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REGULATORY GUIDELINES FOR PRECLINICAL AND CLINICAL VALIDATION OF TRADITIONAL MEDICINES

Dr. Basavaraj K. NanjwadeAssociate Professor of Pharmaceutics

Department of PharmacologyJN Medical College

Belgaum-10e-mail: bknanjwade@yahoo.co.in

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

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

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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

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

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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

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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

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

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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

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

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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

1. Traditional Preparations

2. 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

a. Botanical raw material

b. 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 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

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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

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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

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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: bknanjwade@yahoo.co.in