Regulatory Guidelines For Preclinical And Clinical Validation of Traditional Medicines
-
Upload
dr-basavaraj-nanjwade -
Category
Health & Medicine
-
view
4.250 -
download
0
Transcript of Regulatory Guidelines For Preclinical And Clinical Validation of Traditional Medicines
19/08/2007 KLE University, Belgaum, India 1
REGULATORY GUIDELINES FOR PRECLINICAL AND CLINICAL VALIDATION OF TRADITIONAL MEDICINES
Dr. Basavaraj K. NanjawadeAssociate Professor of Pharmaceutics
Department of PharmacologyJN Medical College
Belgaum-10e-mail: [email protected]
BY
19/08/2007 KLE University, Belgaum, India 2
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”
19/08/2007 KLE University, Belgaum, India 3
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.
19/08/2007 KLE University, Belgaum, India 4
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.
19/08/2007 KLE University, Belgaum, India 5
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
19/08/2007 KLE University, Belgaum, India 6
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
19/08/2007 KLE University, Belgaum, India 7
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.
19/08/2007 KLE University, Belgaum, India 8
"Natural Products" platform
19/08/2007 KLE University, Belgaum, India 9
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.
19/08/2007 KLE University, Belgaum, India 10
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
19/08/2007 KLE University, Belgaum, India 11
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
19/08/2007 KLE University, Belgaum, India 12
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
19/08/2007 KLE University, Belgaum, India 13
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
19/08/2007 KLE University, Belgaum, India 14
Regulatory Approaches FOR MARKETING BOTANICAL DRUG PRODUCTS
19/08/2007 KLE University, Belgaum, India 15
INFORMATION TO BE PROVIDED IN AN IND FOR A BOTANICAL DRUG
INDfor a BotanicalDrug 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 botanicalproduct or marketed botanical product with
known safety issues (Slid No. 19)
Expanded clinical Trial of anybotanical 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 toxicologystudies may be needed (Slid 19)
Is the product atraditional
preparation?
Previous human experience may besufficient to support safety (Slid. No 19)
If the product is marketed onlyoutside the U.S. additional CMC
and nonclinical safety informationmay be needed (Slid. No. 17)
Additional nonclinical safetyinformation may be needed (Slid No. 19)
No
Yes
19/08/2007 KLE University, Belgaum, India 16
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
19/08/2007 KLE University, Belgaum, India 17
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 Used2. Currently Marketed UseB. Chemistry, Manufacturing, and Controls1. Botanical Raw Material2. Botanical Drug Substance3. Botanical Drug Product a. Quantitative description b. The composition or quantitative description manufacturer's certificate of analysis4. Placebo5. Labeling6. Environmental Assessment or Claim of Categorical Exclusion
19/08/2007 KLE University, Belgaum, India 18
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
19/08/2007 KLE University, Belgaum, India 19
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
19/08/2007 KLE University, Belgaum, India 20
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
19/08/2007 KLE University, Belgaum, India 21
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
19/08/2007 KLE University, Belgaum, India 22
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
19/08/2007 KLE University, Belgaum, India 23
Expanded clinical Trial of any botanical product
- Stability data- Container labelC. Botanical drug product- Qualitative description & the composition- Acceptance specifications- Manufacturing process- Quality control tests- Test methods- Containers & closure- Stability datad. Placeboe. Labelingf. Claim of categorical exclusion
19/08/2007 KLE University, Belgaum, India 24
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
19/08/2007 KLE University, Belgaum, India 25
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
19/08/2007 KLE University, Belgaum, India 26
The New Drug Development Process
19/08/2007 KLE University, Belgaum, India 27
19/08/2007 KLE University, Belgaum, India 28
Traditional IND
19/08/2007 KLE University, Belgaum, India 29
19/08/2007 KLE University, Belgaum, India 30
19/08/2007 KLE University, Belgaum, India 31
19/08/2007 KLE University, Belgaum, India 32
19/08/2007 KLE University, Belgaum, India 33
19/08/2007 KLE University, Belgaum, India 34
Conclusions of Exploratory IND
19/08/2007 KLE University, Belgaum, India 35
Conclusions of Exploratory IND
19/08/2007 KLE University, Belgaum, India 36
NDA Process
19/08/2007 KLE University, Belgaum, India 37
Generic Drug (ANDA)Process
19/08/2007 KLE University, Belgaum, India 38
OTC Drug Monograph Process
19/08/2007 KLE University, Belgaum, India 39
e-mail: [email protected]