Regulatory Guidelines For Preclinical And Clinical Validation of Traditional Medicines

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REGULATORY GUIDELINES FOR PRECLINICAL AND CLINICAL
VALIDATION OF TRADITIONAL MEDICINES
Dr. Basavaraj K. Nanjawade
Associate Professor of Pharmaceutics
Department of Pharmacology
JN Medical College
Belgaum-10
e-mail: [email protected]
BY

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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”

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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.

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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.

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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

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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

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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.

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"Natural Products" platform

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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.

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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

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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

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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

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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

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Regulatory Approaches FOR MARKETING BOTANICAL DRUG PRODUCTS

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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

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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

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Initial clinical trial of a marketed botanical product
with no known safety issues
A. Description of Product and Documentation of Human Use
2.Description of Botanicals Used
3.Currently Marketed Use
B. Chemistry, Manufacturing, and Controls
5.Botanical Raw Material
6.Botanical Drug Substance
7.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

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Initial clinical trial of a marketed botanical
product with no known safety issues
C. Pharmacology
2.All Marketed Botanical Products
3.Foreign- Marketed Botanical Products
D. Bioavailability
E. Clinical Considerations

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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
6.Botanical Raw Material
7.Botanical Drug Substance
h.A Quantitative
i.The quantitative description (strength)
j.Manufacturer (Processor)
k.Manufacturing process
l.Quality control tests

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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
d.Qualitative description
e.Composition, or quantitative description
f.Manufacturer
g.Manufacturing process
h.Quality control test
i.Container/Closure
j.Stability data on the drug product
4. Placebo
5. Labeling

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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
3.Traditional Preparations
4.Others
D. Bioavailability
E. Clinical Considerations

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Expanded clinical Trial of any botanical product
A.Description of Product & Documentation of Human Experience
B.Chemistry, Manufacturing, & Controls
c.Botanical raw material
d.Botanical drug substance
-Qualitative identification
-Chemical identification
-Specifications
-Manufacturing process
-Quality control tests
-Test methods
-Reference standards
-Containers & closure

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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

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

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

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The New Drug Development Process

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Traditional IND

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Conclusions of Exploratory IND

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Conclusions of Exploratory IND

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NDA Process

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Generic Drug (ANDA)Process

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OTC Drug Monograph Process

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e-mail: [email protected]