Herbal Drug Regulation

1. Herbal Drug Regulation 02-Jun-2011

2. What is traditional medicine? WHO defines traditional medicine as including diverse health practices, approaches, knowledge and beliefs incorporating plant, animal, and/or mineral based medicines, spiritual therapies, manual techniques and exercises which can be used to maintain well-being, as well as to treat, diagnose or prevent illness.

3. HISTORICAL OVERVIEW • INTRODUCTION OF NEW CATEGORY CALLED “HERBAL PRODUCTS”-1993 • ESTABLISHMENT OF WHOLISTIC HERBAL ASSOCIATION- 1995

4. Traditional and Complementary/Alternative Medicine Categories of TM/CAM Main Popular System of TM/CAM Traditional Chinese Medicine Indian Ayurveda Medicine Arabic Unani Medicine Homeopathy Chiropractic

5. Traditional and Complementary/Alternative Medicine Categories of TM/CAM Medication • Medicinal plants • Mineral materials • Animal materials Non-medication • Acupuncture • Chiropractic • Osteopathy • Manual therapies • Qigong, Taiji, Yoga • Physical, mental and spiritual therapies

6. The Case For Herbal Medicine • Tradition: used throughout history • Natural: perceived as safer • Cost: often less expensive than prescription medicine • Access: no prescription necessary • Synergism: a view that multiple ingredients working together yield better results

7. EXAMPLE: MisaiKuching – Remarkable Malaysian Herb MisaiKuchingwhich means ‘cat whiskers’ - beautiful bluish flowers that resemble the whiskers of a cat. It’s scientific name is OrthosiphonGrandiflorusBoldingh. Traditional Use: • A traditional preparation for the relief of joint aches and stiffness • The plant is said to be effective treatment of arthritis, gout and rheumatism. • MisaiKuching has a long history of use in Asia as a safe and effective herbal diuretic, blood purifier and in treating hypertension and kidney stones. • Used regularly, it helps to remove excessive metabolic waste and acids from the body. • Also known to be effective for diabetic treatment when MisaiKuching is combine with HempeduBumi. • Also, at times the plant is boiled with pokoktemulawak (Curcuma Xanthorrhiza) for elimination of stones in the bladder.

8. Why Regulation required? • Protect consumer interests– unsubstantiated product claims • Protect product integrity- evaluation parameters • Maintain requisite standards – batch to batch consistency • Ensure that public safety not compromised – toxicities • Are safe, effective, beneficial • Products, practices lead to positive clinical outcomes.

9. 1 3 2 4 WHO Traditional Medicine Strategy 2002-2005 Policy: integrate TM/CAM with national health care systems Safety, efficacy and quality: provide evaluation, guidance and support for effective regulation Access: ensure availability and affordability of TM/CAM, including essential herbal medicines Rational use: promote therapeutically-sound use of TM/CAM by providers and consumers

10. Number of Registered Herbal Medicines Number of Countries Total: 66

11. Regulatory status of herbal medicines Respondents were able to answer with more than one option, if applicable, so the total number exceeds number of respondents

12. Herbal Drug Regulation In USA

13. The Case Against Herbal Medicine • Lack of FDA Regulation and Oversight • Lack of Dosage Standardization • Potential for adulteration • Potential for toxicity and drug interactions: natural is not always safer • More effective therapy may be delayed • Many herbs are not superior to prescription medicines

14. Regulatory Issues are Regulated by… • Dietary Supplements Health and Education Act of 1994 (DSHEA)  • Quality • Permissible claim

15. 1) Dietary Supplement Health Education Act (DSHEA) • Signed Oct 25 1994 • to meet the concerns of consumers and manufacturers to help ensure that safe and appropriately labeled products remain available to those who want to use them. • Herbal products are legally food supplements • Manufacturer may state usage and safety, but not make curative claims/ specific health claims without FDA approval • Manufacturer alone is responsible for product safety • FDA must prove product unsafe to remove it from the market

16. IN DSHEA, a dietary supplement is defined under the Dietary as • a product that is intended to supplement the diet and contains any of the following dietary ingredients: • a vitamin • a mineral • an herb or other botanical (excluding tobacco) • an amino acid • a concentrate, metabolite, constituent, extract, or combination of any of the above • Furthermore, it must also conform to the following criteria: • intended for ingestion in pill, capsule, tablet, powder or liquid form • not represented for use as a conventional food or as the sole item of a meal or diet • labeled as a "dietary supplement“ • The hormones pregnenolone (also a steroid) and the pineal hormone melatonin are marketed as dietary supplements in the US

17. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), • the dietary supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is marketed. • FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market. • Generally, manufacturers do not need to register their products with FDA nor get FDA approval before producing or selling dietary supplements.* • Manufacturers must make sure that product label information is truthful and not misleading.

18. FDA's post-marketing responsibilities • include monitoring safety, e.g. voluntary dietary supplement adverse event reporting and product information, such as labeling, claims, package inserts, and accompanying literature. • Domestic and foreign facilities that manufacture/process, pack, or hold food for human or animal consumption in the United States are required to register their facility with the FDA

19. 2) Quality • Under the FDA's final rule on Good Manufacturing Practices (GMP), Quality is defined as meaning "that the dietary supplement consistently meets the established specifications for identity, purity, strength, and composition and has been manufactured, packaged, labeled, and held under conditions to prevent adulteration under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the Federal Food, Drug, and Cosmetic Act".

20. Certification programs • In the U.S., contamination and false labeling are "not uncommon". Independent certification programs exist, but these may have problems as well. • United States Pharmacopeia manages the Dietary Supplement Verification Program (DSVP).

21. Dietary Supplement Verification Program (DSVP) • Its USP Verified Mark seal indicates that the product has been tested for integrity, purity, dissolution, and safe manufacturing, and it is the only certification program which conducts random off-the-shelf testing. • The USP program will not certify products which contain ingredients that the USP's Dietary Supplement Information Expert Committee determines have a safety risk

22. 3) Permissible claims • If a dietary supplement claims to cure, mitigate, or treat a disease, it would be considered an unauthorized new drug and in violation of the applicable regulations and statutes.

23. CLAIMS Dietary supplements are permitted to make • structure/function claims. • health claims and qualified health claims.

24. structure/function claims. • broad claims that the product can support the structure or function of the body • Example: • "glucosamine helps support healthy joints", • "the hormone melatonin helps establish normal sleep patterns” FDA Approval • The FDA must be notified of these claims within 30 days of their first use, and there is a requirement that these claims be substantiated.

25. health claims and qualified health claims • Health claims are permitted to be made if they meet the requirements for the claims found in the applicable regulations. • Qualified health claims can be made through a petition process, including scientific information, if FDA has not approved a prior petition.

26. India regulation for herbal drugs

27. ICMR GUIDELINES • The recognized traditional systems in India are Ayurveda, Siddha and Unani (ASU) besides Yoga, Naturopathy and Homeopathy. • In the traditional Indian medical systems, they are mostly used in • compound forms ,and • multi-component mixtures (including minerals in some of the formulations, and that substantial information is available regarding their prior human use vouchsafing safety and efficacy of these formulations) All the general principles of clinical trials also applicable to herbal remedies.

28. ICMR GUIDELINES • It is important that plants and ASU remedies currently in use or mentioned in literature of recognized Traditional System of Medicine is prepared strictly in the same way as described in the literature while incorporating GMP norms for standardization. • Since traditional remedies have short life, increasing their stability and shelf life, and controlling their batch to batch variation could be challenging tasks for modern scientists and drug controllers to justify the beneficial effects of stored formulations.

29. Three categories of herbal drugs • A lot is known about the use of a plant or its extract, metals, minerals and animal products in the ancient Ayurveda, Siddha or Unani literature or the plant may actually be regularly used by physicians of the traditional systems of medicine for a number of years and the substance is to be clinically evaluated for same indication for which it is being used or as has been described in the texts. • When an extract of a plant or a compound isolated from the plant and any compound formulation having plants, metals, minerals and animal products as ingredients has to be clinically evaluated for a therapeutic effect not originally described in the texts of traditional systems or, the method of preparation is different, it has to be treated as a new substance or new chemical entity (NCE) and the same type of acute, subacute and chronic toxicity data will have to be generated as required by the regulatory authority for synthetic products before it is cleared for clinical evaluation. • An extract or a compound isolated from a plant and any compound formulation having plants, metals, minerals and animal products as ingredients which has never been in use before and has not ever been mentioned in ancient literature, should be treated as a new drug, and therefore, should undergo all regulatory requirements before being evaluated clinically.

30. Ayurveda, Siddha or Unani (ASU) drugs Drugs include herbal and herbo-mineral formulations. The herbal products can belong to one of the three categories given below:- • Category I • Category II & III

31. Category I -

32. For the formulations belonging to this category, it may not be necessary to undertake phase I studies. • In Phase II dose ranging should be explored to find the effective dose as also maximum tolerated dose. • RCTs would be the preferable methodology to validate the claim with placebo or standard drug depending on the ethical requirement. • The clinical trials would mostly fall in the non-inferiority group if literature is not available regarding the proven efficacy of the formulation. • Superiority trial could be designed if the control arm is placebo or modern medicine, which is only weakly effective.

33. Sometimes it would also be right to design pilot observational studies to explore feasibility of conducting larger trials for validation if the outcome is encouraging. • It needs to be emphasized that since the substance to be tested is already in use in Indian Systems of Medicine or has been described in their texts, the need for testing its toxicity in animals has been considerably reduced. • Neither would any toxicity study be needed for phase II trial. • This is the unique reverse pharmacology approach for evaluating traditional formulations for traditional indication. • If there are reports suggesting toxicity or when the herbal preparation is to be used for more than 3 months it would be necessary to undertake 4 - 6 weeks toxicity study in 2 species of animals in the circumstances described above or when a larger multicentric phase III trial is subsequently planned based on results of phase II study.

34. Clinical trials with ASU preparations should be carried out only after these have been standardized and markers identified to ensure that the substances being evaluated are always the same. • However, Good manufacturing Practices (GMP) standards for the formulations to be tried would not be required for Phase I and II trials. • But for Phase III GMP standards would be required for the formulations to be used in the trial as the number of participants would be larger and this will be followed by marketing approvals.

36. Category II & III

37. All the steps involved for regulatory approvals as in the case of synthetic drugs should be followed. • For formulations falling under category II only limited toxicities as mentioned for category I would apply. • All formulations involving herbal component should satisfy following criteria as prescribed by WHO document “Operational Guidance: Information needed to support clinical trials of herbal products (2005)”:

38. Clinical Trials for Herbal IPs • For Phase I / II studies – Herbal Substance: • description of the plant: genus, species (cultivar where appropriate); region(s) and country(ies) of origin; time of harvest; parts to be harvested • plant processing: drying, mechanical disruption, solvent extraction (aqueous or organic solvents, others) • analytical procedures • specification • storage conditions/shelf life.

39. Herbal Product: • amount of active ingredient • list of excipients • type of product (tablet, capsule, etc.) and its method of manufacture • analysis of putative active ingredient(s) via chemical or biological parameters • analysis of a sizeable chemical constituent (analytical marker compound) • analysis via chemical fingerprint (analytical markers) • analysis for lack of contamination by pesticides, herbicides, heavy metals, synthetic drug adulterants, microbials, toxins, etc. • dissolution studies • storage conditions and stability during the length of the trial • specification against which a certificate of analysis can be assessed before the clinical trial material is released

40. b. For Phase III studies- Performing generally the same procedures as for Phase I/II trials, but more extensively and with more stringent oversight. Herbal Substance: • as above for Phase I/II trials. In addition: • statement that the plant is cultivated according to Good Agricultural Practices or harvested according to Good Wildcrafting Practices • reference batch. Herbal Product: • as above for Phase I/II trials In addition: • environmental impact statement.

41. On account of the substantial use of traditional ASU formulations both in animals and humans this relevant information should be included in the protocol for evaluation of these products. • This helps in analysis of the chemistry, manufacturing, and control of the product. • The manufacture of the product should ideally be as per traditionally processed formulation to endorse the claim for efficacy as seen in traditional practice • As the extracts of herbal products and ASU formulations are mixtures of at least partially uncharacterized constituents it is claimed that such a mixture provides a therapeutic advantage, since the unknown constituents may be additive or synergistic in action or may produce a balance to counteract adverse effects of any one constituent.

42. This may thus provide more efficacy than would be provided by the known constituent alone. • Thus, purification of the medicines down to known or otherwise single chemical constituents is not required as it may lead to loss of the advantage provided by the mixture.

43. For standardization and quality control analysis of the active pharmaceutical ingredient(s) • may be best approached by analysis of one or more active biomarker(s), analysis of a chemical constituent that constitutes a sizable percentage of the total ingredients, and a chemical fingerprint of the total ingredients. • The latter two analyses would act as surrogates for analysis of the unknown constituents that contribute to efficacy. • In order to have the best standards by minimizing variation of content from batch to batch several analytical procedures may be needed to adequately quantify the constituents of herbal products or ASU formulations.

44. Quality Control • Contaminating herbicides and pesticides levels as well as toxic contaminations must be particularly addressed in maintaining the quality control of the herbal or herbo-mineral formulation. The presence of adulterants should also be ruled out. • For traditional ASU formulations extraction may be done as per classical method or by a special SOP prepared for it. • Information on each individual plant species used as ingredient must be collected and authenticated and maintained as voucher specimens. • The plant ingredient should be subjected to pharmacognosy and other relevant analysis in phytochemistry • Formulations intended for administration in clinical trials should be prepared in bulk after standardization, and quality control. • The stability and shelf life studies should also be carried out simultaneously for marketing purposes.

45. Conducting an Informed Consent Process • trials have to be approved by the appropriate scientific and ethical committees of the concerned Institutes. • essential that such clinical trials be carried out only when a competent Ayurveda, Siddha or Unani physician is a co-investigator in such a clinical trial. • When a Folklore medicine/ ethnomedicine is ready for commercialization after it has been scientifically found to be effective, then the legitimate rights/share of the Tribe or Community from which the knowledge was gathered should be taken care of appropriately while applying for the Intellectual Property Rights and / Patents for the product.

47. Tripartite Agreement The Golden Triangle partnership under a tripartite Agreement, is among the Department of AYUSH, Council of Scientific & Industrial Research (CSIR) and ICMR to develop formulations / plant based drugs for identified diseases. • Department of AUSH will give technical guidance regarding formulations to be used, • CSIR will carry out the pre-clinical studies on these formulations • ICMR will conduct the clinical trials.

48. The objectives of the program are given below: 1. To develop safe and effective standardized Ayurvedic products for the identified disease conditions. 2. To develop new Ayurvedic and plant based products effective in disease conditions of national / global importance. 3. To develop mechanism to make products affordable in the domestic market. 4. To use appropriate technologies for development of single and polyherbal products to make it globally acceptable. 5. To develop potential patentable products.

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