Herbal medicines have been developed and used by man for thousands of years. Plants have formed the basis of sophisticated traditional medicine systems among which are Ayurvedic, Arabic, Chinese amongst others. Many of the pharmaceuticals available to Western physicians today have a long history of use as herbal remedies such as opium, aspirin, digitalis, and quinine.
The use of herbs to treat disease is almost universal among non-industrialized societies. In developing countries, as much as 80% of the indigenous populations depend on medicinal plants and traditional systems of medicine as their primary source of healthcare. Within the European Community, herbal medicines account for an important share of the pharmaceutical market, with annual sales in the range of US$7 billion. In the US alone, the sale of herbal medicines exceeded $3.3 billion in 1997.
The accurate scientific assessment of herbal medicine is a prerequisite for global harmonization of herbal health claims. In a recent World Health Organisation (WHO) report (WHO Traditional Medicine Strategy 2002-2005) the following was highlighted:
"The use of Traditional Medicine / Complementary and Alternative Medicine (TM/CAM) is increasing rapidly in developed countries. In many parts of the world, policy makers, health professionals and the public are wrestling with questions about the safety, quality, availability, preservation and further development of this type of health care.
Although many TM/CAM therapies have promising potential, and are increasingly used, many of them are untested and their use not monitored. As a result, knowledge of their potential side-effects is limited. This makes identification of the safest and most effective therapies, and promotion of their rational use more difficult. If TM/CAM is to be promoted as a source of healthcare, efforts must be made to promote its rational use, and identification of the safest and most effective therapies will be crucial."
In 1995, as part of its overall global strategy of "Health for All" and due to numerous requests from the member states, the Traditional Medicine Program of the WHO began the extensive task of reviewing the world's scientific literature of commonly used herbal medicines. The WHO monographs published as a result of this work are technical reviews of the quality, safety and efficacy of commonly used herbal medicines and are intended primarily to standardise the proper use of herbal medicines throughout the world.5 The medicinal plant monographs divides the use of each botanical into one of three categories: use supported by clinical data; use described in pharmacopoeias and traditional systems of medicine; and use described in folk medicine and not supported by experimental or clinical data.
In March 2004, The Traditional Herbal Medicinal Products Directive (2004/24/EC) came into force in Europe with the aim to assure the quality, safety and efficacy (QSE.) of traditional herbal medicinal products. This led to the introduction of a simplified registration scheme for manufactured over-the-counter (OTC) traditional herbal remedies in the second half of 2005. However, herbal preparations that are prescribed to the patient after consultation of a medically trained herbal practitioner do not need to be registered under this Directive.
Under the terms of the Directive, a Committee for Herbal Medicinal Products has been established within the EMEA to manage tasks related to the simplified registration and authorisation of traditional medicinal herbal products. Composed of experts in the field of herbal medicinal products, this Committee is also responsible for producing Community herbal monographs. Aided by these Community herbal monographs, harmonisation will be promoted in the Member States as each registration of individual traditional herbal medicinal products is granted.
Quality
The safety problems emerging with herbal medicinal products arises due to lack of effective quality controls. The quality aspect of the medicinal product is independent of its traditional use so that no derogation is made with regard to the necessary physico-chemical, biological and microbiological tests. Products should comply with quality standards
in relevant European Pharmacopoeia monographs or those in the pharmacopoeia of a Member State.
The ingredients that make up herbal medicines are by nature complex mixtures and it can vary considerably depending on environmental and genetic factors. Additionally, the constituents responsible for claimed therapeutic effects are frequently unknown or only partly understood. The position is even more difficult by the common traditional practice of using combinations of herbal ingredients and it is not unusual to have up to five herbal ingredients in one product.
Reliable methods for the authentication of herbal ingredients have been developed, most notably those utilising high-performance liquid chromatography (HPLC). One approach called similarity analysis, confirms the identity of a herbal medicine by comparing its unique chromatographic fingerprint to an already established chromatographic reference standard fingerprint. By utilising statistical algorithms, this technique not only allows samples of different origin to be clearly identified, but also allows confirmation of the same origin of separate samples. Similarity analysis offers a better differentiation of the similarity or difference between herbal ingredients compared to the established method of principal component analysis (PCA) for pharmaceutical ingredients.
Adulteration and substitution of herbal ingredients due to either genuine error or unscrupulous practices can be identified by means of reliable quality control methods. The levels of any microbial contamination, pesticides, fumigants or toxic metals can be also be evaluated and checked against accepted maximum limits.
Being able to ascertain the identity of herbal ingredients is only one aspect of establishing the quality of herbal medicinal products. There is also a requirement to assure the quality control of the herbal medicinal product through the application of standards on: (1) herbal ingredient cultivation; and (2) manufacturing steps to produce the final product. In fact, recommendations have been made for developing and implementing Good Agricultural Practice (GAP) for herbal ingredients and Good Manufacturing Practice (GMP) specific to herbal medicinal products. Analytical standards for raw herbal materials could be established to aid reliable identification of herbal samples.
The European guideline 3AQ22 Quality of Herbal Remedies (May 1989) lists the documentation requirements on the composition, method of preparation, quality control measures used on the starting materials and the finished product, as well the stability and shelf-life data. On the latter point, it should be noted that because the chemical stability of herbal products is complex, determining the expiration date and shelf-life period is difficult.
Safety
The long tradition of the medicinal product makes it possible to reduce the need for clinical trials, in so far as the efficacy of the medicinal product is plausible based on long-standing use and experience. Pre-clinical tests are not deemed necessary where the medicinal product proves not to be harmful in specified conditions from information gathered on its traditional use. However, even a long tradition of use does not exclude the possibility of adverse effects in a patient.
A common misconception about herbalism and the use of 'natural' products in general, is that 'natural' equals 'safe to use'. Many plants have chemical defence mechanisms against predators that can have adverse or even lethal effects on humans. Examples include poison hemlock and nightshade. Herbs can also produce undesirable side-effects just as pharmaceutical products can. These problems are exacerbated by lack of control over the dosage and purity of the herbal product. Furthermore, if taken concomitantly with other medicinal drugs, there is danger of 'summation', where the herb and the drug have similar actions and add together to produce an overdose.
The concerns over the safety of herbal medicinal products have been expressed by a number of regulatory agencies. The UK Medicines Healthcare Regulatory Agency (MHRA) issued a report on the "Safety of herbal medicinal products" in July 2002. This report documented the known intrinsically toxic constituents of herbal ingredients together with any existing restrictions on toxic plant species.
The reported adverse effects of herbal remedies include allergic reactions, toxic reactions, adverse effects related to a herb's desired pharmacological actions, possible mutagenic effects, drug interactions, drug contamination and even mistaken plant identities. The widely used herbal remedy for depression, St John's Wort (Hypericum perforatum), can interact with HIV protease inhibitors, oral contraceptives and warfarin, resulting in a loss or reduction in the intended therapeutic effect of these prescribed medicines. The use of herbal products containing Aristolochia species has been associated with serious renal toxicity. Evidence of substitution of certain ingredients in traditional Chinese medicine, has led to the publication of an EMEA position paper identifying the risks. Examples of developments to address these concerns include the compilation of a Chinese herbal medicine toxicology database. This project set out to retrieve and evaluate scientific evidence on the toxicity of Chinese herbal medicine, to grade the toxicity of individual herbs and to summarise relevant herb data via a searchable electronic database. The resulting database and monographs should assist in promoting the safe and effective use of Chinese herbal medicines.
Special precautions may be required when specific patient groups are concerned. Pregnant or breast-feeding mothers; children; babies; elderly and patients with heart conditions are all groups who may be more susceptible to experiencing adverse events linked to the use of herbal medicinal products.. Herbs that contain volatile oils such as ground ivy and pennyroyal, are irritating to the genito-urinary tract and may induce uterine contractions if ingested in pregnancy. Some of these oils contain the terpenoid constituent, thujone, which is recognised to be abortifacient. Even the excessive consumption of herbal teas, in place of caffeine-containing teas and coffee, is not recommended in these susceptible patient groups owing to the pharmacologically active herbal components that may be present.
In comparison to conventional pharmaceutical drug products, pharmacovigilance for herbal medicines is still in its infancy.. The associated safety risks for some herbal medicinal products are believed to be low but the collated knowledge on the relative safety of herbal medicines remains poor. Standard pharmacovigilance tools have additional limitations when applied to herbal medicines. For example, adverse effects may be reported as being attributed to a pharmaceutical drug even when it has been taken concomitantly with a herbal product.
Efficacy
Compared to conventional pharmaceuticals, there is a paucity of supporting scientific evidence for the efficacy of herbal medicines. Fortunately, scientific evidence on the effectiveness of herbal medicines has grown rapidly in recent years, either in the form of randomised controlled trial data or systematic reviews.Efforts in this area have demonstrated how it is possible to evaluate herbal medicines in much the same way as for conventional pharmaceutical drugs. However, many herbal medicines still remain to be tested with one significant barrier to this being the shortage of supporting funds. Continuing with these lines of scientific investigation will help to establish which herbal medicines do have a beneficial effect for given illnesses and conditions.
Many of the herbal medicinal products in current use have been in use for a long time; in some cases, for hundreds of years. This history of traditional use is recognised in the current legislation within Europe. The European Traditional Herbal Medicinal Products Directive (2004/24/EC) has provisions for granting registration of a traditional herbal product on the basis of well-established medicinal use in the European Community. If the herbal medicine has recognised efficacy and acceptable safety profile, it can be registered without the need for preclinical data or clinical trials.
Regulation of herbal products outside Europe
Currently in the US , herbal products can be marketed only as food supplements and no specific health claims can be made without FDA approval. Since herbal medicines are regulated as dietary supplements under the 1994 Dietary Supplement Health and Education Act (DSHEA), they are not subject to the pre-marketing regulatory clearance required for drugs. The burden of proof is on the US FDA to show a dietary supplement is unsafe.
In Australia, a two-tiered approach to the regulation of therapeutic goods has been developed. This is essentially based on risk, where listed medicines are considered as posing a lower risk than fully registered medicines. Most complementary medicines including herbal medicines are listed. Herbal medicines are assessed as low or high risk depending on the toxicity of the 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 QSE before they are released onto the market. Listed medicines are individually assessed by the Therapeutic Goods Administration for compliance with legislation and they are not evaluated before release. Under the Australian risk management measures, low risk herbal medicines are allowed early market access and are supported by appropriate post-market regulatory activity.
In Japan, China, Korea, and India, patent herbal remedies composed of dried and powdered whole herbs or herb extracts, often in tablet form, are the rule. Traditional herbals are the backbone of China's medicine, managed by the State Administration of Traditional Chinese Medicine. Japan's traditional medicine, kampo, is similar to and historically derived from Chinese medicine but includes traditional medicines from Japanese folklore. In 1988, the Japanese herbal medicine industry established regulations to manufacture and control the quality of extract products in kampo medicine. Those regulations comply with the Japanese government's Regulations for Manufacturing Control and Quality Control of Drugs. In India, moves are being made to establish more effective regulation of QSE of Ayurvedic medicine. Herbal medicines are the staple of medical treatment in many developing countries and are used for a wide range of ailments. Improved regulation that recognises the specific requirements and characteristics of herbal medicines compared to conventional pharmaceutical drugs is key. In Europe, US and other parts of the world, positive steps have been made to devise appropriate strategies to tackle the QSE issues. However, the regulation of herbal medicinal products remains very much in its infancy.
Author is currently a regulatory project manager for Pharmalink Consulting Ltd.He can be contacted at jwan@pharmalinkconsulting.co.uk