1WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth Report. Geneva, World Health Organization, 1996 (WHO Technical Report Series, No. 863).
2 Adapted from WHO document WHO/TRM/91.4. These guidelines were finalized at a WHO consultation in Munich, Germany, 19-21 June 1991. The request for WHO to prepare the guidelines came from the Fifth International Conference of Drug Regulatory Authorities (ICDRA) held in Paris in 1989. The finalized guidelines were presented to the Sixth ICDRA in Ottawa in 1991.
For the purpose of these guidelines, herbal medicines are defined as follows:
Finished, labelled medicinal products that contain as active ingredients aerial or underground parts of plants, or other plant material, or combinations thereof, whether in the crude state or as plant preparations. Plant material includes juices, gums, fatty oils, essential oils, and any other substances of this nature. Herbal medicines may contain excipients in addition to the active ingredients. Medicines containing plant material combined with chemically defined active substances, including chemically defined, isolated constituents of plants, are not considered to be herbal medicines.
Exceptionally, in some countries herbal medicines may also contain, by tradition, natural organic or inorganic active ingredients which are not of plant origin.
The past decade has seen a significant increase in the use of herbal medicines. As a result of WHO’s promotion of traditional medicine, countries have been seeking the assistance of the Organization in identifying safe and effective herbal medicines for use in national health care systems.
In 1991, the Director-General of WHO, in a report to the Forty-fourth World Health Assembly, emphasized the great importance of medicinal plants to the health of individuals and communities. Earlier, in 1978, the Thirty-first World Health Assembly had adopted a resolution (WHA31.33) that called on the Director-General to compile and periodically update a therapeutic classification of medicinal plants, related to the therapeutic classification of all drugs; subsequently resolution WHA40.33, adopted in 1987, urged Member States to ensure quality control of drugs derived from traditional plant remedies by using modern techniques and applying suitable standards and good manufacturing practices; and resolution WHA42.43, of 1989, urged Member States to introduce measures for the regulation and control of medicinal plant products and for the establishment and maintenance of suitable standards. Moreover, the International Conference on Primary Health Care, held in Alma-Ata, USSR, in 1978, recommended, inter alia, the accommodation of proven traditional remedies in national drug policies and regulatory measures.
In developed countries, a resurgence of interest in herbal medicines has resulted from the preference of many consumers for products of natural origin. In addition, manufactured herbal medicines often follow in the wake of migrants from countries where traditional medicines play an important role.
In both developed and developing countries, consumers and health care providers need to be supplied with up-to-date and authoritative information on the beneficial properties, and possible harmful effects, of all herbal medicines.
The Fourth International Conference of Drug Regulatory Authorities, held in Tokyo in 1986, organized a workshop on the regulation of herbal medicines moving in international commerce. Another workshop on the same subject was held as part of the Fifth International Conference of Drug Regulatory Authorities, held in Paris in 1989. Both workshops confined their considerations to the commercial exploitation of traditional medicines through over-the-counter labelled products. The Paris meeting concluded that the World Health Organization should consider preparing model guidelines containing basic elements of legislation designed to assist those countries wishing to develop appropriate legislation and registration.
The objective of these guidelines is to define basic criteria for the evaluation of quality, safety and efficacy of herbal medicines and thereby to assist national regulatory authorities, scientific organizations and manufacturers to undertake an assessment of the documentation/submissions/dossiers in respect of such products. As a general rule in this assessment, traditional experience means that long-term use as well as the medical, historical and ethnological background of those products shall be taken into account. The definition of long-term use may vary according to the country but should be at least several decades. Therefore, the assessment should take into account a description in the medical/pharmaceutical literature or similar sources, or a documentation of knowledge on the application of a herbal medicine without a clearly defined time limitation. Marketing authorizations for similar products should be taken into account.
Prolonged and apparently uneventful use of a substance usually offers testimony of its safety. In a few instances, however, investigation of the potential toxicity of naturally occurring substances widely used as ingredients in these preparations has revealed previously unsuspected potential for systematic toxicity, carcinogenicity and teratogenicity. Regulatory authorities need to be quickly and reliably informed of these findings. They should also have the authority to respond promptly to such alerts, either by withdrawing or varying the licences of registered products containing suspect substances, or by rescheduling the substances to limit their use to medical prescription.
Assessment of quality
This should cover all important aspects of the quality assessment of herbal medicines. It should be sufficient to make reference to a pharmacopoeial monograph if one exists. If no such monograph is available, a monograph must be supplied and should be set out as in an official pharmacopoeia.
All procedures should be in accordance with good manufacturing practices.
Crude plant material
The botanical definition, including genus, species and authority, should be given to ensure correct identification of a plant. A definition and description of the part of the plant from which the medicine is made (e.g. leaf flower, root) should be provided, together with an indication of whether fresh, dried or traditionally processed material is used. The active and characteristic constituents should be specified and, if possible content limits should be defined. Foreign matter, impurities and microbial content should be defined or limited. Voucher specimens, representing each lot of plant material processed, should be authenticated by a qualified botanist and should be stored for at least a 10-year period. A lot number should be assigned and this should appear on the product label.
Plant preparations include comminuted or powdered plant materials, extracts, tinctures, fatty or essential oils, expressed juices and preparations whose production involves fractionation, purification or concentration. The manufacturing procedure should be described in detail. If other substances are added during manufacture in order to adjust the plant preparation to a certain level of active or characteristic constituents or for any other purpose, the added substances should be mentioned in the manufacturing procedures. A method for identification and, where possible, assay of the plant preparation should be added. If identification of an active principle is not possible, it should be sufficient to identify a characteristic substance or mixture of substances (e.g. “chromatographic fingerprint”) to ensure consistent quality of the preparation.
The manufacturing procedure and formula, including the amount of excipients, should be described in detail. A finished product specification should be defined. A method of identification and, where possible, quantification of the plant material in the finished product should be defined. If the identification of an active principle is not possible, it should be sufficient to identify a characteristic substance or mixture of substances (e.g. “chromatographic fingerprint”) to ensure consistent quality of the product. The finished product should comply with general requirements for particular dosage forms.
For imported finished products, confirmation of the regulatory status in the country of origin should be required. The WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce should be applied.
The physical and chemical stability of the product in the container in which it is to be marketed should be tested under defined storage conditions and the shelf-life should be established.
Assessment of safety
This should cover all relevant aspects of the safety assessment of a medicinal product. A guiding principle should be that, if the product has been traditionally used without demonstrated harm, no specific restrictive regulatory action should be undertaken unless new evidence demands a revised risk - benefit assessment.
A review of the relevant literature should be provided with original articles or references to the original articles. If official monograph/review results exist, reference can be made to them. However, although long-term use without any evidence of risk may indicate that a medicine is harmless, it is not always certain how far one can rely solely on long-term usage to provide assurance of innocuity in the light of concern expressed in recent years over the long-term hazards of some herbal medicines.
Reported side-effects should be documented according to normal pharmaco-vigilance practices.
Toxicological studies, if available, should be part of the assessment. Literature should be indicated as above.
Documentation of safety based on experience
As a basic rule, documentation of a long period of use should be taken into consideration when assessing safety. This means that, when there are no detailed toxicological studies, documented experience of long-term use without evidence of safety problems should form the basis of the risk assessment. However, even in cases of drugs used over a long period, chronic toxicological risks may have occurred but may not have been recognized. The period of use, the health disorders treated, the number of users and the countries with experience should be specified. If a toxicological risk is known, toxicity data must be submitted. The assessment of risk, whether independent of dose or related to dose, should be documented. In the latter case, the dosage specification must be an important part of the risk assessment. An explanation of the risks should be given, if possible. Potential for misuse, abuse or dependence must be documented. If long-term traditional use cannot be documented or there are doubts on safety, toxicity data should be submitted.
Assessment of efficacy
This should cover all important aspects of efficacy assessment. A review of the relevant literature should be carried out and copies provided of the original articles or proper references made to them. Research studies, if they exist, should be taken into account.
The pharmacological and clinical effects of the active ingredients and, if known, their constituents with therapeutic activity should be specified or described.
Evidence required to support indications
The indication(s) for the use of the medicine should be specified. In the case of traditional medicines, the requirements for proof of efficacy should depend on the kind of indication. For treatment of minor disorders and for non-specific indications, some relaxation in requirements for proof of efficacy may be justified, taking into account the extent of traditional use. The same considerations may apply to prophylactic use. Individual experiences recorded in reports from physicians, traditional health practitioners or treated patients should be taken into account.
Where traditional use has not been established, appropriate clinical evidence should be required.
As many herbal remedies consist of a combination of several active ingredients, and as experience of the use of traditional remedies is often based on combination products, assessment should differentiate between old and new combination products. Identical requirements for the assessment of old and new combinations would result in inappropriate assessment of certain traditional medicines.
In the case of traditionally used combination products, the documentation of traditional use (such as classical texts of Ayurveda, traditional Chinese medicine, Unani, Siddha) and experience may serve as evidence.
An explanation of a new combination of well known substances, including effective dose ranges and compatibility, should be required in addition to the documentation of traditional knowledge of each single ingredient. Each active ingredient must contribute to the efficacy of the medicine.
Clinical studies may be required to justify the efficacy of a new ingredient and its positive effect on the total combination.
Product information for the consumer
Product labels and package inserts should be understandable to the consumer or patient. The package information should include all necessary information on the proper use of the product.
The following elements of information will usually suffice:
• name of the product
• quantitative list of active ingredient(s)
• dosage form
- dosage (if appropriate, specified for children and the elderly)
- mode of administration
- duration of use
- major adverse effects, if any
- overdosage information
- contraindications, warnings, precautions and major drug interactions
- use during pregnancy and lactation
• expiry date
• lot number
• holder of the marketing authorization.
Identification of the active ingredient(s) by the Latin botanical name, in addition to the common name in the language of preference of the national regulatory authority, is recommended.
Sometimes not all information that is ideally required may be available, so drug regulatory authorities should determine their minimal requirements.
Advertisements and other promotional material directed to health personnel and the general public should be fully consistent with the approved package information.
Utilization of these guidelines
These guidelines for the assessment of herbal medicines are intended to facilitate the work of regulatory authorities, scientific bodies and industry in the development, assessment and registration of such products. The assessment should reflect the scientific knowledge gathered in that field. Such assessment could be the basis for future classification of herbal medicines in different parts of the world. Other types of traditional medicines in addition to herbal products may be assessed in a similar way.
The effective regulation and control of herbal medicines moving in international commerce also requires close liaison between national institutions that are able to keep under regular review all aspects of production and use of herbal medicines, as well as to conduct or sponsor evaluative studies of their efficacy, toxicity, safety, acceptability, cost and relative value compared with other drugs used in modern medicine.