international conclave on traditional medicine, delhi (16-17 th november 2006) development of...
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International Conclave on
Traditional Medicine, Delhi(16-17th November 2006)
Development Of Traditional Drugs For Global Positioning
With Major Emphasis On Efficacy And Safety
C K KatiyarDirector – Herbal Drug ResearchRanbaxy Research Laboratories
Plot 20, Sector 18, Gurgaon, Haryana (INDIA)
Introduction
Why Global Strategy
Results of Global Survey of Regulatory Status
Global Vs Regional Strategy
Proposals
FLOW OF PRESENTATION
CAM 1999 (%)
Use of any CAM in past 12 months 20
Of which: *
Herbal medicine 34
Aromatherapy 21
Homeopathy 17
Acupuncture / acupressure 14
Massage 6
Reflexology 6
Osteopathy 4
Chiropractic 3*: Percentages of those who had used CAM. It must be noted that some individuals use more than oneTherapy and thus the numbers above do not add up to 100.
USE OF CAM IN THE UNITED KINGDOM
Ernst, E. & White, A. 'The BBC Survey of Complementary Medicine Use in the UK' in Complementary Therapies in Medicine, 8 (2000), 32-36.
USE OF CAM IN THE USA
Eisenberg, D.M., Davis, R.B., Ettner, S.L. et al. 'Trends in Alternative Medicine Use in the United States, 1990-1997: Results of a Follow-up National Survey' in The Journal of the American Medical Association, 280 (1998) 1569-1575.
CAM 1990 (%) 1997 (%)
Use of any CAM in past 12 months 33.8† 42.1†
of which‡
Relaxation techniques 13.1 16.3
Herbal medicine 2.5 12.1
Massage 6.9 11.1
Chiropractic 10.1 11.0
Spiritual healing 4.2 7.0
Homeopathy 0.7 3.4
Acupuncture 0.4 1.0†: Percentages of the total sample population (1539 for the 1990 data; 2055 in 1997)‡: Table shows selected figures relating to the top five therapies based on the 1997 survey
Own Fundamental Principles
Own Unique Ingredients
Own Composition
Own Process of Manufacturing
EACH TM/CAM HAS
GLOBAL HERBAL MARKET INCL NUTRACEUTICALS
$ 70.4 BILLION
EXCLUSIVE GLOBAL HERBAL MARKET
$ 24.2 BILLION
GLOBAL SCENARIO
05
10152025
US
$
Bil
lio
n
Year1994
Year1997
Year1999
Year2002
Global Sales of Herbal Medicine
0%10%20%30%40%50%60%70%
% Population using CAM in some Industrialized Countries
49%
31%
70%
10%
33%
49%42%
12.414.0
24.18
19.58
The World Bank estimate world trade in medicinal plants and related products $ 5 trillion by 2050 A.D.
Global Herbal market including Nutraceuticals $ 70.4 Billion with an average growth rate of about 12% a year. However, exclusive herbal drug market is estimated to be around $ 25 Billion.
Worldwide phytopharmaceuticals market is growing @ 12%.
GLOBAL SCENARIO
WHITHER GLOBAL STRATEGY?
INCREASING POPULARITYALSO INVITES
CRITICISM
ARE WE PREPARED TO FACE IT ?
TRADITIONAL SYSTEMS OF MEDICINE
REMEDY OR FALACY
PANACEA OR POISON
THE DEBATE STILL GOES ON……….
2 0 0 0
Obach RS. J Pharmacol Exp Ther. Jul;294(1):88-95
CONCLUSIONS: In vitro data indicate that St. John's Wort preparations contain constituents that can potently inhibit the activities of major human drug-metabolizing enzymes.
Impact on Business: Not MuchConsumer Comments: Don’t give credence to researches conducted by Scientists who don’t know the subject
CONCLUSIONS: Echinacea purpurea, as dosed in this study, was not effective in treating URI symptoms in patients 2 to 11 years old, and its use was associated with an increased risk of rash.
2 0 0 3
Taylor et al. JAMA. Dec 3;290(21):2824-30
CONCLUSIONS: Guggulipid did not improve levels of serum cholesterol over the short term, and might in fact raise levels of LDL-C.
2 0 0 3
Szapary et al. JAMA. Aug 13;290(6):765-72
Rejoinders from India regarding Clinical Trial material remains unanswered
2 0 0 4
Saper et al. JAMA. Dec 15;292(23):2868-73
CONCLUSIONS: 17 out of 70 Ayurvedic/Unani medicines contained heavy metals, therefore, not safe to be consumed.
Does mere presence of a heavy metal in trace amounts in a plant source of soil/other origin make it toxic?
Saper et al. 2004. JAMA. Dec 15;292(23):2868-73
17 out of 70 Ayurvedic/Unani medicines contained heavy metals, therefore, not safe to be consumed.
July 20, 2 0 0 5
Health Canada & MHRA of UK bans Indian Ayurvedic drugs based on controversial JAMA report
October 26, 2 0 0 5
Central Government of India makes heavy metal testing mandatory for Ayurvedic drugs to be exported effective Jan I, 2006
November 17, 2 0 0 5
MHRA of UK recovered further Chinese/Ayurvedic productscontaining heavy metals
WHO - GLOBAL SURVEY(141 countries)
Traditional Medicine/Complementary and Alternative Medicine products are used under the categories which include
Prescription products OTC products Self medication Dietary supplements Health foods Functional foods & Others
World Health Organization (2005), National Policy on Traditional Medicine and Regulation of Herbal Medicines. Report of a WHO global survey. WHO, Geneva.
WHO - GLOBAL SURVEY
Traditional medicine/Complementary & Alternative medicine
Survey Attributes Present Absent
National policy in place 45 (32%) 90 (64%)
National laws framed 54 (38%) 84 (60%)
National program exists 40 (28%) 93 (66%)
National office exists 75 (53%) 61 (43%)
Expert committees constituted
61 (43%) 75 (51%)
National research institutes exist
38 (27%) Traditional medicines46 (33%) Herbal medicines
9 (6%) CAM
A. P O L I C I E S
WHO - GLOBAL SURVEY
Traditional medicine/Complementary & Alternative medicine
B. L A W S & R E G U L A T I O N S
Survey Attributes Present Absent
1. Laws/regulations framed 92 (65%) 48 (34%)
a. Partly same as conventional pharmaceuticals
41
b. Separate laws for herbals 22
c. Same as Pharma 47
2. Registration system exists 85 (61%) 54 (38%)
3. Post Marketing Surveillance conducted
59 (42%) 77 (54%)
WHO - GLOBAL SURVEY
Traditional medicine/Complementary & Alternative medicine
C. S T A T U S O F P H A R M A C O P O E I A
Survey Attributes Yes No
National Pharmacopoeia prepared
34 (24%) 104 (74%)
Other Pharmacopoeia used 58 (56%)
No pharmacopoeia used 31 (30%)
WHO - GLOBAL SURVEY
Traditional medicine/Complementary & Alternative medicine
D. L E G A L S T A T U S
Survey Attributes Yes No
National pharmacopoeia legally binding
29 (85%) 4 (12%)
National monograph on herbal medicine prepared
46 (33%) 90 (63%)
Other monographs in use 34 (38%)
No monographs used 39 (43%)
Monographs legally binding 24 (52% of 46) 17 (37%)
WHO - GLOBAL SURVEY
Traditional medicine/Complementary & Alternative medicine
E. N A T U R E O F C L A I M S A L L O W E D
Status of claim No. of countries
Medical claims 90
Health claims 62
Nutrient content claims 49
Structure function claims 39
Other claims 6
A REGIONAL STRATEGY
Rather than
GLOBALLY HARMONIZED STRATEGY
So Much Diversity Justifies
Guiding Factors for REGIONAL STRATEGY
History of Use of Traditional Medicines
Regulatory Requirements
Geographical Considerations
Socio-Economic Conditions
Level of commitment of respective Governments
and their policies for Traditional Medicines
Prevalence of sound system of Traditional Medicines
Development of Traditional Medicines
Zoopharmacognosy Tribal Practices Observation
Animal use
Human use
Tribal &
Ethnobotanical practices Herbal practices
Knowledge based Philosophical background
Well developed Systems
Viz. TCM & Ayurveda
DocumentationStrong fundamental
principles
QUALITY, SAFETY, EFFICACY, AFFORDABILITY
Classification of Geographical Regions basis Traditional Medicine usage
A. Countries with no official recognition to Traditional
medicines & no regulatory mechanism viz. Africa
Focus on Authentication and adulteration
B. Countries with strong traditional systems of
medicine viz. India, China
Focus on Standardization
C. Countries with no traditional systems but strong
herbal practices viz. Europe & USA
Focus on Efficacy evaluation
Safety Aspects of Traditional Medicine
WHO Survey in 130 countries on Regulatory Requirements
Regulatory requirement No. of countries
Special requirement
- Traditional use without harmful effects
- Ref to documented scientific research on similar products
- Others (Bibliographic data etc.)
82
66
53
21
Same as Pharmaceuticals 57
No requirement 28
Regulatory Requirements vary from country to country
World Health Organization (2005), National Policy on Traditional Medicine and Regulation of Herbal Medicines. Report of a WHO global survey. WHO, Geneva.
Indian Council of Medical Research guidelines for safety on products of
Indian System of Medicine
“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. 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”.
Indian Council of Medical Research (2000). Ethical Guidelines for Biomedical Research on Human subjects, ICMR, New Delhi.
DRAFT Indian guidelines of Safety on Non-Ayurvedic Herbal Medicines
Classification Definition
Class 1 Unprocessed powdered parts of plant
Class 1A Those not containing poisonous plants
Class 1 B Those containing poisonous plants
Class II Processed parts of plant
Class III Processed or unprocessed parts together with metallic and/or mineral substances and/or products
Govt. of India, Circular No. 4-5/93 (1993). Issued by Drugs Controller India, Directorate of Health Services, Ministry of Health & Family Welfare, New Delhi.
Class Sub Class
Formulation in market
Toxicity requirements
Class I A > 5 year< 5 year
Acute toxicityNo comment on toxicity
B > 5 year< 5 year
Chronic toxicityChronic toxicity
A New drug Sub-acute
B New Drug Chronic
Class II - > 5 year< 5 year
No comment on toxicitySub-chronic toxicity
New drug Sub-chronic
Class III - In market Full toxicological profile according to Schedule ‘Y’
DRAFT Indian guidelines of Safety on Non-Ayurvedic Herbal Medicines
Govt. of India, Circular No. 4-5/93 (1993). Issued by Drugs Controller India, Directorate of Health Services, Ministry of Health & Family Welfare, New Delhi.
Efficacy Aspects of Traditional MedicineWHO recommends the following:
A. Evaluate traditional medicine in its own theoretical
framework
B. Evaluate traditional medicine in the theoretical framework
of conventional medicine
C. Compare the efficacy of traditional medicine with
conventional medicine
D. Compare the efficacy of traditional medicine within the
system of traditional medicine
World Health Organization (2000). Annexure IV. General guidelines for methodologies on research and evaluation of traditional medicine, WHO, Geneva.
WHO-Levels of evidence for Efficacy studies
Grade/Level RecommendationA:Ia. Evidence obtained from meta-analysis of randomized controlled trailsIb. Evidence obtained from at least one randomized controlled trial
Requires at least one randomized controlled trial as part of the body of literature of overall good and consistency addressing the specific recommendation.
B.IIa. Evidence obtained from at least one well designed controlled study without randomizationIIb. Evidence obtained from at least one other type of well-designed quasi-experimental studyIII. Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case control studies
Requires availability of well-conducted clinical studies but no randomized clinical trials on the topic of recommendation.
C.IV. Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates absence of directly applicable studies of good quality.
European Union Aspect
Herbal Medicinal Products in the European Union. Study carried out on behalf of the European Union by The Association of the European Self-Medication Industry. Brussels – Belgium.
Country Simplified Proof
Bibliographic Proof
Full Clinical Proof
Austria Yes Only supportive Yes
Belgium Yes (Yes) Yes
Denmark No Yes No
Finland No Yes No
France Yes (Yes) Yes
Germany Yes Yes Yes
Greece No Yes Yes
Ireland No (Yes) Yes
Italy No Yes Yes
Luxembourg No (Yes) (Yes)
Netherland No (Yes) Yes
Portugal No (Yes) Yes
Spain Yes Yes Yes
Sweden No Yes Yes
United Kingdom No Yes Yes
Comparison of the requirements for proof of efficacy
Proposals for Regional Positioning of Traditional Medicines - SAFETY
Since the traditional medicines may contain ingredients of mineral/metal/and or
animal origin in addition to herbal ingredients, the requirement of toxicity
should depend on the composition besides the usage of the product.
Class of drug Acute Tox
28 day Tox
90 day Tox
AMES test
1A. Traditional Herbal Medicine (same composition, formulation & use as in text or traditionally used)*
- - - -
1B. Traditional Herbal Medicine (modified composition, formulation & use)
-
2. Herbo-mineral medicine -
3. Herbo metallic medicine -
4. Herbal Medicine containing known toxic herbs
-
* However, if reports are available suggesting toxicity or if the product is to be used for more than 3 months then 4-6 weeks toxicity studies should be conducted in 2 species.
Proposals for Regional Positioning of Traditional Medicines - EFFICACY
Adopt a flexible approach to review the data with respect to
efficacy.
Randomized double blind placebo controlled studies may not
be always suitable to evaluate the efficacy of Traditional
Medicine products.
Proposed Parameters for assessing Efficacyof Traditional Medicine
1. Traditional/Historical Usage
2. Published/Bibliographical references (incl textbook refs)
3. Uses mentioned in Pharmacopoeia & Monographs e.g. Ayurvedic Pharmacopoeia of India, WHO Monographs, German Commission E Monographs, British Herbal Pharmacopoeia, PDR for Herbals etc.
4. Pharmacological Evidences using appropriate model a). In vitro b). In vivo
5. Clinical Experience/Usage/Trial a). Single case design b). Ethnographic studies c). Consumer Usage Test d). Pragmatic trial design e). Observation Research f). Randomized double-blind placebo controlled design g). Post Marketing Surveillance
Category Ingredients IndicationClinical Trial PMS
I. Classical medicines As per text As per text NA
II. Proprietary medicines
A. With ingredients mentioned in the ASU books & products for same indication already in the market for more than 5 years
As per text As per Mktd products
NA
B. With ingredients mentioned in the ASU books & products for same indication in the market for less than 5 years
As per text As per Mktd products
Claim Support Data to be provided
C. With ingredients mentioned in the ASU books but to be used for new indication
As per text Any (CT using suitable design)
III. Plant based medicines prepared from ingredients not mentioned in traditional medicine books
A. Presence in the International Market for more than 5 years
- Any Bibliography data
B. Presence in the International market for les than 5 years
- Any (Bibliography data & CT on Indian
population)
C. New Products (products not yet marketed)
- Any (CT on Indian population)
Reproduced below is a model which was proposed to Govt. of India to regulate Ayurveda, Siddha and Unani (ASU) drug licensing.
This may be modified for assessing the Efficacy of Traditional Medicines
to evolve a Regional Strategy
TM Product
Documentation Ingredients Mfg process Claims Efficacy requirement
Traditional + Traditional Traditional Traditional NIL
Traditional + Traditional Modified Traditional Experimental studies
New - Traditional New Any Experimental studies or
Human Efficacy studies
New - New New Any Experimental studies and
Human efficacy studies
S U M M A R Y
The popularity of Traditional Medicines is on a Northward movement
Due to non-uniformity in their status in various countries, Regional
harmonization strategies are more appropriate than developing Global
strategies
Stepwise flexible approach should be adopted for considering quality,
regulatory, safety and efficacy requirements considering multiple factors
Traditional/Historical use and Bibliographical referencing should be
given due importance but should not be allowed to be used as a shield
ACKNOWLEDGEMENT
Dr Navin SharmaSr Res Scientist
Herbal Drug ResearchRanbaxy Research Labs
Gurgaon
THANKS