Traditional medicines have been used effectively in Japanese society for more than a thousand years. Japanese traditional medicine may be divided into folk medicine and Chinese medicine from ancient China, the so-called Kampo medicine. It is not possible to show precisely when and how folk medicine came to gain ground in the life of the Japanese people, but the record shows herbal medicines have been used for the past 1 400 years in Japan. The raw medicinal herbs used as folk medicine are combined with modern preparations in many cases, as are many of the Chinese traditional medicines and medicinal herbs .
Market Importance of TCM
Kampo Medicine is extremely popular in Japan, where the per capita consumption of herbal medicine seems to be the highest in the world. The drugs used are known as Kampo drugs. Each Kampo drug is a formula usually consisting of 5-10 different herbs. New features have been introduced into the practice of Kampo. Most of the modern ready-to-use forms of the original formulae are produced in industrialized granular, powdered or other forms based on the classical decoction. Introduced in 1957, it is now estimated that more than 95% of Kampo drugs used in Japan are taken in such a ready-to-use form as ethical drugs. Since 1961, almost 100% of the Japanese population has been covered by the National Health Insurance (NHI). 43 Kampo drugs for ethical use were included in the NHI Drug Price Tariff in 1976, joining a few predecessors. More Kampo drugs were included later, and now 147 Kampo drugs (as formulae) are available as ethical drugs. As these were already registered as drugs by the Ministry of Health and Welfare (MHW), their inclusion might be assumed to have been a matter of course. Their acceptance took place without clinical validation studies .
According to a market survey in 1989, among the top 100 items of over-the-counter drugs sold in Japan, 45 items correspond to the raw herb combined preparations which represent 34% in terms of share of sales with considerable economic importance. Chinese medicine shows a steady growth and, in particular, its remarkable expansion in the prescription drugs area indicates that it is highly valued in modern medical practice. In a survey in 1979, 19% of physicians had experience of having prescribed Chinese medicine, but, by 1989, the percentage had increased to 79%. According to another survey, the percentage of physicians usually using Chinese medicine was 28% in 1983, and 69% in 1989. At least 65% of physicians replied that they administered both Chinese and modern medicines to more than 5% of these patients. Physicians generally recognize Chinese medicine as a complement to modern medicine. It is common knowledge in Japanese society that traditional drugs are safe. In fact, according to an in-hospital side effect monitoring report in 1989, Chinese medicines accounted for only 1.3% of all cases. This percentage is quite low as compared to the market share of 2.5% which Chinese medicine occupies .
Evaluation of Japanese and Chinese Medicines
The difference between Japanese herbal medicine and Chinese medicine lies in the evaluation methods. Therefore, the applicable approval processes are quite different. The effect of a herbal medicine depends entirely on the sum of the pharmacological actions of the effective ingredients contained in the raw herb. There is no significant difference between the methods of evaluation applicable to herbal medicines and those with chemical substances. With respect to the evaluation of efficacy and safety, those raw herbs which have long been used as folk medicine and also been used for a considerable period as components of an industrial product, are listed in the corresponding monograph. They are freely usable within the range of the monograph. On the other hand, local traditional usage alone is not sufficient for approval as a drug. The claims and rules of combinations are determined on the basis of the pharmacological actions of the ingredients which may be contained in the raw herbs. Usually, the scope of claims is clearly specified in the corresponding monograph. In cases where the monograph is not yet completed, the claims shown in the Japanese Pharmacopoeia are used as a guide .
In the evaluation of efficacy of a Chinese medicine, importance is given to the "empirical facts or experience" such as the reference data, clinical test reports, etc., rather than the pharmacological action of each ingredient. In many cases, Chinese medicine is administered in the form of an infusion and/or powders. However, for reasons of convenience or industrialization, raw materials are transformed into extracts and produced and marketed as tablets, granules and powders .
Safety and efficacy have been estimated based on general methods employed by modern medical science. In 1972, the MHW designated 210 formulas as over-the-counter drugs. This selection was based mainly on the experience of doctors actually practising Chinese galenical medicine. In 1976, the Ministry specified 146 prescriptions as NHI applicable prescription drugs. In the case of an application for approval of a prescription other than those mentioned, specified data on safety, stability, comparison with other drugs, clinical test results, etc. are required to be submitted .
New Kampo drugs are regulated in essentially the same way as Western drugs in Japan. They are regarded as a form of combined drug, and the same data required for new Western drugs are required for new Kampo drugs in the NDA. The time-consuming and expensive chronic toxicity tests and special toxicity tests such as for mutagenicity, carcinogenicity and teratogenicity depend on the possible length of treatment and indications that apply to them. Data for three-phase clinical trials are also required. For generic Kampo drugs, bioequivalence data are required, which may discourage development, because pharmacokinetic studies of Kampo drugs are difficult to conduct and bioassay methods are quite limited .
Since 1971, the MHW has been running a programme for the re-evaluation of all drugs marketed before 1967. In 1967, the Japanese government instituted a new policy requiring scientific evidence of the efficacy and safety of new drugs. Results of the first re-evaluation of ethical drugs approved prior to 1967 have been made public in several instalments since 1973, and those of the second re-evaluation of ethical drugs approved from October 1967 to March 1980, since 1988. Re-evaluation of more than 99% and 58% of the total number of the products was completed in the first and second re-evaluations respectively. A new system to re-evaluate the efficacy and safety of all ethical drugs every five years was launched in 1988 .
For re-evaluation of Chinese medicines, an official notification was issued 1 February 1991. Since the methods of re-evaluation are not always clearly established, a first selection was made of eight prescriptions, the manufacturers being requested to furnish the necessary data to prove their effectiveness and safety .
Guidelines on Quality of Kampo Drugs
There was an improvement in the quality control of Kampo drugs in the mid-1980s. After a report on the situation of quality control, the Advisory Committee for Kampo Drugs was established in 1982 in close association with the Pharmaceutical Affairs Bureau of the MHW. A Working Group on the Quality of Kampo Drugs was established and, three years later, a new regulation was issued by the Pharmaceutical Affairs Bureau setting standards for the manufacture and quality control of Kampo drugs. This ensures that the quality of herbs used in each original formula meets precise standards. The regulations also call for quality monitoring of specific ingredients, using at least two different chemical or physical methods to test them .
Since October 1986, Good Manufacturing Practice (GMP), a standard required of pharmaceutical drugs issued by MHW in 1976, applies also to Kampo drugs. In addition, in 1988, the Japan Kampo Medicine Manufacturers' Association drew up self-imposed guidelines that take into consideration the unique nature of Kampo drugs .
In 1985, guidelines for ethical extract products in oriental medicine formulations were developed, according to which the data from a comparative study of the extract and a standard decoction have to be provided by the manufacturer of an ethical extract product. Besides data on the crude drug and on the standard decoction prepared in accordance with the Chinese traditional medicine prescription, a comparative study has to describe the content of an indicator ingredient in the finished product, which is required to be more than 70% of the content of the indicator ingredient in the standard decoction .
Post Marketing Surveillance
The MHW has three major systems for the collection of domestic adverse reaction data. The first is the Adverse Drug Reaction Monitoring System under which 2 915 monitoring hospitals have been designated and requested to report cases of adverse reactions to the MHW. This is a "voluntary" monitoring system, and 1 158 cases of adverse reaction were reported in 1990, of which 15 cases pertained to Kampo drugs.
The second data collection system is the Pharmacy Monitoring System formed by 2 733 pharmacies. This system mainly collects data on cases of adverse reactions to over-the-counter drugs. In recent years, about 400 cases have been reported annually. Among these, reactions caused by Kampo drugs are the most common, though most of these adverse reactions are minor, involving symptoms such as gastric discomfort and skin problems. Fifty cases were reported in 1989.
The third system is Adverse Reaction Reporting from Manufacturers. Several severe cases caused by "Shosikoto", including drug-induced hepatitis and pneumonitis, were documented at medical conferences and in journals and were reported to the MHW by the responsible company in 1990. In addition, since 1988, the newly drafted Good Post-Marketing Surveillance Practice (GPMSP) has been used on a pilot scale for Western drugs dispensed in Japan. When new Kampo drugs are approved and appear on the market, this guideline will also apply to them .