Transcript Slide 1

Development Of Traditional Drugs
For Global Positioning
With Major Emphasis On Efficacy And Safety
International Conclave
on
Traditional Medicine, Delhi
(16-17th November 2006)
C K Katiyar
Director – Herbal Drug Research
Ranbaxy Research Laboratories
Plot 20, Sector 18, Gurgaon, Haryana (INDIA)
FLOW OF PRESENTATION
 Introduction
 Why Global Strategy
 Results of Global Survey of Regulatory Status
 Global Vs Regional Strategy
 Proposals
USE OF CAM IN THE UNITED KINGDOM
CAM
Use of any CAM in past 12 months
1999 (%)
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 one
Therapy and thus the numbers above do not add up to 100.
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
CAM
1990 (%)
1997 (%)
33.8†
42.1†
13.1
16.3
Herbal medicine
2.5
12.1
Massage
6.9
11.1
10.1
11.0
Spiritual healing
4.2
7.0
Homeopathy
0.7
3.4
Acupuncture
0.4
1.0
Use of any CAM in past 12 months
of which‡
Relaxation techniques
Chiropractic
†: 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
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.
EACH TM/CAM HAS
 Own Fundamental Principles
 Own Unique Ingredients
 Own Composition
 Own Process of Manufacturing
GLOBAL SCENARIO
GLOBAL HERBAL MARKET
INCL NUTRACEUTICALS
$ 70.4 BILLION
EXCLUSIVE
GLOBAL HERBAL MARKET
$ 24.2 BILLION
Global Sales of Herbal Medicine
US $
Billion
24.18
25
20
15
10
5
0
19.58
12.4
70%
49%
14.0
49%
33%
31%
10%
Year
1994
Year
1997
Year
1999
Year
2002
42%
GLOBAL SCENARIO
 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 HERBAL DRUG MARKET ($ 70.4 Billion)
North America
$ 7.8 Billion
Others
$ 4.6 billion
EU
$32 Billion
Japan
$ 11.1 Billion
Asia
$ 12.2 Billion
Rest of Europe
$ 2.7Billion
WHITHER GLOBAL STRATEGY?
INCREASING POPULARITY
ALSO INVITES
CRITICISM
ARE WE PREPARED TO FACE IT
?
TRADITIONAL SYSTEMS OF MEDICINE
REMEDY OR FALACY
PANACEA OR POISON
THE DEBATE STILL GOES ON……….
2000
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 Much
Consumer Comments: Don’t
give
credence
to
researches conducted by Scientists who don’t know the
subject
2003
Taylor et al. JAMA. Dec 3;290(21):2824-30
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.
2003
Szapary et al. JAMA. Aug 13;290(6):765-72
CONCLUSIONS: Guggulipid did not improve levels of
serum cholesterol over the short term, and might in fact
raise levels of LDL-C.
Rejoinders from India regarding Clinical Trial
material remains unanswered
2004
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 products
containing 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
A. P O L I C I E S
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 medicines
46 (33%) Herbal medicines
9 (6%) CAM
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
conducted
59 (42%)
77 (54%)
Surveillance
WHO - GLOBAL SURVEY
Traditional medicine/Complementary & Alternative medicine
C. S T A T U S
OF
Survey Attributes
PHARMACOPOEIA
Yes
No
Pharmacopoeia
34 (24%)
104 (74%)
Other Pharmacopoeia used
58 (56%)
No pharmacopoeia used
31 (30%)
National
prepared
WHO - GLOBAL SURVEY
Traditional medicine/Complementary & Alternative medicine
D. L E G A L
Survey Attributes
STATUS
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
OF
Status of claim
CLAIMS
ALLOWED
No. of countries
Medical claims
90
Health claims
62
Nutrient content claims
49
Structure function claims
39
Other claims
6
So Much Diversity Justifies
A REGIONAL STRATEGY
Rather than
GLOBALLY HARMONIZED STRATEGY
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
Animal use
Human use
Tribal Practices
Tribal
&
Ethnobotanical
practices
Observation
Knowledge based
Philosophical
background
Strong fundamental
principles
Documentation
Herbal practices
Well developed
Systems
Viz.
TCM & Ayurveda
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
82
- Traditional use without harmful effects
66
- Ref to documented scientific research
on similar products
53
- Others (Bibliographic data etc.)
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.
DRAFT Indian guidelines of Safety
on Non-Ayurvedic Herbal Medicines
Class
Class I
Class II
Class III
Sub Formulation Toxicity requirements
Class
in market
A
> 5 year
< 5 year
Acute toxicity
No comment on toxicity
B
> 5 year
< 5 year
Chronic toxicity
Chronic toxicity
A
New drug
Sub-acute
B
New Drug
Chronic
-
> 5 year
< 5 year
No comment on toxicity
Sub-chronic toxicity
New drug
Sub-chronic
In market
Full
toxicological
profile
according to Schedule ‘Y’
-
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 Medicine
WHO 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
Recommendation
A:
Ia. Evidence obtained from meta-analysis
of randomized controlled trails
Ib. 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
randomization
IIb. Evidence obtained from at least one
other
type
of
well-designed
quasiexperimental study
III. Evidence obtained from well-designed
non-experimental descriptive studies, such
as comparative studies, correlation studies
and case control studies
C.
IV.
Evidence
obtained
from
expert
committee reports or opinions and/or
clinical experience of respected authorities
Requires
availability
of
well-conducted
clinical studies but no randomized clinical
trials on the topic of recommendation.
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
Comparison of the requirements for proof of efficacy
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
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.
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 Efficacy
of 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
Reproduced below is a model which was proposed to Govt. of India to
regulate Ayurveda, Siddha and Unani (ASU) drug licensing.
Category
Ingredients
Indication
Clinical Trial
PMS
As per text
As per text
NA

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)

I. Classical medicines
II. Proprietary medicines
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)

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 Sharma
Sr Res Scientist
Herbal Drug Research
Ranbaxy Research Labs
Gurgaon
THANKS