HERBAL REMEDIES: NEED FOR REGULATION

• HERBAL REMEDIES: NEED FOR REGULATION
  
  N.Z.Nyazema
  Department of Clinical Pharmacology, Medical School.
  P.O. Box A 178, Avondale
  Harare, Zimbabwe
  E-mail: Nnyazema@healthnet.zw
  
  INTRODUCTION
  
  For the purpose of guidelines, herbal medicines are defined as follows:
  Finished, labeled medicinal products that contain as active ingredients aerial or underground parts of plants, or other plants materials, 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 excipeints in addition to the active ingredients. Medicines containing plant material combined with chemically defined active substances, including chemically defined, isolated constituents of plants, should not be considered to be herbal medicines.
  
  In Zimbabwe, herbal medicines may also contain tradition, natural organic or inorganic active ingredients which are not of plant origin. A good example is the mixture of plant material with crashed blister....,Mylabris alternata. (Fig 8.1)
  
  The past two decades have seen a significant increase in the use of herbal medicines as seen in the chapter on consumer protection. 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 fourty-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 (WHA 31.33) 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 WHA 40.33 adopted in 1987, urged members 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 WHA 42.43 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 benefits, 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 in the same subject was held as part of the Fifty 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 labeled 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 for 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 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 take into account a description in the medical/pharmaceutical literature or similar sources, or a documentation of knowledge on the application of 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 licenses of registered products containing suspect substances, or by rescheduling the substances to limit their use to medical prescription.
  
  In 1977 the WHO gave official recognition to the use of traditional medicines in its resolution adopted by 30th World Health Assembly. Later in September 1978 the Alma Ata Conference on Primary Health Care recommended governments to give priority to the promotion of development of traditional medicines as part of their programmes to achieve the objective of "Health for All by 2000".
  
  At independence the government of Zimbabwe adopted most of the WHO resolutions including the one to encourage the promotion of traditional medicine. Traditional medical practice in Zimbabwe is regulated through the Traditional Medical Practice Act of 1981 (Appendix 8.1). Unfortunately, at present the manufacture, sale distribution and quality of herbal medicines used is not regulated by any statutory administrative measure.
  
  As flora of Zimbabwe is very rich due to the diverse soil conditions of different regions of the country, around 5000 species of plants are estimated to the growing wild in the country. Of these only about a tenth, as seen in Chapter 2, are known to be used extensively for medicinal and veterinary purposes. At the moment the manufacturing of traditional medicines is not recognized. There is no pharmacopoeia which is comprehensive and scientific enough to describe the herbs, and the compounds that they contain, to give useful information about storage, preservation, identification, storage period and age of herbal drugs.
  
  Lack of any control on traditional medicines will result in a situation where marketing of spurious, adulterated substandard and useless medicines will be widespread. Allopathic medicines especially steroids, and antibiotics would be prone to misuse by way of adulteration of traditional herbal medicines.
  
  Standardization and quality control of traditional medicines is essential especially as the older days dosage forms like decoction and infusions used by the traditional healers are being replaced by more concentrated and potent preparations like extracts, tablets, etc. Similarly safety assurance for these medicines is becoming more and more important in view of latest reports and developments in the area of traditional medical practice. By and large traditional healers consider herbal medicines innocent and harmless having no adverse side effects.
  
  The need for national policies and legislation on herbal or traditional medicines was emphasized at the 5th International Conference on Drug Regulatory Authorities in its meeting in Paris in 1989. Some countries in Asia are already exercising such controls on traditional medicines through legislation. New regulations have been introduced in China for example to ensure the quality of such drugs which combine traditional ways of production with modern methods of quality control. The control of non conventional therapies varies in Europe. The Netherlands, UK and Scandinavia have fairly liberal approaches towards non-conventional therapies while there is more restrictive legislation in Belgium, France and Italy. The Commission of Herbal Medicines of the Federal Health Office in Germany has published criteria that it will use in receiving preparations containing plant material.
  
  The Herbal Medicines Act of 1989 published by WHO is useful for guiding the member states in formulating herbal medicines policies and laws. It provides for the registration of herbal medicines, licensing system for importation, distribution, sales and export of these medicines, system of quality control, labeling requirements, control of promotion/advertising besides many other things (ref.).
  
  Standardization, quality control and a system of ascertaining safety of medicinal plants is necessary to make full use of their invaluable therapeutic potential on the one hand and to save this treasure trove from exploits of quacks on the other hand. Standardization is possible for the few herbs for which all active ingredients are known (Box 2), but is technically difficult and would make drugs unaffordable to many people in Zimbabwe.
  
  One problem with herbal remedies is that comparisons of different extracts will, by nature to their chemical complexity, always be approximate. To judge whole plant extracts, rather than one specific compound, could have therapeutic advantages. Botanicals need to be standardised and replicable.
  
  In the USA most herbal products are regulated as unpatented dietary supplements, side stepping US Food and Drug Administration (FDA) rules that products claiming prevention, treatment, mitigation, or cure of disease be treated as drugs. Investigational New Drug (IND) applications for many single botanical compounds are now being made, but FDA has not previously approved pharmaceutical versions of multicomponent botanical extracts. In response, two working groups under the Botanical Subcommittee of FDA's Centre for Drug Evaluation and Research (CDER) have been established to develop regulatory guidelines for the approval of botanicals as pharmaceuticals (Fishman, 1998).
  
  In Europe, the European Medicines Evaluation Agency (EMEA) has set up committees for Proprietary Medicinal Products (CPMP) working parties, one of which is to look into herbal remedies as shown in fig...
  
  One company taking the lead in quality control of so called phytoceuticals is Pharmaprint (Irvine, CA, USA). Their process uses biological and chemical standards to identify and quantify the bioactive years to be developed at the University of South California Medical School (San Diego, CA, USA). It ensures herbal products made from plant extracts have consistency and standardization similar to typical single molecule pharmaceuticals, and provides the consistency in every bottle, for instance, as would be expected with any other drug bought on the market. For example, the FDA approved standardised extracts of saw palmetto to be tested in placebo-controlled-dose-ranging studies for men with voiding dysfunction or benign prostatic hyperplasia. A positive outcome in such an FDA - monitored study would be enormous boon to contemporary pioneers of botanical medicines. It may also speed the adoption of streamlined regulatory process for historically used botanical preparations similar to the ones already in use in countries such as Germany.
  
  The WHO emphasizes that safety should be the over-riding criteria in the selection of herbal medicine for use in the health care system. There are also guidelines for toxicology studies in the Herbal Remedies Act 16 and in other documents on the safety and efficacy. In Zimbabwe, neither the regulatory authority, doctors, traditional healers and nurses are sufficiently aware of the potential toxicity of herbal medicines. This makes it more important and urgent to hold scientific inquiry into the subject and exact relative laws to regulate this sector.
  
  Diluting requirements for registration, for example, must be avoided in order not to introduce double standards, which would be highly controversial. Basically the following should be the requirements for registration of any herbal medicinal product:
  
  1.Assessment of Safety
  
  This should cover all relevant aspects of the safety assessment of a medicinal herbal 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 herbal remedy 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.
  
  2.Toxicological Studies
  
  Toxicological studies, if available, should be part of the assessment. Literature should be indicated as above.
  
  3.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 is no 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 medicines used over a long period, chronic toxicological risks may have occurred but may not have been recognised. The period of use, the health disorders treated and the number of users 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.
  
  4.Pharmaceutical Assessment
  
  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 in an official pharmacopoeia.
  All procedures should be in accordance with good manufacturing practices, GMP.
  
  5.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 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.
  6.Plant Preparation
  
  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 of 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.
  
  7.Finished Product
  
  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 (eg. "chromatographic fingerprint") to ensure consistent quality of the product. The finished product should comply with general requirements for particular dosage forms.
  
  For imported finished herbal 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 (Appendix 8.1).
  
  8.Stability
  
  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.
  
  9.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.
  
  10.Activity
  
  The pharmacological and clinical effects of the active ingredients and, if known, their constituents with therapeutic activity should be specified or described.
  
  11.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.
  
  12.Combination Products
  
  As many herbal remedies consist of a combination of several active ingredients, 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 will result in appropriate assessment of certain traditional medicines.
  
  13.Promotion
  Advertisements and other promotional material directed to health personnel and the general public should be fully consistent with the approved package information.
  
  14.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 usually suffice:
  * name of the product
  * quantitative list of active ingredient(s)
  * dosage form
  * indications
  
  =>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 iteractions
  =>use during pregnancy and lactation
  =>expiry date
  =>lot number
  =>holder of the marketing authorization (WHO, 1991)
  Relative value compared with other drugs used in modern medicine.
  Admittedly not all information required will be available in the documentation. MCAZ will have to determine the minimum requirements for herbal product registration.
  
  On the one hand, a high regimen of medicinal products offers undeniable advantages including equal treatment for all kinds of ailments and close control of medical claims. On the other hand, the basis of the conventional requirements for efficacy, safety and quality is the need to safeguard public health. A typical consumer in Zimbabwe is unable to distinguish between safe and less safe preparations, and herbal medicine-like products may escape regulatory evaluation before marketing, by being presented as food supplements (pharmafood, nutricenticals). A remarkable consequence of this bypass is that the burden of providing data on safety and quality shifts completely to the MCAZ. It has to show that a product is unsafe, while that product may already be in use. This is the exact opposite in the case of pharmaceuticals where the burden rests on the vendor.
  
  There may therefore be a need for special herbal licensing. It will offer opportunity before marketing, to screen the declared constituents, demand proof of product quality, restrict the level of potentially hazardous constituents and enforce warnings about correct and safe use. In addition the possibility will exist to oblige license number on the label would make the regulatory efforts visible to both retailers and consumers.
  
  REFERENCES
  
  RHB Fishman, 1998. Botanical products Seeking Standards of Pharmaceuticals. The Lancet, vol. 351. 1190, 1998
  WHO (1991). Guidelines for the Assessment of Herbal Medicines. WHO/TRM/91.4

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