INTRODUCTION:

Traditional/herbal medicines (TM/HM), which formed the basis of health care throughout the world since the earliest days of mankind are still widely used, and have considerable importance in international trade. According to WHO estimates, the present demand for medicinal plants is ~US $14 billion a year and by the year 2050 it would be ~US $5 trillion. Due to high prices and harmful side effects of synthetic drugs, people rely more on herbal drugs and this trend is growing, not only in developing countries but in developed countries too.^[1] World Bank also reports that trade in medicinalplants, botanical drug products and a raw material is growingat an annual growth rate between 5 and 15%.^[2]

In developed countries, a resurgence of interest in traditional medicines has resulted from the preference of many consumers for products of natural origin. Recognition of their clinical, pharmaceutical and economic value is still growing, although this varies widely between countries.^[3]

Studies show that in Africa up to 80% people use traditional medicines while in China, TM accounts for around 40%. The percentage of the population, which has used CAM at least once, is 48% in Australia, 70% in Canada, 42% in USA, 38% in Belgium and 90% in Germany.^[4] It has been postulated that by 2010 at least two-thirds of the United States population will be using one or more of the alternative therapeutic approaches.^[5]

Despite the extensive use of herbal medicines over many centuries, only a relatively small number of plant species has been studied for possible medical applications. Safety and efficacy data are available for an even smaller number of plants, their extracts and active ingredients and preparations containing them.^[6] This deficiency results into adverse effects of herbal or traditional drugs. Two recent British cases of severe nephropathy caused by Chinese herbal tea administered to treat eczema^[7] illustrate this. There are great variations in the quality of herbal medicinal preparations. When, for example, German commercial products of devil's claw were tested, an unacceptable variability of quality was noted.^[8] A recent study of herbal creams in the United Kingdom also showed that 8 of 11 preparations contained undeclared dexamethasone at a mean concentration of 456 mg/g.^{[ 9]}

Consistency in composition and biological activity are essentialrequirements for the quality safety and efficacy of therapeutic agents.Three key elements of Quality assurance involve adherence to GACP, GMP and GLP guidelines; setting specifications; and quality control measures.^{[ 10]}

Quality Control of Herbal Medicines:

Quality Control is a term that refers to processes involved in maintaining the quality of validity of a manufactured product. Without proper quality control, there is no assurance that the herb contained in the bottle is the same as what is stated on the outside label. The widespread disregard for quality control in the health food industry has tarnished the reputation of many important medicinal herbs.^{[ 11,12]} Numerous drugs have entered the international pharmacopoeia via the study of ethnopharmacology and traditional medicine. For traditional medicines, newer guidelines of standardization, manufacture and quality control and scientifically rigorous research on the scientific basis for traditional treatments will be required as this can offer a more holistic approach to drug design and myriad of possible targets for scientific analysis.^{[13, 14]}

The quality of pharmaceuticals has been a concern of the World Health Organization (WHO) since its inception. The setting of global standards is requested in Article 2 of the WHO Constitution, which cites as one of the Organization’s functions that it should “develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products.”

Legislative controls in respect of medicinal plants have not evolved around a structured control model. There are different ways in which countries define medicinal plants or herbs or products derived from them, and countries have adopted various approaches to licensing, dispensing, manufacturing and trading to ensure their safety, quality and efficacy.^[15]

CHALLENGES TOWARDS THE REGULATION OF HERBAL DRUGS: ^[16]

Challenges related to the regulatory status:

There are great differences between different countries in the definition and categorization of herbal medicines. A single medicinal plant may be defined as a food, a functional food, a dietary supplement or an herbal medicine in different countries, depending on the regulations applying to foods and medicines in each country. This makes it difficult to define the concept of herbal medicines for the purposes of national drug regulation, and also confuses patients and consumers.

Challenges related to the assessment of safety and efficacy:

Requirements and methods for research and evaluation of the safety and efficacy of herbal medicines are more complex than those for conventional pharmaceuticals. A single medicinal plant may contain hundreds of natural constituents, and a mixed herbal medicinal product may contain several times that number. Analysis of such preparations may actually be impossible in practice, particularly in the case of mixed herbal medicines.

Challenges related to quality control:

The safety and efficacy of herbal medicines is closely correlated with the quality of the source materials used in their production. The quality of source materials is, in its turn, determined by intrinsic factors (genetic) and extrinsic factors (environmental conditions, cultivation and harvesting, field collection and post harvest/collection transport and storage). Therefore, it is very difficult to perform quality controls on the raw materials of herbal Drugs.

Challenges related to safety monitoring:

Adverse events arising from consumption of herbal medicines may be due to the use of the wrong species of plant by mistake, adulteration, undeclared medicines, contamination with toxic or hazardous substances, over dosage, misuse by either health care providers or consumers and their use concomitantly with other medicines. Therefore, analysis of adverse events related to the use of herbal medicines is more complicated than the conventional pharmaceuticals.

Lack of knowledge national drug authorities:

The general lack of knowledge about herbal medicines within national drug authorities and the lack of appropriate evaluation methods are factors that delay the creation or updating of national policies, laws and regulations herbal medicines.

In order to meet these challenges WHO has given several guidelines, which can help member states in the regulation and quality control of herbal drugs.

THE WHO TRADITIONAL MEDICINE PROGRAMME:

The World Health Assembly (WHA) has adopted a number of resolutions drawing attention to the fact that a large section of the population in many developing countries still relies on traditional medicine, and that the work force represented by traditional practitioners is a potentially important resource for primary health care.

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 of 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.^[17]

Based on the relevant WHA resolutions, the major objectives of the programme are:

· to facilitate the integration of traditional medicine into national health care systems;

· to promote the rational use of traditional medicine through the development of technical guidelines and international standards in the field of herbal medicine; and

· to act as a clearing house for the dissemination of information on various forms of traditional medicine.

In resolution WHA42.43 (1989), the Health Assembly urged Member States:

· to make a comprehensive evaluation of their traditional systems of medicine;

· to make a systematic inventory and assessment (preclinical and clinical) of the medicinal plants used;

· to introduce measures for the regulation and control of medicinal plant products and for the establishment and maintenance of suitable standards; and

· to identify those medicinal plants or remedies derived from them, which have a satisfactory efficacy/side-effect ratio and which should be included in national formularies or pharmacopoeias.

Guidelines for the assessment of herbal medicines:^[18]

A WHO consultation in Munich, Germany, June 1991, drafted Guidelines for the Assessment of Herbal Medicines (WHO/TRM/91.4), which was adopted for general use by the Sixth ICDRA in Ottawa, October 1991.

· These guidelines contain basic criteria for the assessment of quality, safety, and efficacy and important requirements for labeling and the package insert for consumers' information.

· The requirements for pharmaceutical assessment cover issues such as identification, galenical forms, analysis and stability.

· Safety assessment should at least cover the documented experience of safety and toxicological studies, where indicated.

· The assessment of efficacy and intended use includes evaluation of traditional use through appraisal of the literature and evidence to support the indication claims.

Guidelines for Formulation of National Policy on Herbal Medicines:^[19]

The guideline was proposed to formulate national policies on traditional medicines and to encourage co-operation between Member States. The aim would be to develop regulatory and legal reforms to ensure good practice, and to extend primary health care coverage, while ensuring the authenticity, safety and efficacy of these medicines. Main objectives include the recognition of traditional medicine as an integral part of national health care systems, co-operation between modern and traditional medicine, promotion of the rational use of products, the introduction of quality assurance systems, the guarantee of regular supplies, the promotion of research and development of regulatory measures. It has been recommended to countries that a National Expert Committee be established, which would be the appropriate authority to identify the steps and plans needed to formulate national policy in this area and then to develop, direct and monitor the various phases of its implementation.

Guidelines for the assessment of herbal medicines:

WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. 1996: ^[20]

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.

These guidelines defines the criteria for

- Assessment of quality.

- Assessment of safety.

- Assessment of efficacy.

- Intended use: the guideline also defines the information, which should be given to the consumers for use of the preparation.

General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine WHO/EDM/TRM/2000: ^[21]

The methodologies for research and evaluation of traditional medicine should be based on the following basic principles. On the one hand, the methodologies should guarantee the safety and efficacy of herbal medicines and traditional procedure-based therapies. On the other hand, however, they should not become obstacles to the application and development of traditional medicine.

The specific objectives are to:

Harmonize the use of certain accepted and important terms in- traditional medicine;

Summarize key issues for developing methodologies for research and evaluation of traditional medicine;

Improve the quality and value of research in traditional medicine; and

Provide appropriate evaluation methods to facilitate the development of regulation and registration in traditional medicine.

WHO guideline on good agricultural and collection practices (GACP) for medicinal plant: ^[22]

The guidelines provide a detailed description of the techniques and measures required for the appropriate cultivation and collection of medicinal plants and for the recording and documentation of necessary data and information during their processing.

Good agricultural and collection practices for medicinal plants are the first step in quality assurance, on which the safety and efficacy of herbal medicinal products directly depend upon.

The WHO Traditional Medicine Strategy 2002-2005: ^[4]

The WHO recognizes that the traditional use of herbal medicines refers to the long historical use of these medicines and that they may be accepted by national authorities. As a result of this view, the WHO Traditional Medicines Strategy 2001–2005 was developed to review a framework for action for WHO and its partners aimed at enabling TM/CAM to play a far greater role in reducing excess mortality and morbidity especially among impoverished populations, which is one of WHO’s strategic directions for 2002–2005.60 ^[17]

Specific objectives in TM/CAM for 2002–2005 are accordingly to support countries to:

Integrate TM/CAM with national health care systems.

Promote the safety, efficacy and quality of TM/CAM by expanding the knowledgebase and by providing guidance on regulatory and quality assurance standards.

Increase the availability and affordability of TM/CAM.

Promote therapeutically sound use of appropriate TM/CAM by providers and consumers.

Some of the existing Legal Framework for Herbal Medicines:

REGULATION OF CAMS IN AUSTRALIA: ^[23]

Complementary medicines, including herbal medicines in Australia are regulated under therapeutics goods Legislation. The Therapeutic Goods Act (THA) 1989 ^[24] (the Act) came into effect in 1991. The overall objective of the Act is to ensure the quality, safety and efficacy of therapeutic goods to the Australian public. The Australian Register of Therapeutic Goods (ARTG) is a database maintained by the TGA. It includes details of all therapeutic goods that are imported into, supplied in, or exported from Australia.

Based on risk, Australia has developed a two tiered approach to the regulation of therapeutic goods. Medicines are entered in the ARTG as either Listed or Registered products. Listed medicines (L) are considered to be of lower risk than registered medicines (R). Most, but not all, complementary medicines are listed medicines.

Herbal medicines may be associated with low or high risk depending on the toxicity of ingredients, proposed dosage, appropriateness of the indications and claims for self-diagnosis and management and the potential for adverse reactions. Registered medicines are individually evaluated for safety, quality and efficacy before they are released onto the market.

Managing the risk associated with therapeutic goods, including complementary medicines, is exerted through the processes of licensing of manufacturers; pre-market assessment of products; and post market regulatory activity. Data to support the safety evaluation of new complementary medicine substances includes: characterization of the complementary medicine substance, history and mode and patterns of previous human use, reports of adverse reactions, biological activity, toxicology and clinical trials.

HERBAL MEDICINES IN EUROPEAN REGULATION:

The European Community has developed a comprehensive legislative network to facilitate the free movement of goods, capital, services and persons in the Community. According to Directives 65/65/EEC^[25] and 75/318/EEC^[26], pharmaceutical products require pre-marketing approval before gaining access to the market. Requirements for the documentation of quality, safety, and efficacy, the dossier and expert reports are laid down in Directive 91/507/EEC.^[27] Article 39 para 2 of Directive 75/319/EEC^[28] obliged Member States to check all products on the market at that time, with a deadline of 12 years, to determine whether they met the requirements of these directives. Countries have taken different approaches in reviewing phytomedicines. A decision of the European Court of Justice^[29] supports the interpretation that herbal remedies are medicinal products as defined in Article 1 of the Directive 65/65/EEC.^[24] From the beginning of 1995, the new procedures for EU marketing authorizations are coordinated and setup by the European Medicines Evaluation Agency (EMEA) London.

The EU Council underlined the wider and growing use of medicinal plants and expressed concern that the marked heterogeneity of regulations could have a negative impact on public health and on the free movement of goods.^[30] Herbal medicines should not be allowed to reach the European market unless they have been positively authorized as to their safety, quality and efficacy and claimed indications—this is the key element under Directive 65/65/EEC. ^[31]

According to European Directives, the assessment of safety and efficacy of well-known herbal products is provided not only by new pharmacological, toxicological and clinical trials, but also by published literature giving sufficient evidence that the products have a ‘well-established medicinal use’ with ‘recognized efficacy’ and an ‘acceptable level of safety’. ^[32]

· To achieve free movement of medicines within the common market of the European Union, "decentralized procedure" called "Summary of product characteristics (SPC)" was prepared which provides, as a general rule, that an assessment by one national authority should be sufficient for subsequent registration in other Member States. As uniform criteria at a European level do not exist, there is only a guideline for quality of herbal remedies. ^[33]The European Scientific Cooperative on Phytotherapys (ESCOP) was founded in 1989, the main objectives being to establish harmonized criteria for the assessment of phytomedicines, to support scientific research and to contribute to the acceptance of phytotherapy at a European level which published monographs on medicinal plants. ^[34] To meet the CPMP (Committee on Proprietary Medicinal Products) requirements laid down in European guidelines, the drafts which are planned to be submitted to the CPMP have the format of a Summary of Product Characteristics (SPC). An SPC describing a medicinal plant and its preparations refers to a Pharmacopoeia monograph with respect to quality, and lists the main constituents that may possibly contribute to the effect claimed. The most important parts of an SPC are the therapeutic indications, the dosage and the pharmacological properties. The latter paragraph gives as many details as possible on pharmacodynamic properties, pharmacokinetic properties and preclinical safety data, each statement supported by references. ^[33]

Proposed Quality Control Guidelines for the EU Directive on Traditional Herbal Medicinal Products: Implications for Small- to Medium-Sized Enterprises ^[35]

On June 20, 2005, the European Medicines Agency (EMEA) published an updated draft guidance document entitled Guideline on Specifications: Test Procedures and Acceptance Criteria for Herbal Substances, Herbal Preparations and Herbal Medicinal Products / Traditional Herbal Medicinal Products. ^[36] The stated objective of the new guideline is to provide general principles on the setting and justification of uniform specifications for herbal medicines in order to support the process of applying for marketing authorization or registration according to EU Directives 2001/82/EC ^[37] and 2001/83/EC, ^[38] respectively.

This Directive allows the licensing and over-the-counter sale of herbs that have a history of use anywhere in the world for at least 30 years, 15 of which must be in an EU Member State.

The scope of the EMEA guideline is specifications, i.e., those tests, procedures, and acceptance criteria used to assure the quality of the herbal preparations and herbal medicinal products.

HERBAL MEDICINES REGULATION in US

Since 1976, following the "Proxmire Bill", a civil regulation for the Health Food Market states that foods, including dietary supplements and herbs, are not drugs. This law kept the FDA from making monographs on dietary supplements, vitamins, minerals and herbs, as has been done for several kinds of drugs. ^[39]

In October 1994, the Dietary Supplement Health and Education Act^[40] recognized that dietary supplements have been shown to be useful in preventing chronic diseases and therefore help limit long-term health care costs. Herbs and other botanicals, vitamins and minerals now fall under the definition of a dietary supplement which is presented in a dosage form such as capsules, tablets, liquids etc., and which is not represented as a conventional food, but which is labeled as a dietary supplement.

Under DSHEA manufacturers does not required to obtain pre market approval by the FDA before the products available to the consumers. Instead the FDA bears the burden for showing a product is unsafe before it can take action to regulate its use.

· A Proposed Regulatory Model for Traditional Medicines.^[41] In of 2004 Traditional Medicines Congress (TM congress) was constituted. It believed that the current regulatory system does not, adequately assure continued access to and safety of traditional medicines. These products do not fit neatly into either the current “food” or “drug” categories defined by the Federal Food, Drug and Cosmetic Act. And while some traditional medicines may be marketed under the Dietary Supplement Health and Education Act, which provides a regulatory framework for dietary supplements, these may not be sold as medicines. It made some assumptions and based on that proposed a regulatory model:

Assumptions:

• Establishment of a new regulatory structure for TM may require amending the Federal Food, Drug and Cosmetic Act (FFDCA).

• This TM Congress does not intend to propose amendments to the Dietary Supplement Health and Education Act (DSHEA).

• The focus for development of the envisioned ideal regulatory model is limited to the United States.

• Most TM ingredients and products will remain directly accessible to the public.

• Some TM ingredients and products will be accessible to practitioners only.

• Many ingredients and products that fall into a new traditional medicine regulatory category will also be able to be marketed as dietary supplements under DSHEA.

• Any regulatory structure must address safety, efficacy and product quality.

The congress also believed that it may not be a short term process; it may take several years to pass legislation and to implement regulations.

If this be implemented it would definitely improve the status of herbal medicines in US.

HERBAL MEDICINES REGULATION IN CHINA:

Traditional Chinese medicine (TCM) has a long history of more than 4,000 years and the Chinese Materia Medica is one of the best documented and most extensive sources. 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 labeling. 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. 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. 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". ^[42] The clinical trial or 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 The report 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 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 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. ^[43]

HERBAL MEDICINES REGULATION IN GERMANY:

Herbal medicines are distributed through over-the-counter sales in pharmacies and other distribution channels and on medical prescription through pharmacies. In terms of legal status, herbal medicines are fully considered as medicines. On 1 January 1978, the Second Medicines Act came into force which set new standards for the granting of marketing authorization in accordance with the European framework for the handling of medicines. ^[44] Under this new regulation, proof of quality, safety, and efficacy became an essential pre-condition for the registration of medicines. To meet the requirements of the new Medicines Act, the authorities were obliged to carry out a review process. ^[45] The two steps of the procedure were first a review of active principles, which resulted in monographs, and, second a product-specific verification of pharmaceutical quality and conformity with the published monographs.^{46-,52(a),52(b)} The review of herbal remedies was done by a pluridisciplinary commission of experts, the so-called Commission E, Criteria for registration are set out by European directives and guidelines, such as the Note for Guidance on Quality of Herbal Remedies, the European Pharmacopoeia, and national guidelines and directives such as the guidelines for testing of drugs following section 26 of the Medicines Act (Arzneimittel Prüfrichtlinien). ^[53] In August 1994, the fifth amendment of the German Medicines Act became effective. It provides a new procedure with respect to proof of quality, safety and efficacy, widening the scope of existing legislation for products, including herbal medicines, already on the market.

HERBAL MEDICINES REGULATION IN SOUTH AFRICA:

In 1997, The Medicine Control Council (MCC) appointed a Complementary Medicines Committee (CMC) primarily to attend to issues relating to the QSE (Quality, safety, efficacy) of available complementary medicines (CM). ^[54] A separate committee was additionally established to focus exclusively on the regulation of ATM.

Legislation requires the registration of products by compliance with either pre-market criterion defined for orthodox medicines or by a Listing Procedure (LP) also known as the Expedited Registration Procedure (ERP). Criteria for orthodox medicines refer to the universally accepted standardized methodology required to prove QSE and involves data requisition of pre-clinical and clinical trials. The LP procedure is less burdensome and more economically viable. It has been proposed that safety criteria should be drawn from regulating bodies of the relevant CM disciplines around the world.

Proof of appropriate levels of safety and use in the intended traditional context will be paramount for inclusion in the List. In addition, the following product information will essentially be required for each substance: the scientifically approved name and synonym, its common name, its traditionally understood name, which part of the plant is used, the appropriate safety levels, special warnings, side effects, contra-indications and also the proposed product grading i.e. if it is intended for OTC or prescription sale. Valid indications of requisitioned products will be the responsibility of the applicant and a register of this information will be maintained by the CMC. GMP related requirements will be specified according to the relevant CM discipline since some products such as herbal preparations will require comprehensive product assays while the potency of other products such as flower essences are not as crucial. ^[54]

In addition, the implementation of the proposed Traditional Health Practitioner’s Bill will facilitate the incorporation of ATM into the current health system. This will be actuated by the compulsory registration of the estimated 200,000 practicing traditional healers under the authority of a statutory council which will monitor ethical trade.

HERBAL MEDICINES REGULATION IN INDIA: ^[55]

The first National Health Policy of 1983 mentions that use should be made of India’s rich tradition of health care in national programmes. The National Population Policy states that TM experts and medicines should be used to stabilize the population. The Department of AYUSH, which started in 1995, regulates TM programmes. There are separate directorates of Indian Systems of Medicine and Homeopathy in 21 State Governments. The Government of India has an explicit and separate policy for Indian (Traditional) Medicine since 2002.

Regulation:

TM is also governed by the Drugs and Cosmetics Act, 1940. Licensing of manufacturers and the provisions of the Drugs Act are implemented by the State Governments. GMPs are mandatory since 2002, though not exactly those recommended by WHO, they are based on them. Central and state governments are impressing upon manufacturing units to comply with GMP norms and to ensure quality standards.

COMPARATIVE OVERVIEW OF STATUS OF HERBAL MEDICINE REGULATION AMONG DIFFERRENT COUNTRIES

Australia ^[23]

China^[17]

Europe^[17,32]

Germany^[17]

India ^[55]

Japan ^[17,57]

South Africa ^[54]

US ^[39]

Basis of Approval

The Therapeutic Goods Act 1989

Drug Adminis-tration Law

EMEA

European

Decentralize procedure

As for orthodox medicines

Drugs and Cosmetics Act 1940 And rules thereunder of 1945

MHW

As for Orthodox

Medicines

Proposed new regulations to be implemented

DSHEA

R ®

AR ®

Quality Control

GMP

√

Voluntary

QC of product Ingredients

√

Voluntary

QC of Final Product

√

Voluntary

Standardization of actives if monograph exists

Chinese Pharmacopoeia

CHMP

ESCOP

WHO

Ayurvedic Pharmacopoeia

Japanese

Pharmacopoeia

BP/USP or other recognized Pharmacopoeias

USP and others

Efficacy and Safety

Clinical Data

√

Historical Evidence

√

Adverse event reporting

√

Post marketing surveillance

√

All claims must be supported by acceptable sources

√

Legal preapproval of claims

√

Legal enforcement of penalties

√

R ®, registered products; L, listed products; AR ®, amended regulations for registered products; BP, British Pharmacopeia; EMEA, European Medicines Evaluation Agency ;CHMP, Committee for Herbal Medicinal Products; ESCOP, European Scientific Cooperative on Phytotherapy; WHO, World Health Organization; MHW, Ministry of Health and Welfare ; USP, United State Pharmacopeia ; DSHEA, Dietary Supplement Health and Education Act

HERBAL MEDICINES REGULATION JAPAN:

Japanese TM be divided into folk medicine and Chinese medicine from ancient China, the so-called Kampo medicine. The difference between Japanese herbal medicine and Chinese medicine lies in the evaluation methods. Therefore, the applicable approval processes are quite different. 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. ^[56]

In the case of an application for approval of a prescription other than those mentioned by MHW specified data on safety, stability, comparison with other drugs, clinical test results, etc. are required to be submitted. ^[57]

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. 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. ^[56]

Re-evaluation Process

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. 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. 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. The regulations also call for quality monitoring of specific ingredients, using at least two different chemical or physical methods to test them. ^[56]

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. ^[57]

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. 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. The third system is Adverse Reaction Reporting from Manufacturers.

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 ^[56]

CONCLUSION:

HERBAL medicine is still the mainstay of about 75–80% of the world population, mainly due to better cultural acceptability, better compatibility with the human body and lesser side effects. The regulation of natural products is a contentious issue and currently the focus of a worldwide debate.

Various practices of traditional medicine have been developed in different cultures in different regions without a parallel development of international standards and appropriate methods for evaluating traditional medicine. Especially developing countries do not have any legislative criteria to establish these traditionally used herbal medicines as part of the drug legislation.

The growth of the botanical market has attracted much interest on the part of the pharmaceutical companies, which has in turn stimulated the appearance of pre-clinical pharmacological studies and of well-controlled and randomized clinical trials to prove their safety and efficacy. The most important scientific journals have dedicated significant efforts to publishing both basic and clinical scientific studies on herbal medicines, and thus certainly will create the scientific basis for the physician's prescription of the herbal drugs. In spite of this, so far insufficient data exist to provide an accurate assessment of the quality, efficacy and safety of most herbal medicines.

WHO has taken initiative and give guidelines that contain basic criteria for the assessment of quality, safety, and efficacy and important requirements for labeling and the package insert for consumers' information. These also specify the clinical studies to be performed as well as the level of evidence needed to claim for therapeutic use. The WHO Guidelines are intended to facilitate the work of regulatory authorities, scientific bodies and industry in the development, assessment and registration of herbal medicines.

It can be concluded that more stringent criteria are required to ensure product quality and safety. Responsibilities within the natural products industry need to be explicitly and appropriately delegated and accountability needs to be enforced with legal action when necessary. More emphasis needs to be placed on post-marketing surveillance and efficient adverse events reporting to compensate for more lenient QSE criteria. An improvement in the processes of regulation and a global harmonization is also desirable and certainly necessary to share national experiences in formulating policies on traditional medicinal products and in introducing measures for their registration and regulation, and to facilitate information exchange on these subjects among other countries.

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Received on 26.04.2011 Modified on 10.05.2011

Research J. Pharm. and Tech. 4(7): July 2011; Page 1007-1015

Regulatory Status of Traditional Medicines in Different Countries: An Overview

THE WHO TRADITIONAL MEDICINE PROGRAMME:

Guidelines for the assessment of herbal medicines:

REGULATION OF CAMS IN AUSTRALIA: [23]

HERBAL MEDICINES REGULATION IN SOUTH AFRICA:

China [17]

Efficacy and Safety

HERBAL MEDICINES REGULATION JAPAN:

CONCLUSION:

REGULATION OF CAMS IN AUSTRALIA: ^[23]

China^[17]