You are on page 1of 9

Regulatory Issues for Traditional Medicine – Herbal Research

Dr Arun Bhatt MD (Med) FICP (Ind)
Member Faculty of Pharmaceutical Medicine (Royal College UK)
President Clinical Development
Chembiotek Research International Pvt Ltd
Email: arun@chembiotek.com / arun_dbhatt@hotmail.com

1

manual techniques and exercises. 2 The use of chromatographic techniques and marker compounds for the standardization of herbal products can ensure batch-to-batch consistency.Introduction Traditional medicine is a broad term encompassing health practices. 41% arsenic and 9% cadmium). Quality has to be assured at all stages – herbal raw materials. approaches. herbal medicines present unique challenges in research and regulations. consistency in composition and biologic activity are essential requirements. however. several regulatory guidelines are available in the area of herbal medicines. quality assurance is important. in the traditional medicine for its potential contribution to health care. The incidence of heavy metal contamination is not known. and drug standardization. spiritual therapies. microorganisms. "Their (herbal medicines) potency may vary and their purity is suspect. 3 Medical letter cautions. toxic metals. suspended production license of Pan Pharmaceuticals after an audit. and fumigation agents. 6-8 This article is a brief review of the regulatory issues in traditional medicine herbal research. as quality is a critical determinant of safety as well. pesticides. diagnose and prevent illnesses or maintain well-being. 1 There has been a lot of interest. 4. pharmacology. herbal drugs frequently fail to meet this standard. chlorpheniramine. and phenacetin. animal and mineral based medicines. the amount of ginsenosides varied from 11. toxicology. methyltestosterone. 10 to 15 percent contained lead. Quality of herbal preparations If an herbal remedy is effective. quality assurance is needed to ensure that the product has the expected effects. Among the traditional approaches. issues of clinical research. 2) genetic variability. Recent reviews have focused on the problems of quality.9-327. or arsenic. there are a lot of concerns about the traditional medicine in areas of efficacy. this does not ensure consistent pharmacologic activity or stability. Adulteration of plants is serious problem.7% of the amount on the label. 10 The Lack of standardization of herbal drugs would be a serious problem for a researcher as he would not be able to rely on commercially available herbal products for his research studies. In a study of ginseng preparations. 2-5 In recent years. safety and quality. 3) variations in growing conditions. However. With herbal medicines what is on the label and what is in the bottle may differ considerably. applied singularly or in combination to treat. 11 This can cause serious harm to patients taking such remedies and could confound the assessment of safety in a clinical trial. Current regulatory issues for herbal medicines There are several regulatory concerns in relation to research applications and commercialization of herbal medicines. 2 The drugs most frequently found were ephedrine. knowledge and beliefs which incorporate herbal. but one study showed that 64% of samples collected in India contained significant amounts of lead (64% mercury. Even in the absence of data on efficacy. A recent WHO fact sheet comments “ Unregulated or inappropriate use of traditional medicines and practices can have negative or dangerous effects. which revealed problems with company's quality control standards. and need for new regulations for herbal therapies. today.” 1 Our own National Policy 2001on Indian Systems of Medicine includes issues such as drug standards. processing of herbals and finished herbal medicines 2 . mercury. 4) diversity in harvesting procedures and processing of extracts. However." 9 Australian medicines regulatory body the Therapeutic Goods Administration. Some of the common adulterants are: botanicals. Several organisations have discussed these issues in their approach papers. and 5) the lack of information about active pharmacologic principles. regulations and enforcement’ and focuses the research agenda on clinical trials. Standardization of herbal drugs For safe and effective use of herbal drugs. A US investigation reported that 32 percent of marketed Asian patent medicines contained undeclared pharmaceuticals or heavy metals. microbial toxins. as there are problems such as 1) difficulties in identification of plants.

John's wort caused serum levels of cyclosporine and antiretroviral agents to fall to sub therapeutic levels. as these products were often perceived as so safe that even if they were ineffective. 5 For instance. or even different lots of the same extract are comparable and equivalent. herbal or conventional. 12 The data available is mostly experimental or in animals.Evidence of Clinical Efficacy Scientific evidence from randomized clinical trials is only strong for many uses of acupuncture. as herbal products can not be patented as easily as new chemical entities. Even different species may be known by the same name in local language. extracts. it is difficult to link the improvement to the herbal product. heart attacks and strokes. most Indian trials of hepatoprotectice agents are open and uncontrolled. Garlic is reported to increase clotting time in patients taking warfarin. 6-7 US FDA Guidance for Botanicals 3 . the situation is changing now and there is an increasing body of literature on the side effects and interactions of herbal medicines. hypericum extracts can decrease the concentration of a variety of other drugs by enzyme induction. As most acute liver conditions have a natural recovery. The clinical relevance of the observed effects is not always clear. 4 Safety Concerns . 1 Global Regulatory Scene The above issues have led to an increasing regulatory focus on herbal products in US and Europe. Echinacea products can contain other plant extracts. and the industry professionals argue that it would be not be possible to recover the high research costs. and might have been produced in quite different manners (hydro. controlled trials. both). The herbal industry is not required to conduct clinical trials. High quality studies are necessary to evaluate and compare the value of traditional Indian drugs to modern medicine. Brahmi refers to Centella asiatica and Bacopa monniera. A recent review concluded that evidence-based studies on the efficacy and safety of traditional Indian medicines are limited. 13 The essential ingredient in most formulations is not precisely defined. some herbal medicines and for some of the manual therapies. Nevertheless. the herb Ephedra marketed as a dietary aid in USA. controlled trials are the best way to demonstrate the efficacy of any medicine. different parts (herb. 12 A fundamental problem in all clinical research of herbal medicines is whether different products. little harm resulted. 14 However. For example. For example. pallida or angustifolia).or lipophilic extraction). randomized.15-16 Besides the direct risks of adverse effects and drug interactions there is an indirect risk that an herbal remedy without demonstrated efficacy may compromise. 14 Other well-known safety issues have been hepatotoxicity of kava and renal effects of aristolochic acid. delay. Most trials do not report hard efficacy endpoints and duration of observation periods is generally short. controlled trials. case reports show that severe side effects and relevant interactions with other drugs can occur. 1 Only a small fraction of the thousands of medicinal plants used worldwide has been tested rigorously in randomized. 4 WHO has urged the governments to establish regulatory mechanisms to control the safety and quality of products. For instance. drug interactions of herbal drugs are of a serious concern. or replace an effective form of conventional treatment. root. While this may be probably correct. such observations cannot predict the results of well designed randomized. Lack of regulatory standards regarding the efficacy and safety of herbal products did not arouse much concern in the past. 14 Besides. purpurea. use different plant species (E. Even if the animal studies or anecdotal clinical experiences are promising and use of an herb is widespread. Serious adverse effects have been reported when the addition of St.Adverse Reactions and Drug Interactions Herbal medicines are generally considered comparably safer than synthetic drugs. led to at least a dozen deaths.

such as selection of doses and addition of new botanical ingredients based on response. If there is doubt about the best dose of the product tested. human use) is required to assist FDA in determining the safety of the product for use in initial clinical studies.  If the product is prepared. and placebo-controlled (or dose-response). The guideline is fairly exhaustive and pragmatic. Sponsors are allowed to initiate more definitive efficacy trials early in the development program. parallel. Requirements for botanical product that has not been previously marketed in the United States or anywhere in the world  Certain additional information (CMC.  For expanded i. approval from ethics committee) for all clinical trials. For most conditions potentially treated by botanical drugs (generally mildly symptomatic). double blind. sufficient information may be available to support such studies without standard preclinical testing. This additional information should be provided regardless of whether the product is currently lawfully marketed in the United States or elsewhere as a dietary supplement. The data requirements depend on several factors (Table 1).  All study data should conform to standard ethical guidelines of good clinical practice (informed consent. more detailed information on CMC and preclinical safety is necessary as compared to the information required for a Phase 1 or Phase 2 study. active control equivalence designs would not be credible. and used according to methodologies for which there is prior human experience. because of their extensive though uncontrolled use in humans. Documentation for early trials (IND) 4 . cosmetic or drug and 2) status of botanical – marketed in US. Phase 3 clinical studies on a botanical drug product. toxicology. Some of the general guidelines are:      Traditional herbal medicines or currently marketed botanical products.  As the product is marketed and the dose thought to be appropriate and well tolerated is known. if there are no known safety issues associated with the product and it is used at approximately the same doses as those currently or traditionally used or recommended. there should be little need for pilot or typical Phase 1 studies.  The credible design for clinical trials studies will be randomized. dose-response study may be particularly useful as an initial trial. a randomized.e. 6 The regulatory approach is based on 1) intended use of botanical – as dietary supplement. Requirements for Investigational New Drug (IND) applications of botanicals legally marketed in the United States as dietary supplements or cosmetics  Very little new chemistry manufacturing and controls (CMC) or toxicologic data are needed to initiate early clinical. which will need to be resolved. marketed outside US or not marketed at all. may require less preclinical information to support initial clinical trials than would be expected for synthetic or highly purified drugs.The US FDA has issued draft guidance for botanical products. processed.. Clinical trials of botanical products  There may be special problems associated with the incorporation of traditional methodologies.

5 . The review of literature should identify the current level of evidence for safe and effective use of herbal medicine. 5) lack of proper documents. CMC and clinical) meet the global good laboratory practices (GLP). and Controls  Botanical Raw Material  Botanical Drug Substance  Botanical Drug Product  Placebo  Labelling  Environmental Assessment or Claim of Categorical Exclusion Pharmacology/Toxicology Information Exclusive marketing rights  US FDA has a provision to grant exclusive marketing rights for 3-5 years even in the absence of patent protection. During the period of exclusivity. 7 The guidelines provide grading of recommendations based on previous clinical trial data. Indian Scenario The domestic turnover of traditional medicine industry in India is over Rs 4000 crore. The guideline also covers the good agricultural practices (GAP) in growing and processing of all medicinal plants. but are not formulated as per the traditional formulae. certain competitor products unless the second sponsor conducts all studies necessary to demonstrate the safety and effectiveness of its product. which are quite low compared to Chinese figures of $ 3 billion. Group-II of Task Force on “Pharmaceuticals and Knowledge Based Industries” 1999 has concluded that Indian exports of herbal products is rather low due to several factors like 1) issues related to non-availability of scientific data. The P & P formulations include the ingredients cited in traditional medicine’s authoritative texts. Description of traditional use without supporting clinical or experimental data is not sufficient to establish a sufficient level of efficacy. good clinical practices (GCP) and good manufacturing practices (GMP). 7) availability of free sale certificate. 8) certificate of analysis and 9) the quality of the products. The international regulatory authorities would expect that the data generated (pre-clinical. European Guidelines on Herbal Medicinal Products The data requirements in the European Guidelines depend on the nature and level of indication and available clinical literature. or in some cases even review. The domestic market largely focuses on over the counter (OTC) sales of patent and proprietary (P & P) medicines. 2) price competitiveness. 3) packaging 4) timely delivery schedule. FDA will not approve. 6) government authority to provide certificate confirming compliance of good manufacturing practices. For minor indications. standardization and clinical evidence.    Description of Product and Documentation of Human Use  Description of Botanicals Used  History of Use  Current Investigational Use Chemistry. Manufacturing. Indian exports are around $ 100 million. a low level of evidence (expert opinions or clinical experience of respected authorities) is acceptable if there is support from experimental data. documentation. The level of safety must correspond to the indication claimed for the product. There is an urgent need for Indian research to focus on the areas of quality. National Policy on Indian Systems of Medicine of 2001 has identified a need for efficacy trials for the therapeutic claims of P & P medicines.

Clinical trials should be carried out with herbal preparations only after standardization and identification of markers to ensure that the substances being evaluated are always the same. Ethical guidelines (patient information. The scientific community is concerned about the quality. there are concerns about use of untested and unregulated medicines. the Central Drugs Standard Control Organisation of Directorate General of Health Services has recently issued GCP guidelines.    For the herbal remedies and medicinal plants that are to be clinically evaluated for use in the Allopathic System and which may later be used in allopathic hospitals. When an extract of a plant or a compound isolated from the plant has to be clinically evaluated for a therapeutic effect not originally described in the texts of traditional systems or. Some of the recommendations are:         Plants and herbal remedies should prepared strictly in the same way as described in the literature while incorporating GMP norms for standardization For herbal remedies. 8 These guidelines recommend the approach to clinical trials of herbal remedies and medicinal plants (Table 2). it may not be necessary to undertake Phase 1 studies If there are reports suggesting toxicity or when the herbal preparation is to be used for more than 3 months. An extract or a compound isolated from a plant. should be treated as a new drug. clinical safety and efficacy of herbal remedies. protection of vulnerable populations etc) for biomedical research should be followed. and therefore. it has to be treated as a new substance or new chemical entity (NCE) and the same type of acute. standardization. and compliance with GCP in all clinical trials. toxicity studies (4-6 weeks toxicity study in 2 species of animals) are needed for phase 2 trials. which has never been in use before and has not ever been mentioned in ancient literature. The guidelines divide the herbal products into different categories based on the whether the use and formulation of product are as per the traditional medicine literature or are not as per the traditional documentation. Siddha or Unani physician is a co-investigator Conclusions Although there is a global interest in traditional herbal medicines. Time has to come to accept the same for herbal remedies.In 2001. informed consent. Clinical trials should to be approved by the appropriate scientific and ethical committees of the concerned Institutes. Clinical trials should be carried out only when a competent Ayurvedic. The document also provides general guidelines on clinical trials of herbals. should undergo all regulatory requirements before being evaluated clinically. the method of preparation is different. The experience of allopathic industry suggests that regulations are necessary in order to support science and quality of research. the procedures laid down by the office of the Drugs Controller General of India for allopathic drugs should be followed. toxicity studies. need for standardization. For Phase 3 trial toxicity studies (4-6 weeks toxicity study in 2 species of animals) are needed. sub acute and chronic toxicity data will have to be generated as required by the regulatory authority before it is cleared for clinical evaluation. Unless the research data on 6 .

Indian herbal remedies meet the local and global regulatory standards. The golden dictum for herbal medicines is “ Effective Regulations Improve Research” 7 . our traditional systems will find it difficult to compete with Chinese efforts.

Vickers Saller RA. Bhatt NS Indigenous drugs and liver disease Ind J Gastroenterol 1996 15:63-67 14 Stein MC Are herbal products dietary supplements or drugs? An important question for public safety Clin Pharmacol Therap 2002. Grollman AP Botanical Medicines — The Need for New Regulations N Engl J Med 2002 347:2073-2076 3 Straus SE Herbal Medicines — What's in the Bottle? N Engl J Med 2002 347:1997-1998 4 De Smet PAGM Herbal Remedies N Engl J Med 2002 347:2046-2056 5 Linde K. Riet G. 16 De Smet PAGM Health risks of herbal remedies Drug Saf 1995. Part 2: Herbal medicine BMC Complementary and Alternative Medicine 2001 1:5 6 US FDA Guidance for Industry Botanical Drug Products Centre for Drug Evaluation and Research August 2000 7 European Agency for the Evaluation of Medicinal Products Report from the Adhoc Working Group on Herbal Medicinal Products 1997/1998 EMEA/ HMPWG/25/99 8 Guidelines for Clinical Trials on Pharmaceutical Products in India – Good Clinical Practices Central Drugs Standard Control Organisation Directorate General of Health Services Ministry of Health & Family Welfare Government of India Dec 2001 9 Problems with dietary supplements Med Lett Drugs Ther 2002 44:84-6 10 Complementary medicines industry in crisis after recall of 1546 products BMJ 2003 326:1001 11 Ernst E Heavy metals in traditional Indian remedies Eur J Clin Pharmacol 2002 57:891-64 12 Ladha R. 71: 411-13 15 Fugh-Berman A Herb-drug interactions Lancet 2000.References 1 WHO Fact Sheet N°134. Hondras M. Revised May 2003 2 Marcus DM. 13:81-93 8 . 355:134-138. Bagga A Traditional Indian system of medicine Ann Acad Med Singapore 2000 29:37-41 13 Bhatt AD. Melchart D Systematic reviews of complementary therapies – an annotated bibliography.

Siddha or Unani literature or plant in regular use by traditional systems physicians  Use of plant described in the traditional text but method of preparation of extract is different  A compound isolated from a plant described in the traditional system literature  An extract or a compound isolated from a plant not described in traditional system literature 9 . o Initial clinical trial Phase 1 or 2 o Expanded clinical trial Phase 3 Table 2 Indian Regulatory Categories of Herbal Medicines  Use of plant or its extract well described in ancient Ayurveda.Table 1 US FDA: Factors deciding Data Requirements for Botanicals Herbal preparations  The novelty of the drug o Availability in US as a dietary supplement or OTC o Availability outside US o Non-marketed any where  Extent to which it has been studied previously o Availability of previous human experience o The drug product’s known or suspected risks  Developmental phase of the drug.