International Conclave on Traditional Medicine, Delhi (16-17 th November 2006) Development Of Traditional Drugs For Global Positioning With Major Emphasis.

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