SEMINAR ON REGULATORY ASPECTS OF HERBAL PRODUCTS Organized by BYL Nair Hospital during 29-30 June 2012 in Mumbai. Sensing the need for a public discussion on the regulatory issues related to herbal products, the Department of Clinical Pharmacology of BYL Nair Hospital organized a 2 day Seminar on ‘Herbal Products: Regulatory aspect’. The Seminar was held at BYL Nair Hospital on 29th and 30th June 2012. The main objectives were to review the current regulations on herbal products and to update the stakeholders involved in herbal research/industry with respect to the regulatory requirements for evaluating the safety, efficacy and quality of herbal products. With the draft Good Clinical Practice (GCP) guidelines for clinical trials with herbal products of Department of Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH) now available, one of the objectives of the seminar was to bring the ayurvedic industry and academia together for a fertile discussion. The response to the Seminar was good with 103 participants registering for the Seminar, 48 of whom were from the Pharmaceutical industry (both allopathic and herbal) and 36 were academicians and 19 were postgraduate students working with herbal products. The Program began with the session on ‘Regulations to launch a herbal Product’. Dr. Anand Chaudhary, Banaras Hindu University, presented on the topic ‘Gauging Irrationality in AYUSH Patent & Proprietary Formulations’. He outlined the inadequacy and inaccuracy of details provided with P&P products, either on the physical packaging of the products or that furnished on the internet. He commented that the current changing scenario of the growing inclination of renowned Classical Drug manufacturers toward manufacturing of P&P products needs to be looked at with concern and introspection. According to sources, the share of Government sector in AYUSH pharmaceuticals is a meager 0.4% as against 99.6% of the private sector. This contrast is one of the factors contributing to apathy toward classical formulations with growing inclination toward P&P products. Dr. Chaudhary concluded by making following recommendations: Need for a harmonized Licensing system across the country Branding of Classical formulations. New categorization of Ayurveda, Siddha & Unani (ASU) drugs. Experts from the field of Rasashastra, Bhaishjyakalpana, and Dravyaguna should be consulted to formulate guidelines for rational P&P products. New category should be introduced for P&P ASU drugs based on scientific data. The next presentation of the session was given by Dr. Vijay Chauhan, R&D, Herbals, Nicholas Piramal India Limited, who spoke on ‘Regulatory Scenario for Herbal Supplements in India and other SAARC Countries’. He regarded the present state of affairs with regard to herbal supplements in India as a transitory phase. He identified that lack of clear distinction between health supplements and therapeutically effective products which is crucial from the regulatory aspect and also poses a hindrance to the export of indigenous drugs to foreign markets. The State wise registration of a marketed product also gives way to ambiguity as different states follow different regulations. In India, there is lack of specifications regarding shelf-life of P&P products. This necessitates that the stability study data of the product should be made mandatory for its registration. Dr. Chauhan briefed the audience about some of the latest developments on the Regulatory front, for example: A new category of ‘Phyto Pharmaceuticals’ has been proposed to the Drug Controller General of India (DCGI). Category of drugs where toxicity Studies should be made mandatory: (a) Drugs containing a Schedule ‘E’ drug; (b) Hydro-alcoholic extracts; and (c) Other solvent extracts. ‘Food for Special Use’ category under Food Safety and Standards Act, Section 22, in which about 180 plants may be allowed. The safety and toxicity data of these drugs may be provided if necessary. He added that, in Nepal, any kind of pictorial depiction on the label of medicines is strictly prohibited and there are no discrimination between registration of ayurvedic and allopathic medicines. In Sri Lanka, stringent documentation supplemented with Hazard Analysis and Critical Control Points (HACCP) is essential for registration. In the People's Republic of Bangladesh, a national policy on Traditional Medicines (TM) /Complementary Alternative Medicines (CAM) was issued in 1995. National laws and regulations are currently in development. Herbal medicines are regulated as prescription and over the counter medicines. They may be sold with medical, nutrient content and structure/function claims. The next presentation was given by Dr. Sunil Bhaskaran, Indus Biotech, on ‘Regulatory Pathways for Herbal Drugs in the US’. He mentioned that the USA classified herbal drugs in two main categories: (1) Therapeutic Category which include botanical drugs, products with health claims, and disease-specific medical foods and (2) Claim category which include dietary supplements. He highlighted that therapeutic consistency and bioassay development of the product were critical parameters for Investigational New Drug (IND)/New Drug Application (NDA) approval in the US. He opined that work needs to be done on the development of appropriate bioassay models to demonstrate activity and batch wise consistency of a product. He quoted from his own experiences to assert the status of the US- Food and Drug Administration (FDA) as the ‘Gold Standard’ for regulatory guidelines, for example, a product formulated from specific saponins from Fenugreek for indications such as increasing energy and libido. When applied for approval in Australia, it was approved as a ‘drug’, whereas in the US, it was approved as a ‘Food Supplement’. The last presentation in this session was by Dr. SS Gandhi, Gufic Biosciences, who spoke on ‘Regulations to launch a Herbal Product in European Market’. He explained that with regard to the European FDA, categories for herbal drugs are different from the US FDA. It is not possible to get a ‘Full marketing authorization’ approval for a traditional herbal drug as the regulations are very stringent. For the approval of a traditional herbal medicine, a recorded history of 30 years of use is required in home market, out of which 15 years of use should be in the European market. Regarding food supplements, the European FDA does not allow any health claims to be made and no medicinal product can be categorized as Food. The European FDA deems it necessary to express the Drug Extraction Ratio (DER) regarding use of extract of Herbal drugs as against the percentage expression. Of all the prevalent regulatory certifications, the European Union Good Manufacturing Practice (EU-GMP) is the costliest certification. Dr. Gandhi lamented that the European FDA does not recognize the Indian GMP certification or even the Indian WHO-GMP certification. He emphasized the need for upgradation of the Indian Regulatory standards. The Second session of the day was about the ‘Safety requirements’ pertaining to regulations. Dr. SS Savarikar, RA Podar Medical College (Ayu.), delivered the first presentation of this session on ‘Newer Vistas in Developing GMP for Ayurvedic Drugs’. According to him the scope of GMP is beyond merely manufacturing aspects. He suggested that an ideal GMP should start with Good Agricultural Practices (GAP), Good Harvesting Practices (GHP), Good Storage Practices (GSP), and finally GMP. Incorporation of all these would definitely enhance the quality of the final product, making GMP a more worthwhile exercise. Quality Control should be exerted on a day-to-day processing assessment basis and environmental monitoring should also be assessed. Through examples, he asserted the need for Pre-Lab work, that is, On-Field analysis of raw materials used in herbal products as the source, season, environmental conditions can have a marked effect on the quality and properties of the raw material. The second speaker of the Session was Dr. Amit Agarwal, Natural Remedies Ltd., who discussed the ‘Regulatory Requirements for Safety Data Documentation especially of Therapeutic Good Administration (TGA), Australia’. Australia is a rare country that accepts ayurvedic products as medicines, and not as food supplements. Australia follows the British pharmacopoeia and also recognizes Pharmacopoeia of the People's Republic of China (1997). However, it does not officially recognize the Indian Pharmacopoeia or the Ayurvedic Pharmacopoeia. He cited instances of hardships faced by his company regarding the same; for example one of their products containing Triphala was not approved by the Australian Regulatory Authorities a Terminalia bellerica (Bibhitaka) was not listed in TGA Pharmacopoeia and a study published in 1989 claimed T. bellerica to be toxic. The company then extensively studied the safety and efficacy of T. bellerica and established data on phyto-chemical equivalence between raw material of Ayurvedic kwath and water extract claiming it to be nontoxic. This led to the successful outcome of monograph of T. bellerica being incorporated in the Indian Pharmacopoeia in 2007, followed by its subsequent recognition in the British Pharmacopoeia which is accepted by Australia. He thus highlighted the extent to which publications may harm or benefit the herbal drug industry and the scope of work that needed to be done in establishing a robust and authentic safety profile of herbal drugs. In the third presentation of the session, Dr. Adip Roy, Unilever Pvt. Ltd., spoke on ‘Safety Assessment/Generation of History of Safe Use Data for Herbal Products’. He began his presentation highlighting the points that need to be considered for Safety evaluation of Herbal products, which are mentioned below: In case of a product for local application, whether it is a Leave-on product or a Rinse-off product, as the period of contact is longer in the former case. Abuse conditions, for example, de-odourants (which are used more frequently than prescribed). At Hindustan Unilever they have developed a model for ‘History of Use’ for the purpose of Risk assessment which he described in detail giving examples. The last deliberation of the day was by Dr. C. K. Katiyar, Healthcare Research, Dabur Research & Development. He mentioned that although Ayurveda has been the very essence of Indian Medicinal System with therapeutic properties of a myriad drugs being described in its texts, a drastic transition has taken place over time with regard to air, soil, water, agricultural land, and the ecosystem as a whole. This necessitates the requirement of evaluation of safety and toxicity of classical herbal drugs. Another important issue with regard to safety of herbal drugs is that of Drug-Interaction. In a country like India, self-medication with herbal drugs is remarkably prevalent. It can well be alleged that every diabetic patient in India treats himself with traditional antidiabetic drugs such as Gudmar, Jamun, Neem along with his regular Hypoglycemic medications. There is a legal fallacy with implementation of the ‘Drugs and Magic Remedies Act’ that the fine for infringement is too meager and hence nondeterrent for the defaulters. There is an urgent need to upgrade the stringency of regulation of the concerned act. A point worth consideration in the context of the topic was the selection of an appropriate comparator drug regarding preclinical trials for safety evaluation of Ayurvedic drugs. For example, if a comparative study between Rasakarpura and Rasapushpa is planned, the results should be compared with Mercurous Chloride. He cited a paper published by Dr. Y.K. Gupta on ‘Safety of Arogyawardhini, (Journal of Ethnopharmacology), a control group was included to whom HgCl2 was administered in the dose of 1 mg/kg body weight to evaluate the effects on kidney and brain. He also stated that the duration of toxicity studies should be equal to the duration of usage in human beings. He concluded his presentation by suggesting the Implementation of ‘Toxico-vigilance’ for safety evaluation of Ayurvedic drugs. For this, the blood level monitoring of patients admitted in Government hospitals and undergoing treatment with Ayurvedic medicines should be checked on admission, immediately after completion of treatment and after 3 and 6 months of the treatment. In Chandigarh, during a trial of this kind, it was surprisingly observed that in the preadministration stage itself, the blood levels of Mercury in the patients were already higher than the basal levels due to the increased Mercury concentration in water. The second day of the Seminar started in line with the previous day's discussions with the first session of the day being ‘Efficacy requirements’. Dr. Arun Bhatt, Clinivent Research, presented a study on ‘Regulatory requirements for human studies of Food supplements with botanicals’. He opined that the FSS Act 2006 which was related to functional foods and neutraceuticals or health supplements needed reconsideration as the guidelines mentioned therein left a majority of the decisive parameters to the manufacturer's will. Moreover, the Gazette notification published by Dept. of AYUSH appeared to be a reiteration of the ICH-GCP without any consideration for the particular requirements of the ASU drugs. He said that the regulatory requirements for Human studies of Food supplements with botanicals should be formulated only after meticulous research and consultation with the experts. The drug to be tested should be described elaborately with the identification, method of processing and dose determination. The second presentation in this session was on ‘Claim Substantiation of Food Supplements – in light of FSSAI’, which was made by Dr. Prabodh Halde, Marico Ltd. He said that the Health Food sector is an ever-growing industry worth Rs. 30,000 crores. The differentiation of categorization between Food and Drug is not very clear; for example, Haldi (Turmeric) can be labeled as drug when used for disease mitigation whereas the same can be categorized as a food product as well. It was on this background that the Food Safety and Standards Authority of India (FSSAi) act was formulated. The regulations on Label claims have been divided as (1) Health claims, (2) Nutrition claims, and (3) Risk Reduction claims. For approval of health claims, though substantial data will be required, no guidelines have been laid down as yet. The Nutrition claims will be further approved as Nutrient-content claim and Nutrient comparative claim. For the former, laboratory tests will be required to be conducted in the National Accreditation Board for Testing and Calibration Laboratories (NABL) accredited laboratories and also shelf-life studies in market span will be needed to be conducted. The guidelines for approval of Risk reduction claims have yet to be formulated. However, ‘Product Study’ on a whole will be considered as against ‘Ingredient study’ for the claimed reduction of risks. A period of 20 months is expected between application for a claim and its approval. The FSSAI claim substantiation document is still in the ‘draft’ form and is expected to come into implementation in a month's time. The second session of the day was on ‘Quality requirements’. Dr. Pralhad Patki, Himalaya Healthcare, delivered the first speech on ‘Regulatory Requirements Regarding Quality- Pre-Clinical and Clinical Perspectives’. He highlighted the design for a definite approach toward regulations for Herbal Drug development in view of the increasing demand for herbal drugs worldwide. He stated that the evolution of ‘Evidence Based Medicine’ encompassing the three arms of the golden triangle, that is, Traditional Medicine + Modern Science + Modern Medicine, was the absolute need of the hour. He also mentioned that as Ayurveda has perpetually faced Plant Identity Crisis, along with currently utilized parameters, Rapid amplification of Polymorphic DNA, that is, Random Amplification of Polymorphic DNA ( RAPD) analysis which is absolutely useful for identification can be incorporated as an integral parameter for Herbal Drug Analysis. A handbook for ‘Plant Identification for Herbal Industry’ published by Canada has proven to be very functional in improvising quality of raw materials used. Something on similar lines if formulated in India will definitely improve the current scenario. He also pointed out that regulations regarding stability studies must be made stringent as it reflects on the shelf-life of the marketed product and Accelerated Stability studies have proven insufficient experientially. Dr. Shailesh Nadkarni, Shri Dhootpapeshwara Ltd., was the next speaker, who discussed about ‘Ensuring Quality through Ayurvedic Pharmacopoeia of India’. In his speech, he narrated the work done by Ayurvedic Pharmacopoeia Commission till date. He also briefed about the new addition of ‘bhasma’ in pharmacopoeia. In July 2010, the Ayurvedic Pharmacopeia Commission had started work on monographs of Bhasmas prepared following a single SOP but manufactured at different centers. This work is underway and expected to upgrade quality analysis of Bhasmas. The first half of the afternoon session was dedicated to discussion on ‘Ayush GCP- Need for guidelines’, Dr N. Shrikanth, CCRAS, spoke on the Ethical perspective of the guidelines.” He mentioned that GCP and ethical guidelines have been practiced since the Vedic period. In the present times, however, the fundamental aspects of holistic systems are not appropriately positioned in most of the clinical trials designed to examine the safety and efficacy of AYUSH therapies/approaches. While designing the research trials it would be appropriate to understand differences between designing of the trials between AYUSH and contemporary modern System of medicine. Differences are mainly due to the basic approach to health and diseases, perceptions and also epistemological. Issues like ethical approval, documentation of written informed consent prior to recruitment into clinical studies, patient safety, medical management of adverse events especially serious adverse events, and compensation for research related injuries also need to be considered. Dr. Nagesh Sandu, Sandu Pharmaceuticals, then talked on ‘Industry Perspective of AYUSH GCP’. He said that the current Proposal of GCP guidelines and Schedule Z is laced with numerous fallacies. The following requirements made mandatory have no relevance with respect to ASU drugs, such as: Impurity profile Pharmaco-kinetics Chemical name Manufacturing of active principle Intra-venous infusions and injections. Other laboratory investigations such as Genotoxicity evaluation are not feasible for small scale manufacturers. He also stated that there was remarkable disharmony in Section 158 B, proposed Section 170, and the proposed Schedule Z. An elaborative presentation on the ‘Investigator's Perspective’ was delivered by Dr. Y.K. Gupta, AIIMS. From the experiences garnered from numerous trials at AIIMS, he emphasized the following points that should be considered with respect to clinical trials using ASU products: (1) product standardization, though High Performance Thin Layer Chromatography (HPTLC) is regarded as gold standard, but, the co-relation of biologically inactive markers and therapeutic outcome is arguable. (2) The guidelines should make presence of an allopathic expert mandatory for ASU trials involving Allopathic Drugs and parameters conducted in Ayurvedic Hospitals. (3) The protocol which forms the most crucial part of the entire clinical trial should clearly state the objectives in the most definite way. (4) The problem arises with designing parameters for ASU drugs which are hypothesized to improve quality of life of the patient. (5) The AYUSH GCP guidelines do not address regulations pertaining to Inclusion criteria, Exclusion Criteria, Pathya-Apathya in relation to ASU Product trials. Point of Care Clinical Trials (POC-CT) have not been elaborated in the AYUSH-GCP. The concluding presentation of the day was given by Dr. D.B.A. Narayana on ‘Basic awareness of Intellectual Property rights (IPR). He underlined following highlights of the IPR: (1) Patents are granted for inventions and not discoveries; (2) Rights are given to inventor by the State on disclosure of invention and are valid for specified territory and specific period (generally 20 years); (3) Patents are not granted for prior art. He enlightened the audience that, an invention should not be presented or published prior to grant for its patent, in case the inventor wishes to apply for its patent; (4) Clinical trials are not required for application of patents,. However, data should be cited for earlier discoveries and the need for the patent; and (5) Ayurvedic manufacturers are comparatively ignorant about Patent Regulations and this may lead to legal hassles in future. Even the smallest details such as selection of bottle design should be first confirmed for any existing patents on it. The finale of the Seminar was a Panel discussion on ‘Regulations being Market Enablers’ which was moderated by Mr. Ranjit Puranik, Shri Dhootpapeshwara Ltd. The panelists included The issues discussed were Inaction of Stakeholders Lack of infrastructure upgradation Quality, Packing, Stability, Additives, Innovation Safety—children, pregnancy, geriatrics Missed the bus on neutraceuticals Gain from applied research—Micro and SSI, Medium scale Overpromise of advertisements. These issues were hectically discussed over duration of an hour and half and at the end the following recommendations were made: Ayurvedic Drug Manufacturers Association (ADMA) should design and publish ‘Ethical Guidelines for Rational Advertising’. Branding of classical formulations which will help improve the current apathy toward manufacturing and promote the sale of classical products. AYUSH can be given the responsibility of certification of brands, for example, AYUSH STANDARD or AYUSH PREMIUM certification. Industry should be ready with a mindset for a scientific scrutiny of their products, as this would be a value-addition to their product. A task force or a Forum should be set up for managing data on safety and toxicity of Ayurvedic medicines. One of the outcomes of the Seminar was the decision to formulate an e-group to discuss two major issues that came from the Seminar, that is, ‘Assessing rationality of P & P products’ and ‘Good reviewing/reporting practices’. Those interested can join this e-group by sending a request mail to email@example.com or firstname.lastname@example.org and participate in further discussions. Dr. Ashok Vaidya, MRC-KHS, has proposed a ‘Mumbai Resolution on Regulatory and Academia – Industrial Aspects of Plant – Derived Health Products’, which is presently being circulated to the participants of the Seminar for inputs and the final signed document will be sent to the Dept. of AYUSH for further action.