Regulatory and industry requirements for botanical products, Prof. Dr. Basavaraj K. Nanjwade, KLE University College of Pharmacy, Belgavi/Belgaum, Karnataka, India.

1. Regulatory and Industry
Requirements for Botanical
Drug Products
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
Department of Pharmaceutics
KLE University College of Pharmacy
BELGAUM – 590010, Karnataka, India
Cell No: 00919742431000
E-mail: bknanjwade@yahoo.co.in
01/01/2011 1BIRDEM & ANRAP, Dhaka,
Bangladesh

2. Herbal Medicines
• Although modern medicine is well developed in most
of the world, large sections of the population in
developing countries still rely on the traditional
practitioners, medicinal plants and herbal medicines
for their primary care.
• Moreover during the past decades, public interest in
natural therapies has increased greatly in
industrialized countries, with expanding use of
medicinal plants and herbal medicines.
01/01/2011 2BIRDEM & ANRAP, Dhaka,
Bangladesh

3. Traditional Herbal Medicines and Human
Health
• Herbal medicines which formed the basis of health
care throughout the world since the earliest days of
mankind are still widely used, and have considerable
importance in international trade.
• Recognition of their clinical, pharmaceutical and
economic value is still growing, although this varies
widely between countries.
01/01/2011 3BIRDEM & ANRAP, Dhaka,
Bangladesh

4. • There are different ways in which countries define
medicinal plants or herbs or products derived from
them, and countries have adopted various approaches
to licensing, dispensing, manufacturing and trading to
ensure their safety, quality and efficacy
Traditional Herbal Medicines and Human
Health
01/01/2011 4BIRDEM & ANRAP, Dhaka,
Bangladesh

5. • Despite the use of herbal medicines over many
centuries, only a relatively small number of plant
species has been studied for possible medical
applications.
• Safety and efficacy data are available for an even
smaller number of plants, their extracts and active
ingredients and preparations containing them.
Traditional Herbal Medicines and Human
Health
01/01/2011 5BIRDEM & ANRAP, Dhaka,
Bangladesh

6. Regulation and Registration of Herbal
Medicines
• The legal situation regarding herbal preparations
varies from country to country.
• Developing countries, however, often have a great
number of traditionally used herbal medicines and
much folk-knowledge about them.
01/01/2011 6BIRDEM & ANRAP, Dhaka,
Bangladesh

7. GENERAL REGULATORY APPROACHES
• Many botanical products are used widely in the
United States. Depending on its labeling and intended
use, a botanical product can be a food, a dietary
supplement, and/or a drug.
01/01/2011 7BIRDEM & ANRAP, Dhaka,
Bangladesh

8. • Botanicals used for food and consumed primarily for
their taste, aroma, or nutritive value are regulated as
foods.
• Botanicals can also be dietary supplements if they are
labeled as dietary supplements and otherwise meet
the dietary supplement definition.
GENERAL REGULATORY APPROACHES
01/01/2011 8BIRDEM & ANRAP, Dhaka,
Bangladesh

9. GENERAL REGULATORY APPROACHES
• If a botanical product is intended to affect the
structure or function of the body but does not meet
the definition of a dietary supplement, or does not
meet the requirements for making a
structure/function.
01/01/2011 9BIRDEM & ANRAP, Dhaka,
Bangladesh

10. GENERAL REGULATORY APPROACHES
• As noted above, a botanical product is subject to
regulation as a drug under section 201(g)(1)(B) of the
Act if it is intended for use in diagnosing, mitigating,
treating, curing, or preventing disease.
01/01/2011 10BIRDEM & ANRAP, Dhaka,
Bangladesh

11. GENERAL REGULATORY APPROACHES
• Under section 505(b) of the Act, a drug must be
marketed under an approved NDA unless the
product is excluded from the definition of a new
drug.
• Certain products that FDA determines are
generally recognized as safe and effective in
accordance.
01/01/2011 11BIRDEM & ANRAP, Dhaka,
Bangladesh

12. Marketing Under OTC Drug Monograph
Versus Approved NDA
• A botanical drug product may be marketed in the
United States under (1) an OTC drug
monograph or (2) an approved NDA or ANDA.
• A botanical product that has been marketed in
the United States for a material time and to a
material extent for a specific OTC drug indication
may be eligible for inclusion in an OTC drug
monograph.
01/01/2011 12BIRDEM & ANRAP, Dhaka,
Bangladesh

13. • When a final OTC drug monograph is published for a
specific use of a botanical drug, any person may
market a product containing the same substance and
for the same use, provided the labeling and other
active ingredients (if present) are in accord with all
relevant monographs and other applicable
regulations.
Marketing Under OTC Drug Monograph
Versus Approved NDA
01/01/2011 13BIRDEM & ANRAP, Dhaka,
Bangladesh

14. • In contrast, when a product is approved under an
NDA, the approval is specific to the drug product that
is the subject of the application.
• Mrketing exclusivity for either 5 years (if it is a new
chemical entity) or 3 years from the time of approval,
even in the absence of patent protection.
Marketing Under OTC Drug Monograph
Versus Approved NDA
01/01/2011 14BIRDEM & ANRAP, Dhaka,
Bangladesh

15. CMC Information for Botanical Drug
Products
• Because of the complex nature of a typical botanical
drug and the lack of knowledge of its active
constituent's.
• FDA may rely on a combination of tests and controls
to ensure the
- identity, purity, quality, strength, potency, and
consistency of botanical drugs.
01/01/2011 15BIRDEM & ANRAP, Dhaka,
Bangladesh

16. CMC Information for Botanical Drug
Products
• These tests and controls include
1) Multiple tests for drug substance and drug product
(e.g., spectroscopic and/or chromatographic
fingerprints, chemical assay of characteristic markers,
and biological assay),
2) Raw material and process controls (e.g., strict
quality controls for the botanical raw materials and
adequate in-process controls), and
3) Process validation (especially for the drug
substance).
01/01/2011 16BIRDEM & ANRAP, Dhaka,
Bangladesh

17. CMC and Toxicology Information to Support
Initial Studies
• Many botanical products are legally available in
the United States as dietary supplements.
• Given the wide availability of such products
outside of clinical trials, it is important to assess
the effectiveness of such products.
01/01/2011 17BIRDEM & ANRAP, Dhaka,
Bangladesh

18. • To support initial clinical trials, the nonclinical
pharmacology and toxicology information that
must be provided for legally available botanical
products with no known safety issues.
• In most cases, additional toxicology and CMC
data will not be required for such initial trials.
CMC and Toxicology Information to Support
Initial Studies
01/01/2011 18BIRDEM & ANRAP, Dhaka,
Bangladesh

19. Applicability of Combination Drug
Regulations
• Botanical drug products that are derived from a single
part of a plant (e.g., leaves, stems, roots, or seeds), or
from a single species of alga or macroscopic fungus
(e.g., a mushroom), are not considered to be fixed-
combination drugs.
01/01/2011 19BIRDEM & ANRAP, Dhaka,
Bangladesh

20. • Consequently, they do not have to meet the
requirements for combination drugs,
principally the need to demonstrate that each
component or active ingredient makes a
contribution to claimed effects.
Applicability of Combination Drug
Regulations
01/01/2011 20BIRDEM & ANRAP, Dhaka,
Bangladesh

21. MARKETING A BOTANICAL DRUG
UNDER AN OTC DRUG MONOGRAPH
• A botanical product that has been marketed in the
United States for a material time and to a material
extent for a specific OTC indication may be eligible
for consideration in the OTC drug monograph
system.
• Currently, there are several botanical drugs, including
cascara, psyllium, and senna, that are included in the
OTC drug review.
01/01/2011 21BIRDEM & ANRAP, Dhaka,
Bangladesh

22. • For a botanical drug substance to be included in an
OTC drug monograph, there must be published data
establishing general recognition of safety and
effectiveness, usually including results of adequate
and well-controlled clinical studies.
• Requirements related to safety, effectiveness, and
labeling for drugs to be included in an OTC drug
monograph.
MARKETING A BOTANICAL DRUG
UNDER AN OTC DRUG MONOGRAPH
01/01/2011 22BIRDEM & ANRAP, Dhaka,
Bangladesh

23. MARKETING A BOTANICAL DRUG
UNDER AN NDA
• A botanical drug product that is not generally
recognized as safe and effective for its therapeutic
claims is considered a new drug.
01/01/2011 23BIRDEM & ANRAP, Dhaka,
Bangladesh

24. • NDA must contain substantial evidence of
effectiveness derived from adequate and well-
controlled clinical studies, evidence of safety, and
adequate CMC information.
• The format of an NDA submission and the
requirements for its various sections are discussed in
several CDER guidance documents.
MARKETING A BOTANICAL DRUG
UNDER AN NDA
01/01/2011 24BIRDEM & ANRAP, Dhaka,
Bangladesh

25. INDs FOR BOTANICAL DRUGS
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. Investigator’s Brochure
5. Protocols
6. Chemistry, Manufacturing and Controls (CMC)
7. Pharmacology and Toxicology Information
8. Previous Human Experience With the Product
01/01/2011 25BIRDEM & ANRAP, Dhaka,
Bangladesh

26. INDs FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES
OF LAWFULLY MARKETED BOTANICAL PRODUCTS
WITHOUT SAFETY CONCERNS
A. Description of Product and Documentation of Human
Use
1. Description of Botanical Used
2. History of Use
3. Current Marketed Use
B. Chemistry, Manufacturing and Controls
1. Botanical Raw Material
2. Botanical Drug Substance
3. Botanical Drug Product
4. Animal Safety
5. Placebo
6. Labeling
7. Environmental Assessment or Claim of Categorical Exclusion
01/01/2011 26BIRDEM & ANRAP, Dhaka,
Bangladesh

27. C. Pharmacology/Toxicology Information
1. All Marketed Botanical Products
2. Foreign-Marketed Botanical Products
D. Bioavailability
E. Clinical Considerations
INDs FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES
OF LAWFULLY MARKETED BOTANICAL PRODUCTS
WITHOUT SAFETY CONCERNS
01/01/2011 27BIRDEM & ANRAP, Dhaka,
Bangladesh

28. INDs FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES
FOR NONMARKETED BOTANICAL PRODUCTS AND
PRODUCTS WITH KNOWN SAFETY CONCERNS
A. Description of Product and Documentation of
Human Use
1. Description of Botanical Used
2. History of Use
3. Current Investigational Use
B. Chemistry, Manufacturing and Control
1. Botanical Raw Material
2. Botanical Drug Substance
3. Botanical Drug Product
4. Placebo
5. Labeling
6. Environmental Assessment or Claim of Categorical Exclusion
01/01/2011 28BIRDEM & ANRAP, Dhaka,
Bangladesh

29. C. Nonclinical safety Assessment
1. Traditional Preparations
2. Others
3. Products with Known Safety Issues
D. Bioavailability
E. Clinical Considerations
INDS FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES
FOR NONMARKETED BOTANICAL PRODUCTS AND
PRODUCTS WITH KNOWN SAFETY CONCERNS
01/01/2011 29BIRDEM & ANRAP, Dhaka,
Bangladesh

30. INDs FOR PHASE 3 CLINICAL STUDIES
OF ALL BOTANICAL PRODUCTS
A. Description of Product and Documentation of
Human Experience
B. Chemistry, Manufacturing and Control
1. Expanded Clinical Studies
a. Botanical raw material
b. Botanical drug substance
c. Botanical drug product
2. End-of-Phase 3 Clinical Studies and Pre-NDA Considerations
01/01/2011 30BIRDEM & ANRAP, Dhaka,
Bangladesh

31. C. Nonclinical Safety Assessment
1. Repeat-Dose General Toxicity Studies
2. Nonclinical Pharmacokinetic/Toxicokinetic Studies
3. Reproductive Toxicology
4. Genotoxicity Studies
5. Carcinogenicity Studies
6. Special Pharmacology/Toxicology Studies
7. Regulatory Considerations
D. Bioavailability and Clinical Pharmacology
E. Clinical Considerations
INDs FOR PHASE 3 CLINICAL STUDIES
OF ALL BOTANICAL PRODUCTS
01/01/2011 31BIRDEM & ANRAP, Dhaka,
Bangladesh

32. 01/01/2011 32BIRDEM & ANRAP, Dhaka,
Bangladesh

33. 01/01/2011 33BIRDEM & ANRAP, Dhaka,
Bangladesh

34. 01/01/2011 34BIRDEM & ANRAP, Dhaka,
Bangladesh

35. 01/01/2011 35BIRDEM & ANRAP, Dhaka,
Bangladesh

36. OTC Drug Monograph Review Process
01/01/2011 36BIRDEM & ANRAP, Dhaka,
Bangladesh

37. Cell No: 00919742431000
E-mail: bknanjwade@yahoo.co.in
01/01/2011 37BIRDEM & ANRAP, Dhaka,
Bangladesh