regions, living conditions (growth environment of the plant), whether cultivated or wild-harvested. Clearly state any differences if there are variations in medicinal plants growing in different places, accompanied by color photographs and detailed drawings.

- Record the time and method of harvesting medicinal plants, as well as the processes of preliminary treatment and preparation.

- Clearly state the active ingredients or therapeutic segments according to available reference materials, along with the structural formula of the active ingredient.

- If the raw material used for medicine has been prepared, the changes in the composition of the active ingredient after preparation must be specified.

2. Quality standards

2.1. Authenticity of the raw material.

Describe sensory observations (shape, smell, taste, color), macroscopic and microscopic (microscopic) characteristics, and thin-layer chromatography analysis of powdered herbal samples under a microscope. Identify active ingredients and characteristic substances through specific chemical reactions and thin-layer chromatography. The results of these analyses must be illustrated or photographed in color. If the active ingredients are unknown, the authenticity of the raw material can be determined using a detailed thin-layer chromatogram of a standard extract solution. This chromatogram is considered the fingerprint of the medicinal plant. Specify the extraction conditions, chromatographic running conditions, and spray reagents used.

Clearly specify the permissible limits for the presence of inorganic and organic impurities (for example: parts of other plants, soil, sand mixed in). These impurities within the stated limits must not be toxic and must have no color or odor. Additionally, no other impurities may be present.

2.3. Assay. Clearly state the necessary physicochemical and biological methods to assess the presence of active ingredients, characteristic substances, or therapeutic segments of the extract, along with permissible ranges, to serve quality control according to the procedures set forth in the Vietnamese Pharmacopoeia and the Vietnamese Herbal Materials book published by the Ministry of Health.

For new medicinal plants, reliance should be placed on scientific research works officially published by authors and the official pharmacopoeias of other countries (China, England, France, Russia, USA, etc.).

2.4. Packaging and storage.

Most raw materials can be packaged in common containers. For types that are prone to insect damage and raw materials containing volatile essential oils, they must be stored in sealed wooden boxes, dry containers, or plastic bags. For moisture-absorbent and easily deteriorating raw materials, they must be stored in suitable packaging with desiccants and tightly sealed.

2.5. External label: Must include net weight with and without packaging, harvesting date, packaging date, storage period, storage conditions, and production batch number.

2.6. Storage of fresh and processed medicines.

The warehouse must be cool, dry, clean, and airy. Regular monitoring to prevent mold, pests, rodents, and insects is required.

Special storage conditions must be provided for toxic medicines.

 

V. GENERAL INTRODUCTION TO TRADITIONAL MEDICINE FORMULATIONS

Common traditional medicine formulations include decoctions, extracts, pills, powders, granules, and alcohol-based medicines. Currently, there are also new forms such as round tablets, compressed tablets, capsules, syrups, plaster patches, massage oils, and injectable medicines. These traditional medicine formulations must comply with the following requirements:

1. Name and formula of traditional medicine formulation:

1.1. The name of the traditional medicine formulation must be in Vietnamese. After the Vietnamese name, foreign language annotations may be added. For new formulations, manufacturers may give them proprietary names.

1.2. In the formula, clearly state the name of each herb and the quantity needed to produce 1000 grams or 1000 milliliters of the formulation. The excipients used must also be mentioned.

1.3. Clearly describe the preparation process, including the extraction and separation of active segments or main active groups, solvents used, temperature, time, extraction yield of active groups in the extract, sterilization, and storage methods. Explain the principle of combining herbs, including excipients.

2. Quality standards:

2.1. Authenticity of the formulation:

Describe the sensory characteristics of the formulation (color, taste, clarity, external appearance). If it is a powder, describe the microscopic characteristics observed under a microscope, accompanied by illustrations or color photographs.

Describe the specific reactions to check for the presence of characteristic substances, active ingredients, or active groups, and the specific thin-layer chromatography conditions used as the fingerprint for the formulation, accompanied by illustrations or color photographs.

2.2. Purity. Clearly specify the permissible limits for the presence of heavy metals in extracts and tests to ensure there is no methanol in formulations with alcohol as the solvent.

2.3. Assay. Provide detailed methods to determine the presence and concentration of major active groups. For formulations with multiple components, at least three different active groups must be identified.

For preparations, dissolution tests for tablets made from powdered herbs or extracts, moisture content according to the Vietnamese Pharmacopoeia, alcohol content for alcohol-based extracts and medicinal wines, size for granules, tablets, and powders, along with permissible error ranges, must be conducted.

Conduct tests for microbial contamination according to the WHO/PHRM/92.559 guidelines, page 59.

2.4. Stability. The stability of the traditional medicine formulation must be maintained for at least one year under optimal packaging and storage conditions. There should be no changes exceeding permissible limits in terms of external appearance, sensory characteristics, pH value, alcohol content, active ingredient content, moisture content, microbial contamination, etc.

2.5. Packaging.

Traditional medicine formulations can be packaged for one or multiple doses as a single retail unit on the market. Multiple units can then be packaged in wooden crates or cartons for distribution to treatment facilities or for wholesale markets.

2.6. Label

All preparations must be labeled, on the label, the Vietnamese name must be larger than the foreign language name, the drug formula, dosage for one or multiple uses, method of use, indications and contraindications of the drug, storage time, toxic drugs, in accordance with the Ministry of Health's regulations on drug labels.

2.7. Storage in warehouses. Preparations must be stored in dry, well-ventilated warehouses, away from sunlight, rain, and moisture. In hot climates with high humidity, drugs should not be kept long in storage warehouses and should be packaged in sealed containers with desiccants.

 

ANNEX 2

GUIDELINES FOR THE PHARMACOLOGICAL STUDY OF TRADITIONAL MEDICINE

Traditional medicine has different pharmacological effects. Suitable methods should be used for evaluation. This annex presents issues that need attention during the study and evaluation of the pharmacological effects of traditional medicine.

 

I. EXPERIMENTAL ANIMALS.

1. Source:

1.1. The source of experimental animals plays a crucial role in ensuring the quality of research animals. State breeding facilities should be used to supply laboratories.

1.2. Animals brought from other places must be carefully checked for quality, weight, fur, tail color, teeth, eyes, claws, nipples, external genitalia... and allowed to rest for 1-2 days before experimentation.

1.3. Ensure a stable supply of animals for a research project, for a system of organs, for an observation index.

2. Species, breed, age, weight, and physiological starting points:

2.1. Commonly used experimental animals include mice, white rats, hamsters, rabbits, dogs, cats, and frogs. The species, breed, weight, and appropriate age must be determined for each type of experiment.

2.2. If it is necessary to replace animals used in classical methods with another animal or to use a new method with a new animal, they must be thoroughly and carefully studied and scientific requirements must be met.

2.3. Before each experiment, the physiological starting points of the experimental animals must be checked: body temperature, mammary glands...

3. Feeding regimen of experimental animals:

3.1. Diet formula for experimental animals:

A reasonable diet formula for the unit is required. If in Hanoi, additional food produced by the Institute of Hygiene and Epidemiology should be purchased.

Respect certain feeding regimens for experimental animals according to the requirements of the experiment.

Ensure a consistent feeding regimen without changes throughout the research period.

Do not use food to rapidly increase weight, nor avoid using food that may affect the efficacy of the drug.

3.2. Respect daily feeding times to ensure that when administering the drug, the stomach has been partially emptied, allowing better absorption of the drug and avoiding excessive stomach distension causing abnormal phenomena mistaken for the drug's effect. Usually administer the drug in the morning after about 16 hours since the last meal of the previous day (around 4 PM the previous day).

3.3. Weigh the animals while fasting and also at the time before the experiment. When receiving experimental animals from suppliers, agree on their fasting weight.

4. Number of experimental animals.

4.1. The number of experimental animals is specified for each experiment. Ensure a sufficient number to obtain a statistically reliable probability. Only use experimental animals when necessary.

4.2. Isolated studies: Generally, each biological specimen can provide several experimental specimens. However, for isolated circulation experiments, only one experimental specimen is taken from one biological specimen.

4.3. The experimental process should be suitable for scientific requirements and the ability to supply research animals.

5. Experimental group allocation method:

Due to the use of whole-part drugs in experiments, their effects on experimental animals are often difficult to recognize, especially in whole-body studies. Therefore, the number of research groups depends on the predicted effect of a type of drug. Commonly used experimental groups are:

- Group 1 White: Nothing is used.

- Group 1 Control: Uses distilled water.

- Group 2 Control: Uses solvent.

- Group 3 Control: Uses a known classic drug.

- Treatment Group: Can be divided into different groups based on drug dosage.

In a project, one or all of these groups may be used.

6. Method of evaluating the results of experimental drugs:

Evaluation can be conducted as follows:

6.1. Compare the progression between experimental groups.

6.2. Compare data obtained before and after drug testing at each dose, between control and treatment groups.

6.3. Compare data obtained with constants determined under laboratory conditions of the facility. If there are standard experimental animals, use comparison methods commonly used in advanced countries.

Note: Under current conditions in our country, generally comparing results with those of other projects domestically and internationally is for reference purposes only.

- Do not compare to evaluate two results obtained from different research conditions.

6.4. Results obtained from a sample drug are only valuable for evaluating that sample drug.

6.5. It is necessary to choose an appropriate time to collect data for evaluating the experimental results. Generally, a basic survey is required. Traditional medicine is used in whole-part form, whole-part extraction, and mainly orally, so its effects are slower than modern medicine. Therefore, the time to evaluate the effects of traditional medicine is usually longer than that of modern medicine. For example, the time to check LD 50 for traditional medicine should be from 24 to 48 hours (can observe up to 24 hours, 36 hours, depending on the type of traditional medicine causing death quickly or slowly), while for modern medicine it is 24 hours, for acute anti-inflammatory effects it should be 48 hours, and diuretic effects should be 24 hours, etc., while testing modern medicines, the evaluation time is 5 hours after giving the drug.

7. Experimental methods:

Experimental methods determine the quality of the project. This aspect must be resolved before conducting experiments.

7.1. Whole intact animals: This type of experiment should be prioritized because the pharmacological effects of traditional medicine are determined through clinical practice (on intact bodies).

7.2. Isolated tissues and organs: this type of test is useful when necessary to supplement knowledge about the whole organism, to determine the mechanism of action of the drug, or merely as an observation index of the study (isolated intestine, isolated neuromuscular preparations, isolated blood vessels, etc.).

7.3. In-vivo and in-vitro studies.

In-vivo studies should be prioritized because animals are born, develop, and exist through in-vivo methods.

b. Although in-vitro experiments are less expensive, they do not provide factors that reflect the body's response, such as necessary activating substances for the biological activity of traditional medicine drugs, or biologically active metabolites in animal fluids. In-vitro tests can be effective in simpler testing systems.

c. In-vitro studies should only be conducted when in-vivo studies are not specified. In-vitro studies have more reference value than proving the efficacy of traditional medicine drugs. Typically, in-vitro studies are conducted first to explore effects before transitioning to in-vivo studies.

d. The results of in-vitro and in-vivo tests need to be correlated with theories from traditional and modern medicine, especially when these results do not match clinical outcomes. Attention must be paid to situations where a drug shows effects in in-vitro but not in in-vivo, or vice versa.

e. In principle, when conducting studies on animals, care must be taken to ensure their welfare, and in-vitro methods should be considered if they allow reducing animal experiments.

7.4. Studies on disease models:

This is a good method for studying traditional medicine drugs. Theoretically, it aligns with the principles of drug testing in both traditional and modern medicine. However, in practice, studying traditional medicine drugs on disease models faces many difficulties due to the inability to construct suitable models and often failing to find physiological correlations between the two medical systems.

Disease models can be induced in animals using certain chemicals, immune deficiency models, joint models, stomach models, hypercholesterolemia models, etc.

7.5. Ex-vivo cell cultures and tissue cell cultures.

7.6. Blood and its components.

7.7. Intracellular constituents (subcellular constituents).

8. Special attention should be given to the sensitivity, reproductive capacity, and tolerance of experimental animals or selected testing systems to the drug.

9. Literature review helps in selecting types and testing systems whose results can predict clinical outcomes and provide useful information.

 

II. DRUG USE:

1. Route of administration:

1.1. If a route is used clinically, the same route should be used in experiments. For example, if oral administration is used clinically, it should also be used in experiments. If intravenous injection is used clinically, it should also be used in animal experiments. If applied externally, it should also be applied externally in animals.

However, traditional medicine drugs are primarily administered orally, so oral administration is most appropriate in animal experiments.

1.2. To conduct oral administration experiments with traditional medicine drugs, new experimental methods and preparation methods may need to be developed. Basic research and stabilization of the new method must be ensured to meet scientific requirements.

1.3. When multiple routes of administration are used in a study, conclusions must be rigorously and logically analyzed to draw meaningful conclusions.

2. Number of drug administrations: The number of drug administrations depends on the specific case protocol. For example, a rabbit blood pressure experiment will be conducted over 4 hours (starting from the first dose). If a dose is given every hour, then there will be four administrations.

3. Experimental dosage:

The success of the experiment can be determined by the experimental dosing step. Dosage used on animals does not necessarily have to match clinical dosage.

Generally, the dosage that can induce a response should be based on. However, since it is difficult to prove responses to traditional medicine drugs in intact animals, determining and choosing a single or multiple dosages is necessary. This approach will yield desired results. Dosage can be determined by referencing literature, calculating from existing clinical dosages, or by titration. Titration is the best method even when experimental dosages are provided by literature and clinical data. Depending on the specific case, three to five dosages may need to be tested.

4. Volume of drug administered each time:

When administering the drug to experimental animals, different volumes can be given each time. The volume of the drug used will depend on the route of administration and the type of experimental drug.

For example, for white mice: oral: 0.2 ml/10 grams body weight; subcutaneous injection: aqueous solution 0.2 - 0.3 ml, oil solution 0.1 - 0.2 ml; intraperitoneal injection: 1 ml.

5. Handling of experimental drugs:

5.1. Traditional medicine drugs come in various forms: (extracts, decoctions, pills, powders, oils, alcohol). To conduct experiments, the drugs must be processed into a form that can be administered to experimental animals via different routes. The test drug must be in a homogeneous liquid form, with an appropriate solvent and without additional substances.

5.2. The handling of drugs for animals must be proficient, using optimal experimental equipment.

5.3. The test drug must have a detailed description file. The file must clearly specify the data of the batch of drugs such as control number, registration number. It must ensure the accuracy of all presented items, the formula of the preparation (except for confidential cases), usage, dosage, indications, contraindications, and expiration date. The project leader must have this description file to refer to literature, write a research outline, conduct experiments, and evaluate results.

5.4. In some specific cases, the project leader may need to recheck all aspects related to the test drug. For example, alcohol content, refractive index, pH, moisture content, etc. Sometimes, several analytical methods may need to be used for testing.

5.5. The drug received must be tested as soon as possible. If it has been opened, it must be tested immediately. Throughout the testing process, the drug must be stored according to regulations. If any changes are detected, the opinion of the drug tester must be sought, and the drug may need to be destroyed. For solid drugs, handle them as they are tested. For liquid drugs, only take sufficient quantities for testing each time, and destroy any excess. For alcohol-based drugs, open the cap only when testing and use them on the same day. Properly store the alcohol content to avoid significant reduction compared to the initial alcohol content.

5.6. First, provide information about the results of testing the crude drug that has been used clinically and sent for near-clinical research.

 

III. SPACE AND TESTING TIME

1. Due to the significant impact of climate on the efficacy of drugs, especially traditional medicines. Active measures must be taken to control microclimate in the laboratory such as using air conditioners, or employing common methods to increase or decrease room temperature like heating with stoves or sprinkling water, etc., or conducting tests during spring and autumn seasons starting from 8 a.m. onwards.

2. Pay attention to the physiological characteristics of animals according to the season (reproductive season in winter, breeding season in summer...) to develop appropriate research plans throughout the year.

 

ANNEX 3

GUIDELINES FOR TOXICITY STUDY OF TRADITIONAL MEDICINES

Toxicity studies of traditional medicines include:

I. Acute toxicity testing and observation over 24-48 hours.

II. Chronic toxicity testing over 3-6 months. Subacute toxicity testing can be conducted for 2 months if deemed appropriate.

III. Local toxicity testing.

IV. Special toxicity testing: chromosomal mutation, miscarriage induction, carcinogenesis...

 

I. ACUTE TOXICITY TESTING:

1. Currently in our country, white mice, both male and female, are selected based on the experiment, with quantities ranging from 30 to 100 depending on the method.

2. Mouse weight ranges from 16-22 grams, but the most commonly used is 19+1 grams, aged 45 days.

3. If oral administration is used, administer 0.20 ml of the drug per 10 grams of mouse weight. For a weight of 19 g + 1, uniformly give the mice 0.4 - 0.5 ml of the drug using a slightly curved needle with a blunt tip inserted to the stomach.

4. Given the current conditions in our country, providing mice with relatively uniform weights for each research phase is still challenging (only around 40 mice). Using Behrens' method, the number of mice mentioned can yield the LD50 result with minimal error.

5. Once an appropriate dose is chosen, there will be both a maximum safe dose and a minimum lethal dose, facilitating other experiments. Divide these mice into several groups, with a minimum of 5 groups, and each group having a minimum of 6 mice.

6. Closely monitor the 24-hour period primarily. If necessary, continue monitoring up to 36-48 hours. Record all details of events during this period, including the time of drug administration, appearance of abnormal symptoms, and time of death. After 24 hours, collect data to calculate the results. Monitoring up to 36-48 hours can provide additional insights into toxicity over that period.

7. Monitor acute side effects.

7.1. In acute toxicity tests, important pathological symptoms observed in surviving mice or just before death, such as continuous scratching of the snout, running in panic, tilting, convulsions, tremors, sweating, cyanosis in ears, feet, tail, lying or standing posture, must be fully recorded in the results section.

7.2. On electrocardiograms and electroencephalograms: monitor changes in shape, amplitude, and frequency of waves.

7.3. On blood pressure and respiration: monitor changes in form, amplitude, and frequency of waves.

In many traditional medicine experiments, acute side effects have provided valuable information to better assess the safety of traditional medicines.

8. Conduct gross examination immediately after death for dead mice, and perform gross examination after the end of the experiment for surviving mice. If necessary, conduct microscopic examination of some organs or all organs as required by the project and the pathological condition of the organs in question. If there are no particular findings overall, only examine the liver, kidneys, and intestines.

9. Several issues to pay attention to.

9.1. If an acute toxicity test proceeds smoothly, LD50 (to evaluate the degree of toxicity, to raise awareness when using) is obtained, a maximum safe dose for other experiments is obtained, and valuable symptoms indicating the mechanism of toxicity and clinical follow-up are obtained.

9.2. When conducting acute toxicity tests of traditional medicines, certain complexities may arise, such as differences from traditional medical theory or modern medicine, inability to process the drug for oral administration, and the situation where animal deaths do not follow a dose-response pattern.

9.3. When evaluating the toxicity of a traditional medicine for use:

a. Do not rely solely on LD50, but also pay attention to adverse effects.

b. Do not compare the LD50 of a studied traditional medicine with the LD50 of other traditional medicines that were not tested under the same experimental conditions.

c. Do not compare the LD50 of a traditional medicine with the LD50 of a modern drug that is the active ingredient of the traditional medicine, such as comparing the LD50 of Fu Zi with the LD50 of Aconitine, or the LD50 of Ma Qian with the LD50 of Strychnine.

 

II. CHRONIC TOXICITY TESTING:

- Since traditional medicines generally show their effects after long-term use, chronic toxicity testing has more practical significance.

1. Select experimental animals based on the project's requirements regarding species (rodents, non-rodents), breed, weight, age, etc. Under difficult conditions, rabbits are commonly used for chronic toxicity tests.

2. The minimum number of rabbits used is 6 (3 males, 3 females). A relative quantity of 10-12 is needed to ensure reliability. Weight ranges from 2.5 to 3 kg per rabbit.

3. The duration of the experiment depends on the type of drug used clinically. Generally, the drug should be administered daily for four times the duration used clinically.

A subacute toxicity experiment must be conducted for a minimum period of one and a half months. However, it should be carried out for two months to ensure sufficient data for relatively reliable result determination.

4. The route of drug administration commonly used is oral administration via rubber tubing. The dose for each rabbit per administration is calculated from below the maximum safe dose for mice or from the usual human dosage. The volume of drug administered to each rabbit per administration is 10 ml for oral administration and 3 ml for injection.

5. Observational criteria will depend on the subject matter. Common criteria applicable to any subject matter include:

5.1. Blood: red blood cell count, white blood cell count, white blood cell formula, hemoglobin ratio, clotting time, bleeding time, erythrocyte sedimentation rate, urea and blood sugar levels, serum protein profile. Testing should be done once before drug administration, at least once during the drug administration period, and once prior to animal euthanasia.

5.2. Urine: volume, specific gravity, red blood cells, renal casts, albumin. Testing should be done before drug administration and at least once during the drug administration period.

5.3. Feces: solid, soft, diarrhea form, presence or absence of parasites.

5.4. Food consumption quantity and general condition, weight, fur, activity of the animals.

6. Histological examinations (gross and microscopic) of the animals must be conducted whenever there is an animal death during the research process and when animals are killed after completing the experimental phase.

7. It is necessary to ensure material conditions for long-term experiments.

 

III. LOCAL TOXICITY TESTING:

- Use control, treatment, and check lots. Monitor local and systemic gross and microscopic morphology, biochemistry, hematology, etc., on pathological or normal models. Ensure environmental hygiene to avoid microbial contamination.

- The report of the World Health Organization Western Pacific Region (WP) Expert Group TRM/TCP/TRM/002 - series No RS/92/GE/15 (PHL) March 1993 proposed the following:

"Skin sensitivity testing."

1. Drug preparations used for treating skin diseases must include:

- Solid preparations:

Prepare for testing by wetting the preparation with water or an appropriate solvent to achieve a uniform consistency for application to the skin.

- Soft preparations: Also tested undiluted like those preparations.

- Liquid preparations: Also tested undiluted like those preparations.

However, if necessary, they can be diluted for use.

2. Experimental animals:

Use highly sensitive types. The white mouse is considered the most suitable animal.

3. Testing methods:

3.1. Testing with vehicle and gauze soaked in the drug.

3.2. Buehler test.

3.3. Draize test.

3.4. Complete Freund's adjuvant test.

3.5. Maximization test.

3.6. Open epicutaneous test.

3.7. Optimization test.

3.8. Split adjuvant test.

It should also be noted that these methods differ in probability and degree of response to sensitizing substances. Generally, it is accepted that using the complete Freund's adjuvant test increases sensitivity and thus the ability to detect weak sensitizing substances.

AT In our country, commonly used testing methods are: tests 3.1, 3.4, and 3.6.

4. Evaluation of test results.

The skin reaction of each animal must be evaluated according to the standards of the applied testing method.

 

IV. SPECIAL TOXICITY TESTS.

1. In traditional medicine research, special toxicity tests are generally not used because:

1.1. In practice, traditional medicines used according to classical principles have been proven safe over many generations, with no special toxicity observed.

1.2. Traditional medicines do not provide necessary information through special toxicity tests since they are not strong active ingredients like chemical drugs but whole or total extracts of herbs, making it difficult to detect pharmacological effects.

1.3. Nevertheless, if possible, the special toxicity of some toxic traditional medicines (such as arsenic, elephant creeper) should also be investigated.

1.4. Tests that can be conducted in certain laboratories in Vietnam include:

a. Chromosome structural mutation test.

b. Carcinogenicity test.

c. Reproductive toxicity test: causing miscarriage, premature birth, fetal death, and developmental effects.

1.5. Practical experience shows that in current traditional medicine research, this aspect is only raised when specifically required by a particular project. At that time, a suitable specialized unit will be invited to conduct the test according to the general guidelines of the World Health Organization adapted to Vietnam.

In summary, in preclinical traditional medicine research, it is necessary to:

1. Allocate adequate time for the technical exploration phase to stabilize traditional medicine testing techniques, as previously, modern research techniques were borrowed, and clearly, some modern techniques do not meet the requirements of traditional medicine research.

2. Determine the timing for reading the results of traditional medicine trials (inflammation model, diuretic model, acute and subacute toxicity).

3. Additionally, basic investigations of some issues related to traditional medicines, such as LD50 of very toxic, moderately toxic, and non-toxic traditional medicines, and the effects of traditional formulations, are also needed.

 

 

ANNEX 4

GUIDELINES FOR CLINICAL RESEARCH ON TRADITIONAL MEDICINES.

 

I. CLINICAL STUDY PROPOSAL.

The research team needs to develop a research proposal including the following issues:

1. Name of the research topic.

2. Purpose of the topic. It must be clearly stated.

3. Reason for the topic.

This reason must be valid and based on the comprehensive collection and analysis of clinical and preclinical data both domestically and internationally regarding the safety and efficacy of the researched medicine. This content must be summarized in the literature review section. Research topics that have not yet been studied should be chosen.

4. Medicine formula: must be consistent with the theory of Traditional Chinese Medicine and fundamental points of pharmacodynamics.

5. Types of tests (for example, with or without control groups), and test designs (for example, crossover, randomized, double-blind, single-blind, parallel).

6. Standards for accepting subjects into the research scope, and standards for excluding them from the research scope (based on modern medical diagnosis, traditional medicine diagnosis, or both).

7. Criteria for evaluating results.

8. The number of patients included in the research scope must be determined based on statistical probability.

9. A control group to test the treatment outcomes of the researched drug. Depending on the type of disease being studied, a positive effect drug (therapeutic effect) or a placebo may be used to establish the results of the researched drug. Positive effect drugs can be new drugs or traditional medicines that have been confirmed to be safe and effective.

10. Treatment protocol during clinical research:

There must be a defined form of the researched drug with specific dosage and method of administration.

Details about the drugs used for the control group's treatment must be provided.

11. Fully record subjective and objective clinical observations, as well as laboratory results throughout the research process. Patient symptoms at the end of the clinical research must be thoroughly analyzed in the conclusion when testing traditional medicine. Attention should be paid to the main characteristics of traditional medicine, which relate to the patient's subjective comfort or quality of life. Therefore, at the end of the clinical research, it is necessary to analyze these aspects.

12. Select researchers who are capable and experienced.

13. Determine the facilities and locations for research to facilitate its conduct.

14. Instructions for patients in the research scope to ensure cooperation during the research process.

15. Plan for reporting to the supervising authority.

16. Depending on the stage of research, there may or may not be a plan to follow up patients after the clinical research period.

 

II. STAGES OF CLINICAL RESEARCH

In principle, this is the next step after the researched drug (prescription, herb) has been verified for quality and has been studied for toxicity and pharmacology. However, depending on the drug, preliminary work may be done before preclinical testing, or clinical research may be conducted concurrently with preclinical testing.

Typically, clinical research is divided into the following stages, although the choice of one stage over another depends on the classification of medicinal materials, forms of researched drugs, and the purpose of clinical research.

 

THE EXPLORATORY RESEARCH STAGE

(Stage I)

The primary purpose of this stage is to observe tolerance and initially understand the efficacy and dosage of the drug, thereby providing a safe dosage recommendation for subsequent research steps.

1. Drugs in this stage include new formulations (new prescription structure - new drug form, new usage, new indication), and those beginning inheritance.

2. Research outline: Must be carefully written by experienced doctors and consistent with traditional medical theory or combined with modern medicine and clinical experience if available.

3. Research is conducted on a small number of healthy volunteers aged 20-30 years (10-30 people), with normal liver, heart, and kidney functions, and no history of food or drug allergies. Inheritance studies may be conducted on voluntary patients.

4. Determining the first dose. The first dose must ensure safety, especially for toxic drugs. The dose must be decided by an experienced doctor, and the first dose is usually one-fifth of the determined dose. From the first dose to the maximum dose, it can be divided into several stages. Research ends when the maximum dose is used without causing harmful side effects. If unusual reactions occur, the trial must be immediately stopped. Each person tested uses only one dose.

5. Method of drug administration. Usually oral administration is used. Other methods may be used if necessary.

6. Observation and recording. This stage must be conducted in a hospital. The drug's effects, particularly side effects and objective indicators, must be recorded accurately and completely.

7. Reporting research results.

This report includes the names of the researchers, the research outline, research results, discussion, conclusions, and references. At the same time, a summary must be written that matches the main report.

Note: Prescriptions inherited from traditional doctors or tested in hospitals, departments of traditional medicine are considered to have undergone this stage of clinical research.

 

THE MEDIUM SCALE CLINICAL RESEARCH STAGE

(Stage II)

The main purpose of this stage is to determine the efficacy of the research drug on a clinical basis and further confirm its safety. This is the primary clinical research phase to evaluate the safety and efficacy of traditional medicine.

1. Research outline.

The outline must be written by experienced doctors and should be consistent with the theories and methods of traditional medicine and modern medical theories and methods.

2. Number of patients for research.

The study will be conducted on a limited number of patients and should be divided into two groups: the group using the research drug and the control group. Patients should be randomly or cross-sectionally selected to form these two groups. Each group should have an average of 30 to 50 patients. Alternatively, there may only be one group of patients using the research drug, which would be preferable if they can be observed inpatient.

3. Group allocation for research:

If there are two groups, the quantity, gender, and duration of illness in both groups must be identical. To assess the efficacy of the drug, either a highly effective drug (either new or traditional) should be used as a positive control or a placebo as a negative control.

If there is only one group using the research drug, a before-and-after self-comparison method should be used.

4. Dosage and treatment duration:

The dosage of the drug used during this phase must be based on the results of the preliminary research phase or the theories of traditional medicine and clinical experience.

5. Observation and recording.

During the treatment process, all clinical changes and near-clinical test data of the patients must be carefully observed, recorded accurately without omission. It is particularly important to record any adverse effects or side effects of the drug on the patient if they occur.

6. Evaluation of therapeutic effect.

Therapeutic effects are usually evaluated at four levels:

- Complete recovery or very good.

- Significant progress or good.

- Some progress or moderate.

- No progress or poor.

Clear criteria for each level of evaluation must be specified.

Results must be processed using statistical probability.

7. Reporting research results. As in the preliminary research phase.

 

THE EXTENDED CLINICAL RESEARCH PHASE

(Phase III)

The purpose of this phase is to expand clinical research on a larger scale to re-evaluate the value of evidence already established regarding the efficacy of the drug assessed in the extended clinical research phase. This is a necessary phase for a traditional medicine to be approved by the Ministry of Health for production and circulation in the market.

1. Research outline. As in phases I and II.

2. Number of patients: approximately 100 to 150 patients. Patients should be randomly selected and the research should be conducted under conditions as similar as possible to those in phase II.

3. Location of implementation. At least three centers equipped with facilities and capable staff.

4. Observation and recording. As in phase II.

5. Evaluation of therapeutic effect. As in phase II. 6. Reporting research results. As in phase II.

 

THE CLINICAL TESTING PHASE

(Phase IV)

The main purpose of this phase is to identify cases of toxicity that were not detected in the earlier phases I, II, and III. This phase is only conducted when a drug circulating in the market is found to have a certain level of toxicity to users.

1. Research outline. As in previous phases.

2. Number of patients. Not less than 200 patients.

3. Location of implementation. Conducted at multiple centers across different regions nationwide.

4. Observation and result evaluation: As in phases II and III.

 

NEW INDICATION STUDY OF DRUGS

(Phase V)

This phase is dedicated to studies determining the efficacy of a drug for a new indication, where the drug has already been used for a specific clinical indication.

1. Clinical trial outline. As in previous phases.

2. Number of patients. Not less than 100 patients.

3. Location of implementation. At multiple facilities equipped with facilities and capable staff.

4. Other sections. Similar to previous phases, paying attention to side effects.