1. 19/08/2007 KLE University, Belgaum, India1 REGULATORY GUIDELINES FOR PRECLINICAL AND CLINICAL VALIDATION OF TRADITIONAL MEDICINES Dr. Basavaraj K. Nanjwade Associate Professor of Pharmaceutics Department of Pharmacology JN Medical College Belgaum-10 e-mail: bknanjwade@yahoo.co.inbknanjwade@yahoo.co.in BY

2. 19/08/2007 KLE University, Belgaum, India2 Traditional Medicine “Traditional medicine refers to health practices, approaches, knowledge and beliefs incorporating plant, animal and mineral based medicines, spiritual therapies, manual techniques and exercises, applied singularly or in combination to treat, diagnose and prevent illnesses or maintain well-being”

3. 19/08/2007 KLE University, Belgaum, India3 Traditional Medicine/CAM Non-Industrialized countries population uses for primary health care needs. E.g. Africa up to 80% In industrialized countries, adaptations of traditional medicine are “Complementary” or “Alternative” medicine E.g. USA, EU, Australia etc.

4. 19/08/2007 KLE University, Belgaum, India4 Use and Popularity of TM/CAM 30%-50% of the total medicinal consumption - China. 60% first line treatment - Ghana, Nigeria and Zambia Over 50% of the population have used CAM at least once – Europe & North America 75% of people living with HIV/AIDS use TM/CAM - San Francisco, London & South Africa.

5. 19/08/2007 KLE University, Belgaum, India5 Use and Popularity of TM/CAM 158 million of the adult population use complementary medicines – US US $ 17 billion was spent on traditional remedies in 2000 In UK annual expenditure on alternation medicine is US $ 230 million The global market for herbal medicines currently stands at over US $ 60 billion annual and is growing steadily

6. 19/08/2007 KLE University, Belgaum, India6 TCM Products Traditional Chinese Medicine products are taken to mean “finished TCM products and proprietary products” A finished product is one that has undergone all stages of production, including packaging in its final containers and labeling. A single TCM formula or product may contain between six to twenty different ingredients

7. 19/08/2007 KLE University, Belgaum, India7 TCM Products Chines medicinal materials showed that 86.8%, 12.5% and 0.7% of the products examined could be classified as herb, animal and mineral, respectively.

8. 19/08/2007 KLE University, Belgaum, India8 "Natural Products" platform

9. 19/08/2007 KLE University, Belgaum, India9 Pre-clinical studies Pre-clinical studies serve a vital role in the drug discovery and development processes. These studies can be used to identify lead compounds likely to possess favourable biopharmaceutic and pharmacokinetic properties in humans. In addition, they can facilitate transition through the discovery - development interface and decrease the need for expensive and time-consuming clinical studies.

10. 19/08/2007 KLE University, Belgaum, India10 Pre-clinical studies include - in vivo animal models - isolated perfused liver, kidney, intestine, hind limb and heart - animal and human liver microsomes - bioavailability studies - pharmacokinetic studies - prediction of oral absorption in humans - determination of mechanisms of intestinal absorption

11. 19/08/2007 KLE University, Belgaum, India11 Pre-clinical studies include - assessment of transport, distribution and elimination of compounds - validated models for cytochrome P450 enzymes - metabolism studies in human liver microsomes - assessment of potential for metabolic drug – drug interactions - analysis of drugs and metabolites in biological matrices

12. 19/08/2007 KLE University, Belgaum, India12 Limitations of preclinical studies 1.Suitable pharmacological models have not yet been developed for many common diseases 2.Toxicity testing is time-consuming & expensive. 3. Large numbers of animals must be used. 4. Extrapolation of toxicity data from animals to humans is not completely reliable. 5. Rare adverse effects are unlikely to be detected

13. 19/08/2007 KLE University, Belgaum, India13 Clinical studies include Two types of clinical research 1. Methodology/study design 2. Clinical trials a. Phase one study b. Phase two study c. Phase three study d. Phase four study/Late Phase three-Post Marketing

14. 19/08/2007 KLE University, Belgaum, India14 Regulatory Approaches FOR MARKETING BOTANICAL DRUG PRODUCTS

15. 19/08/2007 KLE University, Belgaum, India15 INFORMATION TO BE PROVIDED IN AN IND FOR A BOTANICAL DRUG IND for a Botanical Drug Product General principles; format and contents (slid No. 16) Initial clinical trial of a marketed botanical product with no known safety issues (Slid No. 17) Initial clinical trial of a nonmarketed botanical product or marketed botanical product with known safety issues (Slid No. 19) Expanded clinical Trial of any botanical product (Slid No. 22) Documentation of use limited CMC information; previous human experience may be sufficient to support safety More documentation of use and more CMC information (Slid No. 17) Same documentation of use but more detailed CMC information; standard nonclinical toxicology studies may be needed (Slid 19) Is the product a traditional preparation? Previous human experience may be sufficient to support safety (Slid. No 19) If the product is marketed only outside the U.S. additional CMC and nonclinical safety information may be needed (Slid. No. 17) Additional nonclinical safety information may be needed (Slid No. 19) No Yes

16. 19/08/2007 KLE University, Belgaum, India16 General principal & format and contents A.IND information for different categories of botanicals B. Basic format for INDs 1. Cover sheet 2.Table of contents 3. Introductory statement and general investigational plan 4. Investigators Brochure 5. Protocol 6.Chemistry, Manufacturing and Controls 7. Pharmacology and Toxicological Information 8. Previous Human Experience with the Product

17. 19/08/2007 KLE University, Belgaum, India17 Initial clinical trial of a marketed botanical product with no known safety issues A. Description of Product and Documentation of Human Use 1. Description of Botanicals Used 2. Currently Marketed Use B. Chemistry, Manufacturing, and Controls 1. Botanical Raw Material 2. Botanical Drug Substance 3. Botanical Drug Product a. Quantitative description b. The composition or quantitative description manufacturer's certificate of analysis 4. Placebo 5. Labeling 6. Environmental Assessment or Claim of Categorical Exclusion

18. 19/08/2007 KLE University, Belgaum, India18 Initial clinical trial of a marketed botanical product with no known safety issues C. Pharmacology 1. All Marketed Botanical Products 2. Foreign- Marketed Botanical Products D. Bioavailability E. Clinical Considerations

19. 19/08/2007 KLE University, Belgaum, India19 Initial clinical trial of a nonmarketed botanical product or marketed botanical product with known safety issues A. Description of Product & Documentation of Human Use 1. Description of Botanicals Used 2. History of Use 3. Current Investigational Use B. Chemistry, Manufacturing, & Controls 1. Botanical Raw Material 2. Botanical Drug Substance a. A Quantitative b. The quantitative description (strength) c. Manufacturer (Processor) d. Manufacturing process e. Quality control tests

20. 19/08/2007 KLE University, Belgaum, India20 Initial clinical trial of a nonmarketed botanical product or marketed botanical product with known safety issues f. Container g. Container label 3. Botanical Drug Product a. Qualitative description b. Composition, or quantitative description c. Manufacturer d. Manufacturing process e. Quality control test f. Container/Closure g. Stability data on the drug product 4. Placebo 5. Labeling

21. 19/08/2007 KLE University, Belgaum, India21 Initial clinical trial of a nonmarketed botanical product or marketed botanical product with known safety issues 6. Environmental Assessment or Claim of Categorical Exclusion C. Preclinical Safety Assessment 1. Traditional Preparations 2. Others D. Bioavailability E. Clinical Considerations

22. 19/08/2007 KLE University, Belgaum, India22 Expanded clinical Trial of any botanical product A. Description of Product & Documentation of Human Experience B. Chemistry, Manufacturing, & Controls a. Botanical raw material b. Botanical drug substance - Qualitative identification - Chemical identification - Specifications - Manufacturing process - Quality control tests - Test methods - Reference standards - Containers & closure

23. 19/08/2007 KLE University, Belgaum, India23 Expanded clinical Trial of any botanical product - Stability data - Container label C. Botanical drug product - Qualitative description & the composition - Acceptance specifications - Manufacturing process - Quality control tests - Test methods - Containers & closure - Stability data d. Placebo e. Labeling f. Claim of categorical exclusion

24. 19/08/2007 KLE University, Belgaum, India24 Expanded clinical Trial of any botanical product 2. End-of-Phase 3 Clinical Studies & Pre-NDA Considerations a. Botanical raw materials b. Manufacturing process c. Batch-to-batch consistency d. Specifications e. Analytical methods & test procedures f. Reference standard g. Stability-indicating analytical h. Comparison of the similarities and/or differences in CMC among preclinical and clinical i. Manufacturing and testing facilities j. Claim for categorical exclusion

25. 19/08/2007 KLE University, Belgaum, India25 Expanded clinical Trial of any botanical product C. Preclinical Safety Assessment (including Pre-NDA) 1. Repeat-Dose General Toxicity Studies 2. Non-clinical Pharmacokinetic/Toxic-kinetic Studies 3. Reproductive Toxicology 4. Genotoxicity Studies 5. Carcinogenicity Studies 6. Special Pharmacology/Toxicology Studies 7. Regulatory Considerations D. Bio-availability & Drug-Drug Interactions E. Clinical Considerations

26. 19/08/2007 KLE University, Belgaum, India26 The New Drug Development Process

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28. 19/08/2007 KLE University, Belgaum, India28 Traditional IND

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34. 19/08/2007 KLE University, Belgaum, India34 Conclusions of Exploratory IND

35. 19/08/2007 KLE University, Belgaum, India35 Conclusions of Exploratory IND

36. 19/08/2007 KLE University, Belgaum, India36 NDA Process

37. 19/08/2007 KLE University, Belgaum, India37 Generic Drug (ANDA)Process

38. 19/08/2007 KLE University, Belgaum, India38 OTC Drug Monograph Process

39. 19/08/2007 KLE University, Belgaum, India39 e-mail: bknanjwade@yahoo.co.inbknanjwade@yahoo.co.in