Traditional Chinese medicine (TCM) has a long history of more than 4 000 years. Discovery of medicinal materials in ancient times was closely related to the life and the labour of people and their natural conditions of living. People found out that many natural materials could be used to treat diseases, and great experience in this field has gradually been accumulated.
The Chinese Materia Medica is one of the best documented and most extensive sources, as well as the one that enjoys the most continued use, including more than 7 000 species of medicinal plant.
Market Importance of TCM
The Constitution of the People's Republic of China stipulates that modern and traditional medicine should be developed simultaneously. Therefore, since the founding of the People's Republic of China, traditional Chinese medicine has developed steadily. By the end of 1995, there were 2 522 TCM hospitals with a total of 276 000 beds. Most of the general hospitals have a TCM department. There are 940 factories and plants for the manufacture of herbal medicines. In 1995, the total value of herbal medicine manufactured reached 17.6 billion Chinese yuan, an increase of 213% compared to 1990. The total sales volume of traditional herbal medicines in 1995 was 15 billion yuan, an increase of 123% compared to 1990. From 1978 to 1993, sales of patent herbal medicines and raw plant materials increased by 10.8 and 2.3 times, respectively. The sale of patent herbal medicines represented 24% of the total sale of medicines countrywide in 1993 (14% in 1978). At the same time, sales of raw plant materials for decoctions were just 9% of the total sale of medicines countrywide in 1993 (compared to 18.7% in 1978) .
The Chinese Pharmacopoeia
The 1990 edition included 784 articles on traditional Chinese medicines and 509 articles on Chinese patent medicines. The monographs describe the source or the substances used, prescriptions, methods of preparation, identification, examination, extraction, effects and main indications as well as methods of use, dosage, precautions, etc. . Further information on herbal medicines is available in the new edition of the "Pharmacopoeia of the People's Republic of China" .
With regard to their legal status, herbal medicines in China are normally considered as medicinal products with special requirements for marketing, for example a quality dossier, safety and efficacy evaluation, and special labelling. New drugs have to be examined and approved according to the Drug Administration Law. After approval, a New Drug certificate is granted an approval number. The factory is then permitted to put the product on the market. This procedure reflects the respect in which traditional experiences are held, while modern scientific and technical knowledge is used in appraising the therapeutic effects and the quality of the modified traditional medicines, and contributes administratively to the exploitation of traditional Chinese medicine .
The Drug Administration Law of the People's Republic of China  was enacted on 20 September 1984. Article 3 states "The State encourages the development of both modern and traditional drugs, the role of which in the prevention and treatment of diseases as well as in health care will be fully brought into play. The State protects the resources of wild herbal drugs and encourages domestic cultivation of herbal drugs".
With regard to a drug manufacturing enterprise, Article 5 states that "It should be staffed with an adequate number of pharmacists or technical personnel with a title equivalent to or higher than associate engineer, and skilled workers adaptable to the scale of drug production". However, "Enterprises for the preparation and slicing of raw plant materials should be staffed with pharmaceutical professionals familiar with the property of raw materials and registered with the health bureau above the county level, if pharmacists or technical personnel with a title equivalent to or higher than associate engineer are not available." Article 6 states "processed medicinal plant materials must be prepared and sliced in compliance with the specifications of the Pharmacopoeia of the People's Republic of China or the processing norms stipulated by the health bureau of the province, autonomous region or municipality".
For the control of drug handling enterprises, Article 11 states that a drug handling enterprise should be established with an adequate number of pharmaceutical technicians adaptable to the scale of its business. However, enterprises engaged in the handling of modern drugs may be staffed with pharmaceutical professionals familiar with the property of drugs and registered with the health bureau above the county level, if pharmaceutical technicians are not available. Article 15 states that in the market of country fairs only the sale of medicinal plant materials is permitted, with certain exceptions.
Article 29 states "The Ministry of Public Health has the authority to restrict or prohibit the exportation of medicinal plant materials and patent herbal medicines if they are in short supply in the domestic market". Article 31 states "The sale of medicinal plant materials newly discovered or introduced from abroad is not allowed unless it is approved by the health bureau of the province, autonomous region or municipality" .
Documentation for Applications for New Drugs
Based on Article 21 of the Drug Administration Law, "the clinical trial or clinical verification of a new drug should be sanctioned by the Ministry of Public Health or the health bureau of the province, autonomous region or municipality". "A new drug will be approved for clinical use and a licence issued by the Ministry of Public Health, if the clinical trial or clinical verification has been completed and an appraisal of its efficacy has been made." Pursuant to Articles 21 and 22 of the Drug Administration Law, on 1 July 1985, the Ministry of Public Health issued and implemented a regulation for the Approval of New Drugs. "New drugs" are referred to as drugs which have not been produced previously in China, or drugs for which a new indication, a change in the route of administration or a change of dosage form is to be adopted. Any unit or individual engaged in the development, production, distribution, prescription, inspection and surveillance of new drugs must adhere to the provisions of the document. The regulation includes general principles concerning new drugs, their classification, research, clinical trials, approval, and manufacture. Several appendices provide detailed information on the application form, list of documents required, and technical requirements of toxicological and clinical studies on new modern drugs, and new TCM drugs .
Based on the Amendment and Supplemental Regulation of Approval of New TCM Drugs, implemented 1 September 1992 , new TCM drugs are classified under five categories, as follows:
- artificial imitations of TCM herbs;
- newly discovered medicinal plants and their preparations;
- single active principle extracted from TCM plants material and their preparations.
- Chinese medicinal herbal injections;
- parts of TCM medicinal plants newly employed as a remedy and their preparations;
- non-single components extracted from TCM and natural plants and their preparations;
- TCM materials obtained by artificial techniques in vivo and their preparations.
- new TCM preparations;
- combined preparations of TCM and modern medicine in which TCM medicine is the main component;
- cultivated material which traditionally is imported.
- new dosage forms or new routes of administration of TCM drug;
- materials introduced from other parts of the country and those for cultivation instead of harvesting in the wild.
- TCM products with new and additional indications.
All research on new medicines should provide data on toxicity, pharmacological properties and clinical research, as well as a detailed documentation on the quality of the medicinal material and the pharmaceutical form. For the five categories mentioned above, different requirements have to be fulfilled for the medicinal material as well as for their pharmaceutical preparation. Proprietary medicines included in the national pharmacopoeia and new medicines approved by the Ministry of Public Health are exempted from clinical testing when only the dosage form is changed, such as from powder into gelatine capsules, or from tablets into granular form infused with boiling water, without changes in the indications for cardinal symptoms or dosage.
The report on the medicinal material should contain the following items in applications for clinical research: purpose of research, previous experience or modern research data, source of material, cultivation, processing, properties, data based on Chinese pharmacology and experience, efficacy with respect to cardinal symptoms, pharmacological research data, acute toxicity tests, data on mutagenicity/carcinogenicity/reproductive toxicity (only for category 1), draft on quality standards, stability, and the proposed plan for the clinical research. A separate application for production should include documentation on quality standards, stability tests, a summary of clinical studies, and packaging material.
The report on pharmaceutical preparation has to meet similar requirements as the report on medicinal material, depending on the drug category.
Technical requirements for pharmacological studies are laid down in a special paragraph. The tests on major drug effects shall be designed in such a way that the special characteristics of the traditional Chinese medicine are taken into consideration. Two or more methods shall be selected for research on the major drug actions, based on the effects of the new medicine on the complex of symptoms or the illness. For new medicines in categories 1, 2 and 3, this research shall be sufficient to verify the major therapeutic functions and other important therapeutic effects. For new medicines in category 4, two (or more) tests on the major effects are required, or else well documented material has to be submitted. For new medicines in category 5, only tests on the major effects of the medicine on "new" cardinal symptoms are required. Research on general pharmacology shall be performed on the nervous system, on the cardiovascular system, and on the respiratory system. Technical requirements for studies on toxicity are also laid down in a special paragraph. Here a difference is drawn between a clinical trial and a clinical verification. Clinical trials shall be conducted for new medicines of categories 1, 2 and 3, and clinical verifications are required for new medicines of categories 4 and 5. Clinical trials are divided into three phases, but clinical verification does not have phases.
The purpose of a clinical trial phase I is to study the reaction and the tolerance of the human body to the new medicine and to find out the safe dosage. Medicines in categories 1 and 2 which have either toxic or incompatible compounds have to go through phase I of the clinical trial. For dosage determination, the dosage used in animal tests may be used as a reference. The purpose of phase II of a clinical trial is to obtain an accurate evaluation of the curative effects of the new medicine and its safety. In addition, a comparison has to be made between the new medicine and known drugs, so as to determine its advantages and disadvantages. Phase II consists of two parts, the first applies when the treatment is performed and the second when the treatment is expanded. The dosage used in the clinical trial shall be based on pharmacodynamic tests made beforehand and clinical facts, or the results of phase I. For the selection of cases, there are strict standards on diagnosis, and the diagnosis is based on overall analyses of symptoms and signs, the course, nature and location of the illness and the patient's physical condition, according to the basic theories of TCM. For the performance of a clinical trial, either the single or the double blind method may be used, according to need or the actual circumstances. When the curative effects are determined, four ratings are applicable: clinical recovery, significantly effective, effective and non-effective. The evaluation of curative effects shall be based on the clinical symptoms (symptoms and physical signs), objective standards for curative effects and the ultimate results on the patient.
The objective of the clinical trial phase III is the further investigation of the safe use or effectiveness of the new medicine on the basis of the findings of phase II. The main purpose is to have clinical trials on a new medicine during its trial production or after it has been put on the market for a period of time. This is to make up for deficiencies in phase II, to observe further the curative effects, and the nature of its effects on cardinal symptoms and adverse reactions.
Clinical verification is applicable for new medicines in categories 4 and 5, the purpose being to observe their curative effects, contra-indications and precautions. Different groups for control and for comparison shall be used. For new medicines that have changed their dosage forms, the control shall be same pharmaceutical form as the original form. For those medicines that have additional curative effects, a known medicine with curative effects on the same illness shall be selected as control.
The summary of the clinical trial shall be objective and comprehensive and shall be an accurate reflection of the whole process. The discussion in the final report shall include the conclusion which is based upon the outcome of the tests, the functions and effects on cardinal symptoms, the scope of application of the new medicine, its administration, the course of treatment, curative effects, safety, adverse reactions (including the measures to be taken), contra-indications and precautions. An objective evaluation on the characteristics of the new medicine shall also be made.
Technical requirements for studies on quality standards for Chinese medicinal material and medicines are laid down in a special chapter. The source (original plant, part of the plant, harvesting conditions), the properties, the identification, the test for impurities, the assay and the processing have all to be described. The quality standards for Chinese medicines shall include the prescription, the way of processing, the properties, the identification, the examination and the assay in accordance with the general guidelines laid down in the pharmacopoeia. A further special paragraph describes the technical requirements for studies on stability, and which items have to be checked for which dosage form.