**Guidance for Industry**

**Botanical Drug Products**

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**June 2004**

**Chemistry**

**Guidance for Industry**

**Botanical Drug Products**

*Copies of this Guidance are available from:*

*Division of Drug Information (HFD-240),*

*Office of Training and Communications,*

*Center for Drug Evaluation and Research (CDER),*

*Food and Drug Administration*

*5600 Fishers Lane, Rockville, MD 20857, (Tel) 301-827-4573*

*Internet at* <http://www.fda.gov/cder/guidance/index.htm>

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**June 2004**

**Chemistry**

**TABLE OF CONTENTS**

# I. INTRODUCTION [1](#i.-introduction) {#i.-introduction-1 .TOC-1}

# II. BACKGROUND [2](#ii.-background) {#ii.-background-2 .TOC-1}

# III. GENERAL REGULATORY APPROACHES [3](#iii.-general-regulatory-approaches) {#iii.-general-regulatory-approaches-3 .TOC-1}

## A. Marketing Under OTC Drug Monograph Versus Approved NDA [4](#a.-marketing-under-otc-drug-monograph-versus-approved-nda) {#a.-marketing-under-otc-drug-monograph-versus-approved-nda-4 .TOC-2}

## B. CMC Information for Botanical Drug Products [5](#b.-cmc-information-for-botanical-drug-products) {#b.-cmc-information-for-botanical-drug-products-5 .TOC-2}

## C. CMC and Toxicology Information to Support Initial Studies [5](#c.-cmc-and-toxicology-information-to-su-pport-initial-studies) {#c.-cmc-and-toxicology-information-to-support-initial-studies-5 .TOC-2}

## D. Applicability of Combination Drug Regulations [6](#d.-applicability-of-combination-drug-regulations) {#d.-applicability-of-combination-drug-regulations-6 .TOC-2}

# IV. MARKETING A BOTANICAL DRUG UNDER AN OTC DRUG MONOGRAPH [6](#iv.-marketing-a-botanical-drug-under-an-otc-drug-monograph) {#iv.-marketing-a-botanical-drug-under-an-otc-drug-monograph-6 .TOC-1}

# V. MARKETING A BOTANICAL DRUG UNDER AN NDA [7](#v.-marketing-a-botanical-drug-under-an-nda) {#v.-marketing-a-botanical-drug-under-an-nda-7 .TOC-1}

# VI. INDs FOR BOTANICAL DRUGS [7](#vi.-inds-for-botanical-drugs) {#vi.-inds-for-botanical-drugs-7 .TOC-1}

## A. IND Information for Different Categories of Botanicals [7](#a.-ind-information-for-different-categories-of-botanicals) {#a.-ind-information-for-different-categories-of-botanicals-7 .TOC-2}

## B. Basic Format for INDs [9](#b.-basic-format-for-inds) {#b.-basic-format-for-inds-9 .TOC-2}

### 1. Cover Sheet (see § 312.23(a)(1)) [9](#cover-sheet-see-312.23a1) {#cover-sheet-see-312.23a1-9 .TOC-3}

### 2. Table of Contents (see § 312.23(a)(2)) [9](#table-of-contents-see-312.23a2) {#table-of-contents-see-312.23a2-9 .TOC-3}

### 3. Introductory Statement and General Investigational Plan (see § 312.23(a)(3)) [9](#introductory-statement-and-general-investigational-plan-see-312.23a3) {#introductory-statement-and-general-investigational-plan-see-312.23a3-9 .TOC-3}

### 4. Investigator′s Brochure (see § 312.23(a)(5)) [9](#investigators-brochure-see-312.23a5) {#investigators-brochure-see-312.23a5-9 .TOC-3}

### 5. Protocols (§ 312.23(a)(6)) [9](#protocols-312.23a6) {#protocols-312.23a6-9 .TOC-3}

### 6. Chemistry, Manufacturing, and Controls (§ 312.23(a)(7)) [10](#chemistry-manufacturing-and-controls-312.23a7) {#chemistry-manufacturing-and-controls-312.23a7-10 .TOC-3}

### 7. Pharmacological and Toxicological Information (§ 312.23(a)(8)) [13](#pharmacological-and-toxicological-information-312.23a8) {#pharmacological-and-toxicological-information-312.23a8-13 .TOC-3}

### 8. Previous Human Experience With the Product (§ 312.23(a)(9)) [13](#previous-human-experience-with-the-product-312.23a9) {#previous-human-experience-with-the-product-312.23a9-13 .TOC-3}

# VII. INDs FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES OF LAWFULLY MARKETED BOTANICAL PRODUCTS WITHOUT SAFETY CONCERNS [14](#vii.-inds-for-phase-1-and-phase-2-clinical-studies-of-lawfully-marketed-botanical-products-without-safety-concerns) {#vii.-inds-for-phase-1-and-phase-2-clinical-studies-of-lawfully-marketed-botanical-products-without-safety-concerns-14 .TOC-1}

## A. Description of Product and Documentation of Human Use [14](#a.-description-of-product-and-documentation-of-human-use) {#a.-description-of-product-and-documentation-of-human-use-14 .TOC-2}

### 1. Description of Botanicals Used (§ 312.23(a)(3)(i)) [14](#description-of-botanicals-used-312.23a3i) {#description-of-botanicals-used-312.23a3i-14 .TOC-3}

### 2. History of Use (§ 312.23(a)(3)(ii),(a)(9)) [14](#history-of-use-312.23a3iia9) {#history-of-use-312.23a3iia9-14 .TOC-3}

### 3. Current Marketed Use (§ 312.23(a)(3)(ii), (a)(9)) [14](#current-marketed-use-312.23a3ii-a9) {#current-marketed-use-312.23a3ii-a9-14 .TOC-3}

## B. Chemistry, Manufacturing, and Controls [15](#b.-chemistry-manufacturing-and-controls) {#b.-chemistry-manufacturing-and-controls-15 .TOC-2}

### 1. Botanical Raw Material (§ 312.23(a)(7)(i)) [15](#botanical-raw-material-312.23a7i) {#botanical-raw-material-312.23a7i-15 .TOC-3}

### 2. Botanical Drug Substance (§ 312.23(a)(7)(iv)(a)) [15](#botanical-drug-substance-312.23a7iva) {#botanical-drug-substance-312.23a7iva-15 .TOC-3}

### 3. Botanical Drug Product (§ 312.23(a)(7)(iv)(b)) [15](#botanical-drug-product-312.23a7ivb) {#botanical-drug-product-312.23a7ivb-15 .TOC-3}

### 4. Animal Safety Test (§ 312.23(a)(8)) [17](#animal-safety-test-312.23a8) {#animal-safety-test-312.23a8-17 .TOC-3}

### 5. Placebo (§ 312.23(a)(7)(iv)(c)) [17](#placebo-312.23a7ivc) {#placebo-312.23a7ivc-17 .TOC-3}

### 6. Labeling (§ 312.23(a)(7)(iv)(d)) [17](#labeling-312.23a7ivd) {#labeling-312.23a7ivd-17 .TOC-3}

### 7. Environmental Assessment or Claim of Categorical Exclusion (§ 312.23(a)(7)(iv)(e)) [17](#environmental-assessment-or-claim-of-categorical-exclusion-312.23a7ive) {#environmental-assessment-or-claim-of-categorical-exclusion-312.23a7ive-17 .TOC-3}

## C. Pharmacology/Toxicology Information [17](#c.-pharmacologytoxicology-information) {#c.-pharmacologytoxicology-information-17 .TOC-2}

### 1. All Marketed Botanical Products [17](#all-marketed-botanical-products) {#all-marketed-botanical-products-17 .TOC-3}

### 2. Foreign-Marketed Botanical Products [18](#foreign-marketed-botanical-products) {#foreign-marketed-botanical-products-18 .TOC-3}

## D. Bioavailability [18](#d.-bioavailability) {#d.-bioavailability-18 .TOC-2}

## E. Clinical Considerations [19](#e.-clinical-considerations) {#e.-clinical-considerations-19 .TOC-2}

# VIII. INDs FOR PHASE 1 and PHASE 2 CLINICAL STUDIES FOR NONMARKETED BOTANICAL PRODUCTS and Products with known safety concerns [19](#viii.-inds-for-phase-1-and-phase-2-clinical-studies-for-nonmarketed-botanical-products-and-products-with-known-safety-concerns) {#viii.-inds-for-phase-1-and-phase-2-clinical-studies-for-nonmarketed-botanical-products-and-products-with-known-safety-concerns-19 .TOC-1}

## A. Description of Product and Documentation of Human Use [19](#a.-description-of-product-and-documentation-of-human-use-1) {#a.-description-of-product-and-documentation-of-human-use-19 .TOC-2}

### 1. Description of Botanicals Used (§ 312.23(a)(3)(i)) [19](#description-of-botanicals-used-312.23a3i-1) {#description-of-botanicals-used-312.23a3i-19 .TOC-3}

### 2. History of Use (If Any) (§ 312.23(a)(3)(ii), (a)(9)) [20](#history-of-use-if-any-312.23a3ii-a9) {#history-of-use-if-any-312.23a3ii-a9-20 .TOC-3}

### 3. Current Investigational Use (If Any) (§ 312.23(a)(3)(ii), (a)(9)) [20](#current-investigational-use-if-any-312.23a3ii-a9) {#current-investigational-use-if-any-312.23a3ii-a9-20 .TOC-3}

## B. Chemistry, Manufacturing, and Controls [20](#b.-chemistry-manufacturing-and-controls-1) {#b.-chemistry-manufacturing-and-controls-20 .TOC-2}

### 1. Botanical Raw Material (§ 312.23(a)(7)(i)) [20](#botanical-raw-material-312.23a7i-1) {#botanical-raw-material-312.23a7i-20 .TOC-3}

### 2. Botanical Drug Substance (§ 312.23(a)(7)(iv)(a)) [21](#botanical-drug-substance-312.23a7iva-1) {#botanical-drug-substance-312.23a7iva-21 .TOC-3}

### 3. Botanical Drug Product (§ 312.23(a)(7)(iv)(b)) [24](#botanical-drug-product-312.23a7ivb-1) {#botanical-drug-product-312.23a7ivb-24 .TOC-3}

### 4. Placebo (see section VII.B.5) [25](#placebo-see-section-vii.b.5) {#placebo-see-section-vii.b.5-25 .TOC-3}

### 5. Labeling (see section VII.B.6) [25](#labeling-see-section-vii.b.6) {#labeling-see-section-vii.b.6-25 .TOC-3}

### 6. Environmental Assessment or Claim of Categorical Exclusion [25](#environmental-assessment-or-claim-of-categorical-exclusion) {#environmental-assessment-or-claim-of-categorical-exclusion-25 .TOC-3}

## C. Nonclinical Safety Assessment [26](#c.-nonclinical-safety-assessment) {#c.-nonclinical-safety-assessment-26 .TOC-2}

### 1. Traditional Preparations [26](#traditional-preparations) {#traditional-preparations-26 .TOC-3}

### 2. Others [27](#others) {#others-27 .TOC-3}

### 3. Products with Known Safety Issues [27](#products-with-known-safety-issues) {#products-with-known-safety-issues-27 .TOC-3}

## D. Bioavailability [27](#d.-bioavailability-1) {#d.-bioavailability-27 .TOC-2}

## E. Clinical Considerations [27](#e.-clinical-considerations-1) {#e.-clinical-considerations-27 .TOC-2}

# IX. INDs FOR PHASE 3 CLINICAL STUDIES OF ALL BOTANICAL PRODUCTS [28](#ix.-inds-for-phase-3-clinical-studies-of-all-botanical-products) {#ix.-inds-for-phase-3-clinical-studies-of-all-botanical-products-28 .TOC-1}

## A. Description of Product and Documentation of Human Experience [28](#a.-description-of-product-and-documentation-of-human-experience) {#a.-description-of-product-and-documentation-of-human-experience-28 .TOC-2}

## B. Chemistry, Manufacturing, and Controls [28](#b.-chemistry-manufacturing-and-controls-2) {#b.-chemistry-manufacturing-and-controls-28 .TOC-2}

### 1. Expanded Clinical Studies [28](#expanded-clinical-studies) {#expanded-clinical-studies-28 .TOC-3}

### 2. End-of-Phase 3 Clinical Studies and Pre-NDA Considerations [33](#end-of-phase-3-clinical-studies-and-pre-nda-considerations) {#end-of-phase-3-clinical-studies-and-pre-nda-considerations-33 .TOC-3}

## C. Nonclinical Safety Assessment [35](#c.-nonclinical-safety-assessment-1) {#c.-nonclinical-safety-assessment-35 .TOC-2}

### 1. Repeat-Dose General Toxicity Studies [35](#repeat-dose-general-toxicity-studies) {#repeat-dose-general-toxicity-studies-35 .TOC-3}

### 2. Nonclinical Pharmacokinetic/Toxicokinetic Studies [36](#nonclinical-pharmacokinetictoxicokinetic-studies) {#nonclinical-pharmacokinetictoxicokinetic-studies-36 .TOC-3}

### 3. Reproductive Toxicology [36](#reproductive-toxicology) {#reproductive-toxicology-36 .TOC-3}

### 4. Genotoxicity Studies [36](#genotoxicity-studies) {#genotoxicity-studies-36 .TOC-3}

### 5. Carcinogenicity Studies [37](#carcinogenicity-studies) {#carcinogenicity-studies-37 .TOC-3}

### 6. Special Pharmacology/Toxicology Studies [37](#special-pharmacologytoxicology-studies) {#special-pharmacologytoxicology-studies-37 .TOC-3}

### 7. Regulatory Considerations [37](#regulatory-considerations) {#regulatory-considerations-37 .TOC-3}

## D. Bioavailability and Clinical Pharmacology [38](#d.-bioavailability-and-clinical-pharmacology) {#d.-bioavailability-and-clinical-pharmacology-38 .TOC-2}

## E. Clinical Considerations [38](#e.-clinical-considerations-2) {#e.-clinical-considerations-38 .TOC-2}

# glossary [40](#glossary) {#glossary-40 .TOC-1}

# QUESTIONS AND ANSWERS [43](#questions-and-answers) {#questions-and-answers-43 .TOC-1}

# ATTACHMENT A: Regulatory Approaches FOR MARKETING BOTANICAL DRUG PRODUCTS [48](#attachment-a-regulatory-approaches-for-marketing-botanical-drug-products) {#attachment-a-regulatory-approaches-for-marketing-botanical-drug-products-48 .TOC-1}

**Guidance for Industry**[^1]

**Botanical Drug Products**

This guidance represents the Food and Drug Administration\'s (FDA\'s)
current thinking on this topic. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirements of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of this
guidance.

# I. INTRODUCTION

This guidance explains when a botanical drug may be marketed under an
over-the-counter (OTC) drug monograph and when FDA regulations require
approval for marketing of a new drug application (NDA), submitted under
section 505(b) of the Federal Food, Drug, and Cosmetic Act (the Act), 21
U.S.C. 355(b). In addition, this document provides sponsors with
guidance on submitting investigational new drug applications (INDs) for
botanical drug products, including those botanical products (or
*botanicals*) currently lawfully marketed as foods (including
conventional foods and dietary supplements) in the United States.

This guidance also discusses several areas in which, because of the
unique nature of botanicals, FDA finds it appropriate to apply
regulatory policies that differ from those applied to synthetic,
semisynthetic, or otherwise highly purified or chemically modified drugs
(including antibiotics derived from microorganisms). This latter group
of drug substances is referred to in this guidance as synthetic or
highly purified drugs*.* Therefore, when the recommendations on a
specific topic discussed in this guidance differ from those in other
existing guidances (e.g., *Submitting Supporting Documentation in Drug
Applications for the Manufacture of Drug Substances*, 1987), [^2] this
guidance takes precedence. In particular, this guidance states that
applicants may submit reduced documentation of nonclinical (preclinical)
safety and of chemistry, manufacturing, and controls (CMC) to support an
IND for initial clinical studies of botanicals that have been legally
marketed in the United States and/or a foreign country as dietary
supplements without any known safety concerns.

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency\'s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# II. BACKGROUND

*Botanical products* are finished, labeled products that contain
vegetable matter as ingredients.[^3] A botanical product may be a food
(including a dietary supplement), a drug (including a biological drug),
a medical device (e.g., gutta-percha), or a cosmetic under the Act. An
article is generally a food if it is used for food (21 U.S.C.
312(f)(1)). Whether an article is a drug, medical device, or cosmetic
under the Act turns on its "intended use" (21 U.S.C. 312(g)(1)(B) and
(C), (h)(2) and (3), (i)). "Intended use" is created by claims made by
or on behalf of a manufacturer or distributor of the article to
prospective purchasers, such as in advertising, labeling, or oral
statements.

For the purposes of this document, the term *botanicals* includes plant
materials, algae, macroscopic fungi, and combinations thereof. It does
not include:

-   Materials derived from genetically modified botanical species (i.e.,
    by recombinant DNA technology or cloning).

```{=html}
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```
-   Fermentation products (i.e., products produced by fermentation of
    yeast, bacteria, and other microscopic organisms, including when
    plants are used as a substrate, and products produced by
    fermentation of plant cells), even if such products are previously
    approved for drug use or accepted for food use in the United States
    (e.g., antibiotics, amino acids, and vitamins).

```{=html}
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```
-   Highly purified substances (e.g., paclitaxel) or chemically modified
    substances (e.g., estrogens synthesized from yam extracts) derived
    from botanical sources.

This guidance addresses all botanical drug products (in all dosage
forms) that are regulated under the Act, except those also regulated
under section 351 of the Public Health Service Act (42 U.S.C. 262).
Although this guidance does not address drugs that contain animals or
animal parts (e.g., insects, annelids, shark cartilage) and/or minerals,
either alone or in combination with botanicals, many scientific
principles described in this guidance may also apply to those products.
When a drug product contains botanical ingredients in combination with
either (1) a synthetic or highly purified drug or (2) a biotechnology
derived or other naturally derived drug, this guidance only applies to
the botanical portion of the product.

# III. 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. Botanicals used for food and consumed
primarily for their taste, aroma, or nutritive value (e.g., lettuce,
herbs used as seasonings) are regulated as foods. Botanicals can also be
dietary supplements if they are labeled as dietary supplements and
otherwise meet the dietary supplement definition in section 201(ff) of
the Act (21 U.S.C. 321(ff)).

If a botanical product is intended for use in diagnosing, mitigating,
treating, or curing disease, it is a drug under section 201(g)(1)(B) of
the Act and is subject to regulation as such. If a botanical product is
intended to prevent disease, it is also a drug under section
201(g)(1)(B), except that a product that bears a health claim authorized
in accordance with section 403(r) of the Act (21 U.S.C. 343(r)) is not a
drug solely because its labeling contains such a claim. If the intended
use of a botanical product is to affect the structure or function of the
human body, it may be regulated either as a dietary supplement or as a
drug, depending on the circumstances.

Under the Dietary Supplement Health and Education Act of 1994 (DSHEA),
an orally ingested product that meets the definition of a "dietary
supplement" under section 201(ff) of the Act may be lawfully marketed
with a statement that (1) claims a benefit related to a classical
nutrient deficiency disease (and discloses the prevalence of the disease
in the United States), (2) describes how the product is intended to
affect the structure or function of the human body, (3) characterizes
the documented mechanism by which the product acts to maintain such
structure or function, or (4) describes general well-being from
consumption of the product (section 403(r)(6)(A) of the Act).[^4] A
dietary supplement statement of the type described above may not claim
to diagnose, mitigate, treat, cure, or prevent a specific disease or
class of diseases (section 403(r)(6) of the Act).[^5]

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 claim
under section 403(r)(6) of the Act, it is subject to regulation as a
drug under section 201(g)(1)(C) of the Act. 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 (except for a product marketed with
certain health claims authorized under section 403(r) of the Act). Under
section 505(b) of the Act, a drug must be marketed under an approved
NDA[^6] unless the product is excluded from the definition of a new drug
under section 201(p) of the Act. Certain products that FDA determines
are generally recognized as safe and effective in accordance with
section 201(p) may be marketed under FDA′s OTC drug monograph system.

## A. 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 codified in\
> 21 CFR parts 331-358. The manufacturer would need to submit a petition
> in accordance with 21 CFR 10.30 to amend the monograph to add the
> botanical substance as a new active ingredient.
>
> Under current regulations, if there is no marketing history in the
> United States or a foreign country for a botanical drug product,[^7]
> if available evidence of safety and effectiveness does not warrant
> inclusion of the product in an OTC drug monograph, or if the proposed
> indication would not be appropriate for nonprescription use, the
> manufacturer must submit an NDA to obtain FDA approval to market the
> product for the proposed use (sections 201(p) and 505 of the Act). An
> NDA for a botanical drug could seek approval for either prescription
> or OTC use, depending on the indication and characteristics of the
> product and whether it is safe for use outside of the supervision of a
> practitioner licensed by law to administer it. If existing information
> on the safety and effectiveness of a botanical drug product is
> insufficient to support an NDA, we recommend that new clinical studies
> be conducted to demonstrate safety and effectiveness.[^8]
>
> 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. 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 (the applicant's drug product),
> and the applicant may be eligible for marketing 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. A new botanical
> drug (containing multiple chemical constituents) may qualify as a new
> chemical entity under § 314.108(a). If a product qualifies as a new
> chemical entity, during the period of exclusivity, FDA will not
> approve, or in some cases even review, certain competitor products
> unless the second sponsor conducts all studies necessary to
> demonstrate the safety and effectiveness of its product and submits a
> 505(b)(1) application. Therefore, if a person wishing to market a
> botanical drug product that is not included in an existing OTC drug
> monograph desires marketing exclusivity for the product, the person
> should seek approval of an NDA rather than petition the Agency to
> amend a monograph. Attachment A contains a schematic showing different
> regulatory approaches that can be taken for marketing botanical drug
> products in the United States, including OTC drug monograph and NDA
> procedures.

## B. CMC Information for Botanical Drug Products

> Botanical drug products have certain unique characteristics that
> should be taken into account in the application of FDA regulations and
> guidance. Botanical drugs are derived from vegetable matter and are
> usually prepared as complex mixtures. Their chemical constituents are
> not always well defined. In many cases, the active constituent in a
> botanical drug is not identified, nor is its biological activity well
> characterized. Therefore, the CMC documentation that should be
> provided for botanical drugs will often be different from that for
> synthetic or highly purified drugs, whose active constituents can be
> more readily chemically identified and quantified. For example, FDA
> would expect an NDA for a synthetic or highly purified drug to
> identify the active ingredient. However, it would not be essential for
> the sponsor of a botanical drug to identify the active constituents
> (although FDA recommends that this be done if feasible). Even if the
> sponsor were to eventually identify the active constituents in the
> NDA, the active constituents might not be identified during the IND
> stage.
>
> 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. 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).

## C. CMC and Toxicology Information to Su pport 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. To support initial clinical trials,
> the nonclinical pharmacology and toxicology information that must be
> provided under 21 CFR 312.22(b) for legally available botanical
> products with no known safety issues (see section VI.A) may be
> markedly reduced compared to that expected for synthetic or highly
> purified new drugs that are not legally marketed and for which there
> is no prior human experience. In most cases, additional toxicology and
> CMC data will not be required for such initial trials.

## D. 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 within the meaning of 21 CFR 300.50 and
> 330.10(a)(4)(iv). 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.
>
> Botanical drugs composed of multiple parts of a single species of
> plant, alga, or macroscopic fungus, or of parts from different species
> of plants algae, or macroscopic fungi, currently are subject to the
> combination drug requirements. However, FDA is considering revising
> its regulations to allow for the exemption of such botanical drugs
> from application of the combination drug requirements under certain
> circumstances.

# IV. 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. 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 (see §§ 314.126(b) and 330.10). Requirements related to
safety, effectiveness, and labeling for drugs to be included in an OTC
drug monograph are set forth in 21 CFR part 330.

A request to amend an OTC drug monograph to include a botanical
substance must be submitted by citizen petition in accordance with
§§ 10.30 and 330.10(a)(12). There should be publicly available quality
standards for such a botanical drug substance in the drug section (i.e.,
not in the National Formulary or other nondrug sections) of the *United
States Pharmacopeia* (USP).[^9] In the absence of a USP drug monograph,
the petitioner should include suitable quality standards for the
botanical drug substance in its citizen petition and simultaneously
propose adoption of those standards in the USP. Additional criteria and
procedures by which a botanical drug substance may become eligible for
inclusion in the OTC drug monograph system are set forth in § 330.14.
FDA regulations on current good manufacturing practices (CGMPs) apply to
all OTC drug monograph products, including any listed botanical drug
products (see § 330.1(a)).

For further information on the OTC drug monograph approach to marketing
a botanical drug product, sponsors are encouraged to contact CDER′s
Division of Over-the-Counter Drug Products (HFD-560).

# V. 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 under
section 201(p) of the Act. Section 505(a) of the Act requires any person
wishing to market a botanical drug product that is a new drug to obtain
FDA approval of an NDA or ANDA for that product. According to section
505(d) of the Act and § 314.50, an 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 set
forth in part 314 and discussed in several CDER guidance documents.

# VI. INDs FOR BOTANICAL DRUGS

If available information is insufficient to support an NDA for a
botanical drug, the sponsor will need to develop further data. An IND is
required under section 505(i) of the Act and\
21 CFR part 312 (unless exempt under § 312.2(b)) when a botanical
product is studied in the United States for a drug use (see section
201(g) of the Act), even if such study is intended solely for research
purposes. Under § 312.22, an IND must contain sufficient information to
demonstrate that the drug product is safe for testing in humans and that
the clinical protocol is properly designed for its intended objectives.

## A. IND Information for Different Categories of Botanicals

> Under § 312.22(b), the amount of information that must be submitted in
> an IND for a particular drug product depends on, among other things,
> the novelty of the drug, the extent to which it has been studied
> previously, the drug product′s known or suspected risks, and the
> developmental phase of the drug. Sections VII and VIII of this
> guidance describe the information that we recommend a sponsor provide
> in meeting the requirements in § 312.23 for an IND for initial (i.e.,
> phase 1 and phase 2) clinical studies of a botanical drug. As noted
> above, for botanicals legally marketed under the DSHEA, there will
> often be very little new CMC or toxicological data needed to initiate
> such trials, as long as there are no known safety issues associated
> with the product and it is to be used at approximately the same doses
> as those currently or traditionally used or recommended. A botanical
> drug is considered to have a known safety issue when FDA has evidence
> that it produces serious and/or possibly life-threatening effects.
> Nonclinical evaluation to characterize toxicities may be appropriate
> for products with known safety issues. For example, nonclinical data
> may be appropriate to help establish safe doses and to determine ways
> to better monitor potential toxicities in humans. Such nonclinical
> studies may be needed early in development (see § 312.23(a)(8)).
>
> Properly conducted early clinical investigations, including controlled
> effectiveness trials in phase 2, will allow a determination of whether
> there is a clinical effect worth pursuing and will provide a more
> systematic evaluation of safety than previously available. If a
> botanical drug product shows promise of effectiveness in such early
> trials, the potential for wider use for particular purposes will
> create a need for greater assurance of product quality and consistency
> and for expanded (i.e., phase 3) clinical studies of safety and
> effectiveness (§ 312.22(b)). IND information appropriate for expanded
> clinical studies of botanical drugs is discussed in section IX.
>
> Under § 312.22(b), the IND sponsor of a botanical product that has
> been previously marketed but *not* in the United States must provide
> sufficient additional information to assist FDA in determining the
> safety of the product for use in initial clinical studies (section
> VII). Such additional information is appropriate under that regulation
> because these products are not already marketed in the United States
> and evidence of safety should be provided before patients are exposed
> to them.
>
> This guidance also addresses the type of information that should be
> provided under § 312.22 in INDs for initial studies on botanical
> products that have not been lawfully marketed anywhere or have known
> safety issues (section VIII). In contrast to botanical products that
> have been marketed in some form, considerably less information may be
> available on the safety of a new botanical product that has not been
> marketed anywhere as a food or dietary supplement and has not been
> tested as a drug in humans. Consequently, it is appropriate that,
> under § 312.22(b), sponsors of INDs for initial trials of botanical
> products that have not previously been lawfully marketed anywhere, or
> for which there are known safety issues, provide certain additional
> information to FDA.
>
> The information to be provided in an IND for a botanical drug product
> is illustrated schematically in Attachment B and discussed in this
> section and sections VII-IX below. FDA encourages sponsors of INDs for
> initial studies of botanical drugs to seek input from CDER review
> divisions (organized based on the therapeutic classes of the drugs) to
> ensure that the appropriate information is submitted and that the
> clinical protocols are well designed. Many guidance documents specific
> to particular indications or dosage forms are also available from the
> respective review divisions.
>
> FDA may place an IND for initial studies of a botanical drug on
> clinical hold (i.e., an order issued by the Agency to delay a proposed
> clinical study) if it finds that the IND does not contain sufficient
> information required under § 312.23 to assess the risk to subjects of
> the proposed studies (§ 312.42(b)(1)(iv)). However, the lack of any
> specific item of information listed in § 312.23 for a phase 1 study
> will not necessarily justify imposing a clinical hold. Possible
> grounds for a clinical hold are set forth in § 312.42(b) and discussed
> in CDER′s guidance for industry on *Content and Format of
> Investigational New Drug Applications (INDs) for Phase 1 Studies of
> Drugs, Including Well-Characterized, Therapeutic,
> Biotechnology-derived Products* (November 1995).

## B. Basic Format for INDs

> The format and general requirements for IND submissions are stated in
> § 312.23 and discussed in several CDER guidance documents, including
> the phase 1 guidance referenced above. These requirements are
> summarized below, with guidance on the specific types of information
> that we recommend sponsors of botanical drug products provide to meet
> these requirements:

### 1. Cover Sheet (see § 312.23(a)(1))

### 2. Table of Contents (see § 312.23(a)(2))

### 3. Introductory Statement and General Investigational Plan (see § 312.23(a)(3))

### 4. Investigator′s Brochure (see § 312.23(a)(5))

### 5. Protocols (§ 312.23(a)(6))

### 

> Section 312.23(a)(6) requires information on protocols for planned
> studies. In general, clinical evaluation of botanical drug products
> for safety and effectiveness does not differ significantly from
> evaluation of synthetic or highly purified drugs. For study results to
> be interpretable, clinical studies must be well designed and carefully
> executed (see § 314.126). A sponsor need not differentiate the
> clinical effects of each molecular entity in a botanical product
> derived from a single part of a plant (see section III.D,
> Applicability of Combination Drug Regulations). Even where the
> components of a combination product must be studied under § 300.50,
> initial controlled studies could be used to evaluate the entire
> combination product. For additional information on the clinical
> development of new drugs, see the CDER guidance *Format and Content of
> the Clinical and Statistical Sections of an Application* (July 1988)
> and other guidances related to the submission of applications
> involving specific drug classes and diseases.

Clinical studies of botanical products may pose special problems
associated with the incorporation of traditional methodologies, such as
selection of doses and addition of new botanical ingredients based on
response, that will need to be resolved. In almost all cases, credible
studies will be randomized, double blind, and placebo-controlled (or
dose-response) (see § 314.126). Studies with only active controls may be
appropriate when it is unethical to use a placebo, as would be the case
in serious and life-threatening conditions for which there is
established effective therapy. However, active studies pose special
difficulties in interpretation and should be used only when a placebo
cannot be used and there is good reason to expect the botanical
treatment to be effective. With respect to serious illnesses for which
there is established effective therapy, we generally encourage sponsors
to use an "add-on" design for the initial trials: The botanical product
would be compared to a placebo, each being added to the standard
treatment. For symptomatic disorders where the use of a placebo poses no
ethical problem, placebo-controlled trials should almost always be
conducted because active control trials are particularly difficult to
interpret in such situations. Having a concurrent active treatment group
in addition to placebo control (e.g., a three-armed study) is advisable
in certain cases (as in psychiatric trials) to verify the assay
sensitivity of the study. The sponsor is encouraged to consult
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) guidance *E10 Choice
of Control Group and Related Issues in Clinical Trials* (May 2000).

For botanical as well as for synthetic or highly purified drugs,
absolute safety does not exist for any therapeutic intervention, and FDA
must assess risks in light of potential clinical benefits (see
§ 312.22). For more comprehensive information on safety evaluations, see
other CDER guidance documents. As is the case for synthetic or highly
purified drugs, the best safety data on newly developed botanicals will
be derived from controlled efficacy trials, but for chronic indications,
long-term, open-label extensions also will be important. For chronic
conditions, exposures of at least 6-12 months' duration are usually
appropriate (see ICH guidance *E1A The Extent of Population Exposure to
Assess Clinical Safety: For Drugs Intended for Long-term Treatment of
Non-Life-Threatening Conditions* (March 1995)).

Section VII.E of this guidance provides recommendations on the protocol
design of initial clinical trials for botanical products legally
marketed under the DSHEA. Sections VIII.E and IX.E provide information
on the design of initial clinical trials for nonmarketed botanical drug
products and for expanded studies on all botanical drug products,
respectively.

As with any clinical study, appropriate human research subject
protections must be followed, including submission of the protocol to an
institutional review board (IRB) and obtaining proper informed consent
(see 21 CFR parts 56 and 50). Pursuant to § 50.25, the consent form
should describe any procedures that are experimental along with a
description of the risks, benefits, and alternatives of taking the
product. We recommend that the consent form acknowledge any lack of
additional chemical or toxicological characterization.

### 6. Chemistry, Manufacturing, and Controls (§ 312.23(a)(7))

> The requirements for the content and format of the CMC section of an
> IND are stated in § 312.23(a)(7)(iv)*(a)-(e)*. These regulations
> require documentation of the drug substance, drug product, placebo,
> labeling, and an environmental analysis.

Plant materials used in the production of botanical drug products often
are not completely characterized and defined or are prone to
contamination, deterioration, and variation in composition and
properties. In many cases, the active constituent in a botanical drug is
not identified, nor is its biological activity well characterized.
Therefore, in contrast to the situation with synthetic or highly
purified drug products, it may be difficult to ensure the quality of a
botanical drug by controlling only the corresponding drug substance and
drug product. To ensure that a botanical drug product used in clinical
trials is of consistently good quality, and that sufficient information
exists to meet the requirements of § 312.23(a)(7)(iv), the sponsor
should have, in addition to final product testing, appropriate quality
controls for the botanical raw materials. The manufacturing process
should be well defined, with adequate in-process controls, especially
for the drug substance.

As noted in section III.C, sponsors of initial clinical trials on
botanical products that have been legally marketed as dietary
supplements and that do not have safety issues can submit less CMC
information than must be provided under §§ 312.22(b) and 312.23(a)(7))
for later studies or for studies on products not previously marketed.
Section VII.B describes the CMC information that generally will be
necessary under § 312.23(a)(7) for initial trials on previously marketed
botanicals without safety issues.

To comply with §§ 312.22(b) and 312.23(a)(7), sponsors must submit
additional CMC information for initial studies of nonmarketed botanical
products and marketed botanicals with safety issues (see section VIII.B)
and for expanded trials on all botanical products (see section IX.B).
Additional guidance (not specific to botanical drugs) on the submission
of CMC information in INDs and marketing applications can be found in
other CDER guidance documents.

In the initial stage of clinical studies of a botanical drug, it is
generally not necessary to identify the active constituents or other
biological markers or to have a chemical identification and assay for a
particular constituent or marker. Identification by spectroscopic and/or
chromatographic fingerprinting and strength by dry weight (weight minus
water or solvents) can be acceptable alternatives. Attributes for lot or
batch release testing should be determined as the clinical study
progresses, although appropriate acceptance criteria for batch release
need not be established until later in phase 3 studies. Batch analyses
on clinical batches should be submitted as they become available, to
demonstrate batch-to-batch consistency and to help establish appropriate
acceptance criteria for fingerprinting. Identification of active
constituents is helpful in optimizing manufacturing procedures, ensuring
batch consistency, and contributing to an understanding of the clinical
effects of the botanical product. Therefore, when feasible, active
constituents should be identified during phase 3 studies.

> A single formulation (i.e., one in which the components or ingredients
> and composition of the drug substance and drug product are kept
> constant) and a single dosage form should be used throughout the
> different stages of the clinical trials unless this proves impossible.
> Screening of a number of sources/batches for product quality is
> recommended to ensure that the material used in initial trials will
> yield interpretable results that can be used to guide later
> development. Once a batch or source of acceptable quality is
> identified, sufficient quantities should be obtained to sustain the
> initial clinical trials. This is especially important if the sponsor
> does not have access to the manufacturing and controls information on
> the botanical drug substance and finished product. In addition,
> sufficient quantities of the botanical raw material and drug substance
> from the same batch should be retained for future chemical
> characterization and/or pharmacological/toxicological testing. It is
> also important to obtain the botanical drug product from a source
> willing to provide FDA with detailed manufacturing and controls
> information when needed, or as clinical evaluation of the product
> progresses. These factors are crucial if the sponsor intends to pursue
> FDA approval for a new drug application for the botanical product.
>
> Consistency should be maintained when multiple batches are used in the
> nonclinical and clinical trials. It also is important that the
> material used in phase 1/2 trials be verified for its authenticity
> (see VIII.B.1 below). Samples from phase 1/2 studies should be
> retained for comparison with batches to be used in the phase 3 trials
> to ensure consistency. Bridging studies (clinical and/or nonclinical)
> should be performed if the use of batches with different
> characteristics in different phases cannot be avoided.
>
> Botanical raw materials may sometimes be dispensed at clinics on an as
> needed or by prescription basis and subsequently prepared by patients
> themselves at home. We recommend avoiding these practices during
> clinical trials if at all possible because data related to such use
> may not be reliable because of variability in preparation by patients.
> When absolutely necessary, dispensing in such a manner may be
> considered for initial clinical studies. But as clinical trials are
> expanded, the botanical drug product should be produced in a
> controlled manner by an established manufacturer to ensure the
> validity and reliability of data.

If previously available nonclinical and/or clinical data are provided or
referenced in the IND, a comparison should be made of the botanical drug
products used in the referenced studies, the products to be used in the
proposed trials, and (if appropriate) the products intended for
marketing (including their corresponding botanical raw materials, drug
substances, and formulations).

If a synthetic or highly purified drug or a biotechnology- or other
naturally derived (non-botanical) drug is added to a botanical drug
product, the CMC data for this added substance should be described or
cross-referenced according to § 312.23(b) and guidances. Under
§ 312.23(a)(7), animal parts (e.g., insects, annelids, shark cartilage)
or minerals that are combined with a botanical in a drug product, must
be accompanied by additional manufacturing and controls information
specific to these materials because they are part of the drug substance
being studied.

CMC information on a botanical raw material, drug substance, and/or drug
product may be submitted by the sponsor as part of the IND or by the
manufacturer (if different from the sponsor) in a drug master file
(DMF). A DMF is a submission from a manufacturer to FDA that may be used
to provide confidential information on a human drug (§ 314.420(a)). The
information contained in a DMF may be cross-referenced to support an IND
or NDA and is reviewed and used by FDA only when authorized by the
manufacturer. However, the sponsor relying on information in a DMF
should have adequate acceptance testing (e.g., identification test,
assay) before accepting the raw material, drug substance, or drug
product received from the DMF holder for further processing or for use
in humans directly.

### 7. Pharmacological and Toxicological Information (§ 312.23(a)(8))

### 

The content and format for pharmacological and toxicological information
to be provided in an IND are described in § 312.23(a)(8). Nonclinical
pharmacology and toxicology studies are useful in guiding early clinical
studies and in predicting the potential toxicity of a new drug.

Ordinarily, less nonclinical information will be required to support the
initial clinical trials of currently marketed orally ingested botanical
products than is expected for synthetic or highly purified drugs. For a
botanical product that is not currently lawfully marketed in the United
States, but is administered orally and prepared, processed, and used
according to methodologies for which there is prior human experience,
sufficient information may be available to support initial clinical
studies without standard nonclinical testing. However, for a botanical
drug with a route of administration other than oral, additional
pharmacology/toxicology information may be necessary before initial
clinical studies.

After initial clinical studies, further pharmacology and toxicology
studies of a botanical drug generally would be needed before later
phases of clinical development and before approval for marketing.
Sections VII.C, VIII.C, and IX.C provide details on the pharmacological
and toxicological information that should be provided for clinical
trials on botanical drugs.

### 8. Previous Human Experience With the Product (§ 312.23(a)(9))

Under § 312.23(a)(9), an IND sponsor must submit information about
previous human experience with an investigational drug. Many botanical
products have been marketed or tested in clinical studies (often
involving few patients). When such studies have been conducted, data
from the studies must be included in an IND for a botanical drug to
assist FDA in its overall safety assessment. Sections VII.A, VIII.A, and
IX.A of this guidance provide additional recommendations on the
submission of information on previous human experience with a botanical
product.

# VII. INDs FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES OF LAWFULLY MARKETED BOTANICAL PRODUCTS WITHOUT SAFETY CONCERNS

This section provides more detailed guidance on the submission of
certain types of information for INDs for initial clinical studies on
botanical products that have been lawfully marketed and that do not
raise safety issues (for drugs with known safety concerns, see section
VIII). This section also notes where additional information must be
provided under § 312.22(b) when an IND is for a botanical product that
has been marketed in one or more foreign countries but not the United
States.

## A. Description of Product and Documentation of Human Use

### 1. Description of Botanicals Used (§ 312.23(a)(3)(i))

### 

> The following information should be provided for ***each*** of the
> botanical raw materials used as ingredients in a botanical drug
> product:

-   Common or usual names of the plant, alga, or macroscopic fungus

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-   Synonyms (e.g., Latin, Greek, English, Spanish, Chinese)

-   Name of variety, species, genus, and family, including the name of
    the botanist who first described the species or variety, if known

-   Chemical class of the active constituent (the chemical constituent
    that is responsible for the claimed pharmacological activity or
    therapeutic effect) or characteristic marker (a chemical constituent
    used for identification and/or quality control purposes), if known

### 2. History of Use (§ 312.23(a)(3)(ii),(a)(9))

> The sponsor should include information found in historical sources
> (e.g., books of medical practice in Ayurveda, traditional Chinese
> medicine, Unani, Sida) and scientific literature about the prior human
> use of the botanical product, and each of its ingredients, in
> traditional foods and drugs. Any literature submitted must be provided
> in English (and in its original language, if other than English)
> (§ 312.23(c)).

### 3. Current Marketed Use (§ 312.23(a)(3)(ii), (a)(9))

> The sponsor must include information about the nature and extent of
> the current worldwide use of the botanical product, and each of its
> ingredients, in foods and drugs, including evidence concerning its
> marketing experience in the United States and/or foreign countries.
> For a foreign-marketed botanical product, the sponsor should provide
> data that verify its safe human use, including proof of the annual
> sales volume, an estimate of the size of the exposure population, and
> the rate of adverse effects.

## B. Chemistry, Manufacturing, and Controls

##  

> Outlined below is the CMC information that we recommend you submit, in
> meeting the requirements of § 312.23(a)(7), in an IND to support a
> phase 1 or phase 2 clinical trial on a botanical product that is
> currently lawfully marketed without any known safety issues in the
> United States and/or a foreign country. Literature references and
> relevant official compendia or published standards should be provided
> whenever possible.

### 1. Botanical Raw Material (§ 312.23(a)(7)(i))

The information discussed in section VII.A.1 should be provided for all
currently lawfully marketed products. It is important for the safe
conduct of clinical trials to ensure the proper identity of botanical
raw materials used in the trials. Since there is no history of U.S.
experience for botanical raw materials marketed only outside the United
States, a certificate of authenticity of the plant and plant parts
should be provided for such materials. A trained professional who is
competent to determine authenticity should sign this certificate. This
information also should be provided, if available, for a botanical raw
material marketed in the United States.

### 2. Botanical Drug Substance (§ 312.23(a)(7)(iv)(a))

> The general method of preparation (e.g., pulverization, decoction,
> expression, aqueous extraction, or ethanolic extraction) must be
> provided under § 312.23(a)(7)(iv)(*a*). This is especially important
> where more than one process exists in the literature on which the
> safety of the botanical drug substance is based.

### 3. Botanical Drug Product (§ 312.23(a)(7)(iv)(b))

> A botanical drug product is manufactured from a botanical drug
> substance by adding one or more excipients, mixing, blending,
> granulating, tableting, encapsulating, or performing other
> dosage-form-specific procedures, followed by packaging. When packaged
> without further processing, a botanical drug substance is considered
> the drug product. We recommend that the following information be
> provided for a botanical drug product:

#### A qualitative description of the finished product, including the dosage form, route of administration, names of all ingredients (i.e., botanical drug substance and excipients), and a statement that the product is not adulterated with potent, toxic, or addictive botanical substances, synthetic or highly purified drugs, biotechnology-derived drugs, or other naturally derived drugs.

#### The composition or quantitative description of the finished product (i.e., the quantity of the botanical drug substance and each excipient, if any) expressed in terms of amount per dosage unit. We recommend that sponsors provide this information in tabular form.

**Example for a single-herb botanical drug product**

+------------------------+---------------------+----------------------+
| #                      | ######### **        | #########            |
| ######## **Component** | Amount per tablet** | **Amount per batch** |
+------------------------+---------------------+----------------------+
| Senna leaf extract     | 250 mg              | 10.0 kg (equivalent  |
|                        |                     | to 80.0 kg of dried  |
| (8:1 powdered aqueous  |                     | leaves)              |
| extract)               |                     |                      |
+------------------------+---------------------+----------------------+
| Excipient 1            | 100 mg              | 4.0 kg               |
+------------------------+---------------------+----------------------+
| Excipient 2            | 10 mg               | 0.4 kg               |
+------------------------+---------------------+----------------------+

The amount may also be expressed on the basis of amount of botanical raw
material (e.g., weight of dried leaves).

+-----------+-------------------------+-------------------------------+
| **Co      | ########                | #                             |
| mponent** | # **Amount per tablet** | ######## **Amount per batch** |
+-----------+-------------------------+-------------------------------+
| Senna     | 250 mg (equivalent to   | 10.0 kg (equivalent to 80.0   |
|           | 2000 mg dried leaves)   | kg of dried leaves)           |
+-----------+-------------------------+-------------------------------+
| Excipient | 100 mg                  | 4.0 kg                        |
| 1         |                         |                               |
+-----------+-------------------------+-------------------------------+
| Excipient | 10 mg                   | 0.4 kg                        |
| 2         |                         |                               |
+-----------+-------------------------+-------------------------------+

Example for a multi-herb botanical drug product:

+-------------------------------+---------------+---------------------+
| **Component**                 | **Amount per  | #######             |
|                               | tablet**      | ## Amount per batch |
+-------------------------------+---------------+---------------------+
| A 5:1 powdered, aqueous       | 600 mg        | 24 kg               |
| extract from 1:1 mixture of   |               |                     |
| *Forsythia suspensa* Vahl.    |               |                     |
| flowers and *Lonicera         |               |                     |
| japonica* Thunb. fruits       |               |                     |
+-------------------------------+---------------+---------------------+
| Excipient 1                   | 100 mg        | 4.0 kg              |
+-------------------------------+---------------+---------------------+
| Excipient 2                   | 10 mg         | 0.4 kg              |
+-------------------------------+---------------+---------------------+

#### The manufacturer′s certificate of analysis for the study product or, if none is available, authorization to allow FDA to cross-reference the manufacturer's previous submission for the relevant CMC information. If this information is unavailable for a foreign-marketed product, the sponsor should perform quality testing on the product according to the recommendations listed under section VIII.B.3. In addition to those tests, heavy metal analysis, and an animal safety test (see below), if applicable, should be performed. The test methods and results should be provided in the IND. The study product should be from a single source and, where feasible, from a single batch. A product sample from the batch to be used in the clinical study should be retained for possible future testing by FDA and/or the sponsor.

### 4. Animal Safety Test (§ 312.23(a)(8))

> An animal safety test (different from the rabbit pyrogen test, USP
> \<151\>) is an acute animal toxicity test applied only to injectable
> drug products. We recommend that this test be performed for crude
> extracts from natural sources, especially when the raw material,
> process, and final product cannot be fully characterized and
> controlled.

### 5. Placebo (§ 312.23(a)(7)(iv)(c))

> The components of any placebo used must be described.

### 6. Labeling (§ 312.23(a)(7)(iv)(d))

> The following labeling information must be provided:

#### A copy of the container label and the immediate outer carton label of the marketed product to be used in the clinical study.

#### 

#### A mock or printed representation of the proposed container label that will be provided to the investigators in the proposed clinical study. It should contain the following information: protocol number; patient number; sponsor′s name; product name or code number; strength and/or potency; recommended storage conditions; lot number; and (as required under § 312.6) the statement, "Caution: New drug \-- Limited by Federal law to investigational use." In a placebo-controlled clinical trial, both the study drug and the placebo should be properly labeled to protect the integrity of the blinded study.

### 7. Environmental Assessment or Claim of Categorical Exclusion (§ 312.23(a)(7)(iv)(e))

> A claim for categorical exclusion from the requirement for preparation
> of an environmental assessment (EA) ordinarily can be made for an IND
> (21 CFR 25.31(e)).

## C. Pharmacology/Toxicology Information 

### 1. All Marketed Botanical Products

> Under § 312.23(a)(8), previous human experience and available animal
> toxicity data concerning the clinical formulation and the individual
> botanical ingredients within the formulation must be provided to
> support initial clinical trials (phase 1 and phase 2) of a botanical
> drug product for the proposed use. As noted in section VI.A, initial
> studies for botanical products with no known safety concerns and that
> have been marketed in the United States as dietary supplements may
> generally be conducted without further pharmacologic/toxicologic
> testing. Nevertheless, available information should be provided. A
> database search should be conducted, when feasible, to identify
> information relevant to the safety and effectiveness of the following:

-   the final formulation of the intended commercial botanical drug
    product

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-   the individual botanical ingredients

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-   the known chemical constituents of the botanical ingredients.

> Under § 312.23(a)(8)(ii), an integrated summary of available data from
> medical and toxicological databases (e.g., Medline, Toxline, TOMES,
> RTEC) must be submitted for review. Using the information gathered
> from this literature, the sponsor should address, as appropriate for
> the proposed study, the following issues concerning the botanical drug
> product:

-   general toxicity

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-   target organs or systems of toxicity

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-   teratogenic, carcinogenic, or mutagenic potential of any botanical
    ingredient in the product

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-   relationship of dosage and duration to toxic responses

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-   pharmacological activity.

### 2. Foreign-Marketed Botanical Products

> For the reasons discussed in section VI, additional information must
> be provided in accordance with § 312.22(b) for a botanical product
> that has been previously marketed but not in the United States. In
> addition to the information listed above, the sponsor should provide
> data that support safe human use and should include the annual sales
> volume, an estimate of the size of the exposure population, and
> available data on the rate of adverse effects. The nature of
> nonclinical pharmacology/toxicology information needed before a
> sponsor conducts an initial clinical study will be determined on a
> case-by-case basis, depending on the indications, proposed dose,
> duration and size of study, and available data supporting safe human
> experience.

## D. Bioavailability

> Pharmacokinetic and pharmacodynamic information is helpful in the
> design and interpretation of clinical studies. Since botanical
> products often consist of more than one chemical constituent and the
> active constituents are often unknown, standard pharmacokinetic
> measurements to demonstrate systemic exposure to a product in animals
> and/or humans may be difficult to obtain. However, when feasible,
> sponsors are encouraged to monitor the blood levels of known active
> constituents, representative markers, or major chemical constituents
> in a botanical drug product (see section IX.D).

## E. Clinical Considerations

> The initial clinical trial for a botanical product currently marketed
> under the DSHEA will ordinarily be a well-controlled study capable of
> demonstrating effectiveness. Because the product is marketed and the
> dose that is thought to be appropriate and well tolerated is known,
> there should be little need for pilot or typical phase 1 studies, and
> uncontrolled observations are unlikely to be useful. Sponsors are
> therefore strongly encouraged to initiate more definitive trials early
> in the development program to determine whether a botanical product
> has efficacy for one or more claimed indications. Safety data should
> be collected during the trials. If there is doubt about the best dose
> of the product tested, a randomized, parallel, fixed-dose,
> dose-response study may be particularly useful as an initial trial.
>
> Regarding the safety of the drug, a botanical preparation lawfully
> marketed in the United States will generally be considered acceptable
> for at least short-term (e.g., up to several months) use in clinical
> trials. For foreign-marketed botanical products, safety considerations
> will be based on available CMC, pharmacology, and toxicology
> information, as well as indications, proposed doses, duration and size
> of the study, and available data supporting safe human use.

# VIII. INDs FOR PHASE 1 and PHASE 2 CLINICAL STUDIES FOR NONMARKETED BOTANICAL PRODUCTS and Products with known safety concerns

This section discusses the type of information that we recommend be
provided in meeting the requirements for INDs for initial trials of
botanicals that (1) have not previously been lawfully marketed in the
United States or elsewhere or (2) that have been marketed and have known
safety issues.

## A. Description of Product and Documentation of Human Use

> In addition to the information outlined in section VII.A.1-2, the
> following should be provided in accordance with the listed subsections
> of § 312.23 for each raw material contained in a botanical product not
> lawfully marketed in either the United States or other countries:

### 

### 1. Description of Botanicals Used (§ 312.23(a)(3)(i))

-   Morphological and anatomical description (including gender, if
    applicable) and a photograph of the plant or plant part, alga, or
    macroscopic fungus used

-   Natural habitat and geographical distribution of the plant, alga, or
    macroscopic fungus

-   Current sources of the plant, alga, or macroscopic fungus, including
    its geographical location and whether it is cultivated or harvested
    from the wild

-   A statement indicating whether the species is any of the following:

> − Determined to be endangered or threatened under the Endangered
> Species Act or the Convention on International Trade in Endangered
> Species of Wild Fauna and Flora;
>
> − Entitled to special protection under some other Federal law or
> international treaty to which the United States is a party;
>
> − The critical habitat of a species that has been determined to be
> endangered or threatened

### 2. History of Use (If Any) (§ 312.23(a)(3)(ii), (a)(9))

-   Method of preparation, processing, and formulation

-   Routes, schedules, and doses of administration

-   Medical claims

-   Contraindications and adverse events associated with use in humans
    and animals

-   Traditional geographical areas and populations in which such use
    occurred

-   A description of the similarities and/or differences between the
    traditional preparation and the proposed clinical formulation

### 3. Current Investigational Use (If Any) (§ 312.23(a)(3)(ii), (a)(9))

-   Proposed therapeutic claim and dose regimen (mg/kg/dose and
    dose/day)

-   All available information in the literature that addresses the
    proposed therapeutic claim, including both positive and negative
    studies

## B. Chemistry, Manufacturing, and Controls

> Outlined below is the CMC information that should be submitted, in
> meeting the requirements of § 312.23(a)(7), in an IND to support a
> phase 1 or phase 2 clinical trial using a botanical product that is
> not currently lawfully marketed in the United States or a foreign
> country, or for which there are known safety issues.

### 1. Botanical Raw Material (§ 312.23(a)(7)(i))

> A botanical drug substance can be derived from one or more botanical
> raw materials. The following recommendations apply to each individual
> botanical raw material used.
>
> The botanical raw material should be described as outlined in sections
> VII.A.1 and VIII.A.1. If the botanical raw material has no documented
> history of use, the IND sponsor should so indicate. The following
> information should be provided:

-   Identification by trained personnel of the plant, plant parts, alga,
    or macroscopic fungus used, including organoleptic, macroscopic, and
    microscopic examination. The identification should be done against a
    voucher specimen (reference specimen). If more than one variety of a
    given species is used, each should be specified. A sample of the
    plant, plant parts, or other botanical materials should be retained
    and stored under appropriate conditions by the raw material supplier
    and botanical drug substance manufacturer for each batch. These
    samples will be used for verification of identity, if needed.

-   A certificate of authenticity

-   A list of all grower(s) and/or supplier(s) (including names and
    addresses). The following items should be provided for each
    grower/supplier, if available:

> − Harvest location
>
> − Growth conditions
>
> − Stage of plant growth at harvest
>
> − Harvest time
>
> − Collection, washing, drying, and preservation procedures
>
> − Handling, transportation, and storage conditions

### 2. Botanical Drug Substance (§ 312.23(a)(7)(iv)(a))

The following information should be provided for all botanical drug
substances, regardless of whether they are prepared from one or more
botanical raw materials:

#### A qualitative description of the drug substance, including the name, appearance, physical and chemical properties, active constituent (if known), biological activity (if known), and clinical indication (if known) of each botanical raw material. If the active constituent, biological activity, and/or clinical indication is unknown, the IND sponsor should clearly so state. In the case of a multi-herb substance, the sponsor should state whether the drug substance is prepared by combining individually processed botanical drug substances or by processing combined botanical raw materials.

#### The quantitative description (strength) of the drug substance. Historically, the strength of a botanical drug substance is expressed simply as the absolute dry weight of the processed substance. The batch size and the yield of the process, relative to the botanical raw material, also should be indicated. Furthermore, where the active constituents or other chemical markers are known and measurable, the amount in which they are present in the botanical drug substance should be declared. For a multi-herb substance, its composition should be expressed in terms of the relative ratio of the individually processed botanical drug substances or of the botanical raw materials before processing, whichever is appropriate.

#### The name and address of the drug substance manufacturer (processor).

#### A description of the manufacturing process for the botanical drug substance. The description should include the quantity of botanical raw material, solvents, extraction and/or drying, and yield. The yield of the process, expressed as the amount of the original botanical raw material relative to the amount of the extract, also should be indicated. If more than one botanical raw material is introduced to produce a multi-herb substance, the quantity of each raw material and the sequence of addition, mixing, grinding, and/or extraction should be provided. If a multi-herb substance is prepared by combining two or more individually processed botanical drug substances, the process leading to each botanical drug substance should be described separately.

#### 

#### The quality control tests performed on each batch of the drug substance, the analytical procedures used, and the available test results. These tests should include, but need not be limited to, the following attributes:

#### 

> -- Appearance
>
> -- Chemical identification by spectroscopic and/or chromatographic
> fingerprints. Examples of spectroscopic methods include ultraviolet,
> infrared, Fourier transformed infrared, and mass spectroscopy.
> Examples of chromatographic methods include high performance liquid
> chromatography (HPLC), HPLC with diode array detection, thin layer
> chromatography (TLC), 2-dimensional-TLC, and gas chromatography.
>
> -- Chemical assay (i.e., assay) for active constituents or
> characteristic markers. If several botanical raw materials are
> combined to produce a multi-herb substance and a quantitative
> determination of each individual active constituent or marker is
> infeasible, a joint determination can be made for several active
> constituents or markers. When multiple active constituents or markers
> are known, they should be chemically characterized and their relative
> amounts should be defined.
>
> -- Biological assay (when the active chemical constituent(s) are not
> known or quantifiable), if available. If the botanical drug substance
> is considered potent (i.e., highly active), toxic, addictive, or has
> abuse potential (e.g., ephedra or marijuana), an assay for biological
> activity and/or a chemical assay for the active constituent(s) should
> be performed.
>
> -- Strength by dry weight (equivalent to botanical raw material)
>
> -- Heavy metals
>
> -- Microbial limits
>
> -- Animal safety test, if applicable

#### A description of the container/closure in which the botanical drug substance is to be stored and/or shipped.

#### 

#### Available stability data on the drug substance. The sponsor should develop stability-indicating analytical methods and conduct stability studies as the IND progresses.

#### 

#### The container label, which should reflect the qualitative and quantitative description of the botanical drug substance, as discussed above, and recommended storage conditions. Examples of labeling for single-herb and multi-herb substances are shown below:

> [Single-herb substance]{.underline}:
>
> − Expressed in terms of yield:
>
> Senna, 10 kg, equivalent to 80 kg of dried leaves
>
> or
>
> Senna, 10 kg, 8:1 (w/w) powdered extract of dried leaves
>
> − Expressed in terms of active constituents:
>
> Senna, 10 kg extract, containing 2 kg of hydroxyanthracene glycosides
> (sennosides), calculated as sennoside B
>
> − Expressed in terms of chemical markers:
>
> Valerian, 10 kg extract, containing 0.1 kg valerinic acid
>
> [Multi-herb substance]{.underline}:
>
> − Prepared by combining individually processed botanical drug
> substances:
>
> *Lonicera japonica* Thunb. and *Forsythia suspensa* Vahl., 6 kg,
> containing 3 kg of *Lonicera japonica* Thunb. 4:1 solid extract and 3
> kg of *Forsythia suspensa* Vahl. 6:1 solid extract
>
> − Prepared by processing combined botanical raw materials:
>
> *Lonicera japonica* Thunb. and *Forsythia suspensa* Vahl., 6 kg, a 5:1
> powdered extract prepared from 15 kg of *Lonicera japonica* Thunb. and
> 15 kg of *Forsythia suspensa* Vahl

### 3. Botanical Drug Product (§ 312.23(a)(7)(iv)(b))

> The following information should be provided:

-   A qualitative description of the finished product (see section
    VII.B.3.)

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-   The composition, or quantitative description, of the finished
    product (i.e., the name and quantity of the botanical drug substance
    and of each excipient (if any), expressed in terms of amount per
    dosage unit and amount per batch). This information should be
    provided in tabular form. A quantitative description of the drug
    substance should be provided as described in section VIII.B.2.

> Example:

+--------------+-------------------------+-----------------------------+
| *            | ####                    | ######### Amount per batch  |
| *Component** | ##### Amount per tablet |                             |
+--------------+-------------------------+-----------------------------+
| Senna        | 250 mg (equivalent to   | 10.0 kg (equivalent to 80.0 |
|              | 2000 mg dried leaves)   | kg of dried leaves)         |
+--------------+-------------------------+-----------------------------+
| Excipient 1  | 100 mg                  | 4.0 kg                      |
+--------------+-------------------------+-----------------------------+
| Excipient 2  | 10 mg                   | 0.4 kg                      |
+--------------+-------------------------+-----------------------------+

-   The name and address of the manufacturer of the finished drug
    product

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-   A description of the manufacturing process. (If the botanical drug
    substance is filled and packaged directly as the finished product
    without the addition of excipients and further processing, this item
    and items listed in the immediately preceding two bullets will not
    apply.)

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-   A list of the quality control tests performed on each batch of the
    drug product, and the analytical procedures used and the available
    test results. These tests should include, but need not be limited
    to, the following attributes:

> -- Appearance
>
> -- Chemical identification by spectroscopic and/or chromatographic
> fingerprints
>
> -- Assay for active constituents or characteristic markers, if
> available. If several botanical raw materials are combined to produce
> a multi-herb substance and a quantitative determination of each
> individual active constituent or marker is infeasible, a joint
> determination can be carried out for several active constituents or
> markers. When multiple active constituents or markers are known, they
> should be chemically characterized and their relative amounts should
> be defined.
>
> -- Biological assay (when the active chemical constituent(s) are not
> known or quantifiable), if available. If the botanical drug substance
> is considered potent (i.e., highly active), toxic, addictive, or has
> abuse potential (e.g., ephedra or marijuana), an assay for biological
> activity and/or a chemical assay for the active constituent(s) should
> be performed.
>
> -- Strength by dry weight (of drug substance)
>
> -- Microbial limits
>
> -- Other attributes specific to the dosage form of interest (e.g.,
> dissolution for solid oral dosage forms, sterility and nonpyrogenicity
> for parenterals, animal safety test for parenterals, when
> appropriate).

-   A description of the container/closure in which the drug product is
    to be packaged

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-   Available stability data on the drug product. The sponsor should
    develop stability-indicating analytical methods (using markers when
    feasible) and conduct stability studies as the IND progresses.

### 4. Placebo (see section VII.B.5)

### 5. Labeling (see section VII.B.6)

> Additionally, a quantitative description of the drug substance per
> dosage unit (as described in section VIII.B.2.h and 3.b) should be
> provided. An example of a quantitative description for a multi-herb
> botanical drug product is shown below:
>
> BRAND X. 100 tablets. Each 1-gram tablet contains:
>
> 300 mg of *Lonicera japonica* Thunb.4:1 solid extract and
>
> 300 mg of *Forsythia suspensa* Vahl. 6:1 solid extract

### 6. Environmental Assessment or Claim of Categorical Exclusion

> A claim for categorical exclusion from the requirement for preparation
> of an EA ordinarily can be made for an IND (§ 25.31(e)). However, FDA
> will require at least an EA for any specific action that ordinarily
> would be excluded if extraordinary circumstances indicate that the
> specific proposed action may significantly affect the quality of the
> human environment (21 CFR 25.21; 40 CFR 1508.4). CDER will evaluate
> INDs on a case-by-case basis when the drug or biological product is
> derived from wild plants or animals to determine whether the
> extraordinary circumstance provision in § 25.21 is applicable. FDA
> encourages early consultation with the Agency on environment-related
> aspects of a requested action, especially one that involves harvesting
> a wild species, to ensure that planning and decisions reflect
> environmental values, avoid delays later in the process, and avoid
> potential conflicts (§ 25.10(b) and (c)). For additional information,
> see 21 CFR part 25, 40 CFR parts 1500-08, and the CDER/CBER guidance
> for industry on *Environmental Assessment of Human Drug and Biologics
> Applications* (July 1998). An environmental assessment or a claim for
> categorical exclusion must be provided as required under § 25.15(a).

## C. Nonclinical Safety Assessment

### 1. Traditional Preparations

> Nonclinical pharmacology and toxicology studies are particularly
> important in establishing the safety of a new botanical drug for which
> there is no current marketing experience. The information is used for
> assessing the botanical drug\'s risk-to-benefit ratio, guiding early
> clinical studies, and predicting potential toxicity.
>
> Because of their extensive use in humans, there may be sufficient
> information on traditional herbal medicines to support initial
> clinical studies without standard nonclinical testing. Therefore, such
> products may require fewer nonclinical safety studies under
> § 312.23(a)(8) than would be expected for synthetic or highly purified
> drugs with which there is little experience.
>
> A traditional herbal preparation, which may have evolved over time,
> generally has the following characteristics:

-   It meets official compendia or other published standards in terms of
    the botanical identity and plant part used for each botanical raw
    material.

-   In the case of a multi-herb substance, it is composed of the same
    formulation as a historical formula, with the amount of each
    botanical ingredient falling within the range of traditional usage.

-   It is prepared by the same processing methodology as traditionally
    used.

-   It is used in the traditional manner in terms of therapeutic
    indication, route and schedule of administration, and quantities or
    doses.

> For initial clinical studies on a botanical drug product that is not
> currently lawfully marketed in the United States or elsewhere but is
> prepared, processed, and used by humans according to an established
> methodology, sufficient information might be available to support the
> studies without standard nonclinical testing. In general, the
> considerations listed under section VII.C are applicable. When the
> initial clinical study for such a drug shows promising results and
> further clinical development of the drug is intended, pharmacology and
> toxicology studies carried out prior to the later phases of the
> clinical trials may be needed to support a risk-benefit assessment and
> to identify potential toxicities not readily detected in clinical
> studies (see section IX.C below).

### 2. Others

> For a botanical product that is not prepared according to a
> traditional methodology, the extent of variation from the traditional
> formulation, preparation, or processing should be described in full
> detail. The nature of nonclinical pharmacology/toxicology information
> needed before conducting an initial clinical study (in addition to
> that described under section VII.C) will be determined on a
> case-by-case basis, depending on the indications, extent of safe human
> experience, and safety concerns about the new formulation,
> preparation, or processing methodology used.

### 3. Products with Known Safety Issues

### 

> For those botanical drugs for which there are known safety issues, the
> nature of the nonclinical pharmacology/toxicology information needed
> will be determined on a case-by-case basis to address those issues
> (see section VI.A).

## D. Bioavailability

> Pharmacokinetic and pharmacodynamic information is helpful in the
> design and interpretation of clinical studies. As stated in section
> VII.D, a botanical product's active constituents may be unknown, and
> standard pharmacokinetic measurements to demonstrate systemic exposure
> to a product in animals and/or humans may be infeasible due to the
> complexity of the botanical drug. However, when feasible, a sponsor is
> encouraged to monitor the blood levels of known active constituents,
> representative markers, or other major chemical constituents in a
> botanical drug product. Because there is less human use experience
> with botanical products that have never been lawfully marketed than
> with those that have been, a sponsor of a drug that has not been
> lawfully marketed should consult FDA's guidances *Drug Metabolism/Drug
> Interaction Studies in the Drug Development Process: Studies In Vitro*
> (April 1997) and *In Vivo Drug Metabolism/Drug Interaction
> Studies---Design, Data Analysis, and Recommendations for Dosing and
> Labeling* (November 1999) to assess potential drug-drug interaction
> when a clinical study includes co-administration with another drug
> (see section IX.D).
>
> For a botanical product that is prepared according to traditional
> methodology, the nature of clinical pharmacology information needed
> should be determined on a case-by-case basis, depending on the
> indications, extent of human experience, target patient population,
> and projected length of clinical use.

## E. Clinical Considerations

> In general, initial clinical investigations of nonmarketed botanical
> preparations should be similar to those of marketed products (see
> section VII.E). Because of the lack of current marketing experience,
> however, greater concerns could exist about toxicity. Therefore, FDA
> will seek greater assurance of the safety of the product for initial
> clinical trials in the United States. Such assurance may be provided
> in the form of additional chemical analysis and/or additional
> toxicology data. It may also be helpful to provide documentation of
> the product′s previous safe human use by referencing literature and/or
> pharmacopoeias.

# 

# IX. INDs FOR PHASE 3 CLINICAL STUDIES OF ALL BOTANICAL PRODUCTS

When conducting expanded (i.e., phase 3) clinical studies on a botanical
drug product, an IND sponsor is expected to provide more detailed
information on CMC and nonclinical safety than when conducting a phase 1
or phase 2 study (§ 312.22(b), 312.23(a)(7)(i) and (8)). The better
definition of the product will ensure an ability to apply data from
trials to a well-controlled, reproducible substance. The additional
toxicology data are needed to support wider use. This additional
information should be provided regardless of whether the product is
currently lawfully marketed in the United States or elsewhere as a
dietary supplement.

For phase 3 clinical studies of a botanical product, the following
information should be provided in meeting the requirements of § 312.23:

## A. Description of Product and Documentation of Human Experience

See sections VII.A and VIII.A for guidance on how to describe the
botanical product and human experience with it.

## B. Chemistry, Manufacturing, and Controls

> To support phase 3 clinical trials of a botanical product, regardless
> of its marketing experience in the United States or other countries,
> the following CMC information should be provided in accordance with
> § 312.23(a)(7) unless already submitted in the IND for phase 1/phase 2
> studies on the product:

### 1. Expanded Clinical Studies

a.  Botanical raw material

-   A description of the botanical raw material as outlined in sections
    VII.A.1 and VIII.A.1. If the botanical has no documented history of
    use, this should be indicated. Proper identification by trained
    personnel of the plant, plant parts, alga, or macroscopic fungus
    used, including organoleptic, macroscopic, and microscopic
    examination, should be provided. The identification should be done
    against a voucher specimen (reference specimen). If more than one
    variety or source of a given species is used, they should be blended
    in a fixed proportion in a consistent manner. A sample of the plant,
    plant parts, or other botanical materials should be retained for
    every batch by the raw material supplier and drug substance
    manufacturer, and stored under appropriate conditions for future
    verification of identity. In addition, a certificate of authenticity
    and information on the grower and/or supplier, growing conditions
    (including pesticides used), harvest location, harvest time
    (including stage of plant growth at harvest), handling, and shipping
    should be provided.

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-   A spectroscopic and/or chromatographic fingerprint of each botanical
    raw material and the chemical identity of the active constituents or
    characteristic markers in the botanical raw material

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-   The name and address of the botanical raw material manufacturer
    (processor)

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-   A description of the preparation of the botanical raw material,
    including collection, washing, drying, preservation, and/or
    detoxification and preservation procedures. Equipment and quantity
    used, temperature employed, processing time, in-process controls,
    and yield should be specified.

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-   The quality control tests and analytical procedures applied by the
    botanical raw material supplier, and the proposed acceptance
    criteria. These tests should include, but need not be limited to,
    the following attributes:

> -- Botanical identification
>
> -- Chemical identification by spectroscopic and/or chromatographic
> fingerprint
>
> -- Chemical identification for active constituents or characteristic
> markers if active constituents are not known
>
> -- Assay for active constituents or characteristic markers if active
> constituents are not known
>
> -- Biological assay (when the active chemical constituents are not
> known or quantifiable), if available
>
> -- Heavy metals
>
> -- Microbial limits
>
> -- Residual pesticides, including parent pesticides and their major
> toxic metabolites
>
> -- Adventitious toxins (e.g., aflatoxins)
>
> -- Foreign materials and adulterants
>
> In some cases (e.g., when the botanical raw material undergoes further
> processing to prepare the botanical drug substance), reduced testing
> may be appropriate for certain assays (e.g., heavy metals), if these
> assays are routinely performed on the botanical drug substance. If
> some of these tests cannot be performed by the raw material supplier,
> the botanical drug substance manufacturer should perform the tests
> upon receipt of the botanical raw material.

-   A photocopy of the voucher specimen (reference specimen) of the
    botanical raw material used in identification, fingerprinting, and
    other comparative and noncomparative tests

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-   A certificate of analysis for representative batch(es) of the
    botanical raw material

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-   A description of the storage conditions, including the
    container/closure system and temperature

#### b. Botanical drug substance (§ 312.23(a)(7)(iv)(*a*))

-   A qualitative and quantitative description of the drug substance and
    the name and address of the manufacturer (see section VIII.B.2).

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-   A chemical identification for the active constituents or
    characteristic markers in the drug substance, if possible. If the
    chemical identity is unknown, a representative spectroscopic and/or
    chromatographic fingerprint may suffice.

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-   Appropriate acceptance specifications (tests, test procedures, and
    acceptance criteria) for the botanical raw material, similar to the
    list of quality control specifications in section IX.B.1.a,
    established by the botanical drug substance manufacturer. Upon
    receipt of each batch of the raw material and its certificate of
    analysis, the manufacturer should, at a minimum, conduct an
    identification test and assay.

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-   A description of the manufacturing process for the botanical drug
    substance. The description should include the quantity of botanical
    raw material, equipment, solvents, temperature/time for mixing,
    grinding, extraction and/or drying, yield, and in-process controls.
    The yield of the process, expressed as the amount of the original
    botanical raw material relative to the amount of the extract, also
    should be indicated. If more than one botanical raw material is
    introduced to produce a multi-herb substance, the quantity of each
    raw material and the sequence of addition, mixing, grinding, and/or
    extraction should be provided. If a multi-herb substance is prepared
    by combining two or more individually processed botanical drug
    substances, the process leading to each botanical drug substance
    should be described separately.

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-   The quality control tests performed on each batch of drug substance,
    the analytical procedures used, and the proposed acceptance
    criteria. These tests should include, but need not be limited to,
    the following attributes:

> -- Appearance
>
> -- Chemical identification by spectroscopic and/or chromatographic
> fingerprints
>
> -- Chemical identification for the active constituents or, if unknown,
> the characteristic markers
>
> -- Chemical assay for the active constituents, or the characteristic
> markers if the active constituents cannot be determined. If several
> botanical raw materials are combined to produce a multi-herb substance
> and a quantitative determination of each individual active constituent
> or marker is infeasible, a joint determination can be made for several
> active constituents or markers. When multiple active constituents or
> markers are known, they should be chemically characterized and their
> relative amounts should be defined.
>
> -- Biological assay (when the active chemical constituents are not
> known or quantifiable), if available. If the botanical drug substance
> is considered potent (i.e., highly active), toxic, or addictive, or
> has abuse potential (e.g., ephedra or marijuana), an assay for
> biological activity and/or a chemical assay for the active
> constituent(s) should be performed.
>
> -- Strength by dry weight
>
> -- Residue on ignition
>
> -- Water content
>
> -- Residual solvents
>
> -- Heavy metals
>
> -- Microbial limits
>
> -- Animal safety test, if applicable
>
> -- Residual pesticides
>
> -- Radioisotope contaminants, if applicable
>
> -- Adventitious toxins (e.g., aflatoxins)
>
> -- Endogenous toxins (e.g., pyrrolizidine alkaloids)
>
> -- Other attributes specific to the botanical raw materials from which
> the drug substance is derived

-   Validation reports of all analytical procedures, where appropriate

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-   A description of the batch of botanical drug substance designated as
    the *reference standard* for use in fingerprinting and other
    comparative tests

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-   Batch analysis (i.e., test results for representative batches)

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-   A description of the container and closure used to package the
    botanical drug substance

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-   Sufficient stability data on the drug substance to support its safe
    use during clinical studies; stability-indicating analytical methods

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-   Information on the container label as described in section VIII.B.2

#### c. Botanical drug product (§ 312.23(a)(7)(iv)(*b*))

-   A qualitative description and the composition of the dosage form and
    the name and address of the manufacturer (see section VIII.B.3)

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-   Appropriate acceptance specifications established by the botanical
    drug product manufacturer for the botanical drug substance, similar
    to the quality control tests in section IX.B.1.b. Upon receipt of
    each batch of the drug substance and its certificate of analysis,
    the manufacturer should, at a minimum, conduct an identification
    test and assay.

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-   A description of the manufacturing process, without the actual batch
    record. The description should include weighing, mixing, blending,
    sieving, in-process controls, and other processes, as appropriate.

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-   The quality control tests performed on each batch of drug product,
    the analytical procedures used, and the proposed acceptance
    criteria. These tests should include, but need not be limited to,
    the following attributes:

> -- Appearance
>
> -- Chemical identification by spectroscopic and/or chromatographic
> fingerprints
>
> -- Chemical identification for the active constituents or, if unknown,
> the characteristic markers
>
> -- Chemical assay for active constituents or, if unknown, the
> characteristic markers. If several botanical raw materials are
> combined to produce a multi-herb substance and a quantitative
> determination of each individual active constituent or marker is
> infeasible, a joint determination can be made for several active
> constituents or markers. When multiple active constituents or markers
> are known, they should be chemically characterized and their relative
> amounts should be defined.
>
> -- Biological assay (when the active chemical constituent(s) are not
> known or quantifiable), if available. If the botanical drug substance
> is considered potent (i.e., highly active), toxic, addictive, or has
> abuse potential (e.g., ephedra or marijuana), an assay for biological
> activity and/or a chemical assay for the active constituent(s) should
> be performed.
>
> -- Strength by dry weight (of drug substance)
>
> -- Residual solvents
>
> -- Microbial limits
>
> -- Adventitious toxins (e.g., aflatoxins)
>
> -- Other attributes specific to the dosage form of interest (e.g.,
> dissolution for solid oral dosage forms, sterility for parenterals,
> animal safety test for parenterals, when appropriate).

-   Validation reports of all analytical procedures, where appropriate

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-   Batch analysis (i.e., test results for representative batches)

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-   A description of the container and closure used to package the
    finished product

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-   Sufficient stability data on the drug substance to support its safe
    use during clinical studies. Stability-indicating analytical methods
    should be established.

#### d. Placebo (see section VII.B.5)

#### e. Labeling (see sections VII.B.6 for investigational labels and VIII.B.5 for

#### quantitative description)

#### f. An EA or a claim of categorical exclusion (see section VIII.B.7)

### 

### 2. End-of-Phase 3 Clinical Studies and Pre-NDA Considerations

> Sponsors must continue to characterize the drug substance and the drug
> product throughout the entire clinical development program
> (§ 312.23(a)(7)). By the end of the phase 3 clinical trial, as the
> sponsor prepares to submit an NDA, the following objectives should be
> reached:

-   Adequate controls for botanical raw materials should be established.

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-   The manufacturing processes of the drug substance and the drug
    product should be finalized and validated, and in-process controls
    should be established. An executed batch record should be available.

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-   Batch-to-batch consistency should be demonstrated for the botanical
    drug substance and drug product based on results from all chemical,
    physical, and biological tests on all relevant batches. To achieve
    this goal, multiple fingerprints, using a combination of analytical
    methods with different separation principles and test methods, can
    be useful. All chemical constituents detected by spectroscopic
    and/or chromatographic fingerprinting should be qualitatively and
    quantitatively comparable from batch to batch.

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-   Appropriate specifications (i.e., tests, analytical procedures, and
    acceptance criteria), including identification and assay for active
    constituents, identification and assay for characteristic markers,
    and/or biological assay (when the active chemical constituent(s) are
    not known or quantifiable), should be established to control the
    quality of the drug substance and product. Both the active
    constituents and the biological assay should be clinically relevant.
    If the identity of the active constituents is not known or a
    suitable assay cannot be developed, the characteristic markers
    should be demonstrated to be clinically relevant by direct or
    indirect correlation to the clinical outcome.

-   Analytical procedures should be properly validated. Analytical
    procedures used for fingerprinting should be verified for
    specificity and should be capable of detecting as many chemical
    classes (e.g., proteins, carbohydrates, fatty acids, small organic
    compounds) present and as many individual chemical constituents as
    possible. Additionally, when multiple fingerprints are used, the
    analytical procedures in combination should be able to demonstrate
    the mass balance in the test sample, on the basis of the different
    classes of chemicals and, if appropriate, among the individual
    constituents detected within a chemical class.

-   A suitable voucher specimen (reference specimen) for each of the
    botanical raw materials should be established, along with a
    reference standard for the drug substance and drug product.

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-   Stability-indicating analytical methods should be developed to
    monitor the stability of the drug substance and drug product. The
    stability of a botanical drug substance or product generally should
    not be based entirely on the assay of the active constituents, assay
    of the characteristic markers, or biological assay, because
    degradants formed during storage from other chemical constituents in
    the botanical drug substance or product should also be controlled.
    An analytical method capable of detecting these degradants (such as
    a spectroscopic and/or chromatographic fingerprint) should be
    established through exploratory studies by subjecting the drug
    substance and drug product to stress conditions.

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-   A biological assay, when used for characterization and quality
    control of a drug substance and drug product, should be properly
    validated. The ICH Guideline *Q6B Specifications: Test Procedures
    and Acceptance Criteria for Biotechnological/Biological Products*
    (August 1999) and the USP XXV *Biological Tests \<111\>: Design and
    Analysis of Biological Assays* provide useful information on
    biological assays. Performing a biological assay calls for the use
    of a suitable reference standard and, frequently, positive and
    negative controls. Because biological assays are usually more
    variable than chemical assays, a relatively higher coefficient of
    variation is generally justifiable.

-   A comparison of the similarities and/or differences in CMC among the
    nonclinical, clinical, and intended commercial products should be
    made regarding raw materials, drug substance, and drug product.

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-   The manufacturing, processing, and controls (receipt,
    identification, storage, handling, sampling, testing, and approval
    or rejection of components, drug products, and container closures)
    for botanical drug products must be in conformance with CGMP as set
    forth in 21 CFR parts 210 and 211. In addition, the manufacturing,
    processing, and controls for the botanical drug substance (starting
    from the botanical raw material) should be in conformance with CGMP
    because these elements can affect the quality, safety, and efficacy
    of the drug product. A satisfactory inspection is necessary for NDA
    approval.

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-   A sponsor should be preparing the submission in the NDA of either an
    EA or a claim for categorical exclusion from the requirement for
    preparation of an EA (§ 25.15(a)). Classes of NDAs that are
    categorically excluded and, therefore, ordinarily do not require
    preparation of an EA are listed in § 25.31. However, FDA will
    require at least an EA for any specific action that ordinarily would
    be excluded if extraordinary circumstances indicate that the
    specific proposed action may significantly affect the quality of the
    human environment (§ 25.21; 40 CFR 1508.4). The Agency regards the
    submission of an NDA for a drug derived from plants taken from the
    wild as an extraordinary circumstance requiring the submission of an
    EA. See section VIII.B.6 for additional information.

> Applicants are encouraged to discuss with the review division any CMC
> issues regarding a botanical drug prior to the preparation and
> submission of an NDA.

## C. Nonclinical Safety Assessment 

> To support safety for expanded clinical studies or to support
> marketing approval of a botanical drug product, toxicity data from
> standard toxicology studies in animals may be needed in accordance
> with § 312.23(a)(8). A botanical product submitted for marketing
> approval as a drug will be treated like any other new drug under
> development. Safety data from previous clinical trials conducted in
> foreign countries will be considered in determining the need for
> nonclinical studies. However, previous human experience may be
> insufficient to demonstrate the safety of a botanical drug product,
> especially when it is indicated for chronic therapy. Systematic
> toxicological evaluations could be needed to supplement available
> knowledge on the general toxicity, teratogenicity, mutagenicity, and
> carcinogenicity of the final botanical drug product. Depending on the
> indication (e.g., target patient population, disease to be treated),
> route of administration, and duration of recommended drug exposure,
> the timing of these animal studies in relation to concurrent clinical
> trials and other requirements for nonclinical animal studies can vary.
>
> In general, animal studies should, as much as possible, be conducted
> using the same drug substance prepared and processed in the same
> manner as the drug substance used in clinical trials.
>
> The following are points to consider in preparing a nonclinical
> pharmacology/toxicology development plan for a botanical drug product
> that is intended to be used in large-scale human trials or to support
> an NDA. If questions arise during any stage of the clinical
> development of a botanical drug, sponsors are encouraged to consult
> the appropriate review division in CDER.

### 1. Repeat-Dose General Toxicity Studies

> The primary objective of long-term, repeat-dose toxicity studies in
> animals is to identify the organs and/or systems that are the targets
> of the drug's toxicity and the threshold doses for producing toxic
> effects. The studies provide information valuable for designing
> long-term clinical studies at safe doses, with appropriate monitoring
> for predicted adverse reactions. Existing literature on the animal
> toxicity of a botanical drug is often limited to single-dose (acute)
> studies. These studies would be inadequate to support long-term use.
>
> To support expanded clinical trials, repeat-dose toxicity of a
> botanical drug should usually be evaluated in two mammalian species
> (one of which is a nonrodent) by employing sufficiently high doses to
> produce a toxic effect or by using a maximum feasible dose. If
> possible, the drug should be tested using the same route of
> administration as proposed for clinical use. Animal studies should be
> of a duration at least equal to that of the clinical trial (usually a
> minimum of 2 weeks). Routinely, general animal toxicity studies need
> not exceed 6 months of testing in a rodent species and 9 months of
> testing in a nonrodent species. For additional information on the
> timing of animal toxicity studies in relation to clinical trials, see
> the ICH guidance *M3 Nonclinical Safety Studies for the Conduct of
> Human Clinical Trials for Pharmaceuticals* (November 1997).

### 2. Nonclinical Pharmacokinetic/Toxicokinetic Studies

> In the development of a new drug that is a single molecular entity, it
> is often useful to compare pharmacokinetics in animals and humans and
> to relate exposure levels to toxicities in both animals and humans.
> Because botanical drugs usually consist of more than one chemical
> constituent, standard pharmacokinetic measurements to substantiate the
> systemic exposure of a botanical drug product in animals may be
> technically infeasible. However, monitoring representative chemical
> constituents in a botanical drug can provide valuable information
> regarding systemic exposure. Depending on the complexity of the
> botanical drug product to be studied, pharmacokinetics could be
> helpful in the design and interpretation of toxicity studies. For
> additional information on toxicokinetic evaluations, see the ICH
> guidances *S3A Toxicokinetics: The Assessment of Systemic Exposure in
> Toxicity Studies* (March 1995) and *S3B Pharmacokinetics: Guidance for
> Repeated Dose Tissue Distribution Studies* (March 1995).

### 3. Reproductive Toxicology

> Reproductive toxicology studies, such as those on
> fertility/reproductive performance, teratology, and prenatal/perinatal
> development in animals, provide information on the potential of a
> botanical drug for producing toxicity during the different stages of
> reproductive and developmental processes. In the absence of documented
> data on reproductive toxicity in humans or animals, these tests should
> be conducted prior to expanded clinical trials. For detailed
> information regarding reproductive toxicology, sponsors should refer
> to the ICH guidances *S5A Detection of Toxicity to Reproduction for
> Medicinal Products* (September 1994) and *S5B Detection of Toxicity to
> Reproduction for Medicinal Products: Addendum on Toxicity to Male
> Fertility* (April 1996).

### 4. Genotoxicity Studies

> We recommend that information on the potential of a botanical drug to
> produce genetic toxicity be obtained as early as possible, preferably
> before the initiation of human clinical trials (see ICH *M3
> Nonclinical Safety Studies for the Conduct of Human Clinical Trials
> for Pharmaceuticals* (November 1997)). A complete assessment of
> genetic toxicity may be needed before expanded clinical trials. A
> standard battery of tests is defined in the ICH guidances *S2A
> Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals*
> (April 1996) and *S2B Genotoxicity: A Standard Battery for
> Genotoxicity Testing of Pharmaceuticals* (November 1997).
>
> If the standard battery of tests chosen indicate that a drug is devoid
> of genetic toxicity, additional genotoxicity studies may not be needed
> to comply with § 312.23(a)(8)(ii)(*a*). If one or more test results
> are positive, the sponsor may need to carry out additional
> genotoxicity tests to comply with this provision, in consultation with
> the appropriate CDER review division.

### 5. Carcinogenicity Studies

> Carcinogenicity studies may be needed to comply with
> § 312.23(a)(8)(ii)(*a*) to support marketing approval of a botanical
> drug, depending on the duration of therapy or any specific cause for
> concern. The toxicity profile of the botanical drug and the indication
> and duration of the intended use may influence the need under this
> regulation for carcinogenicity studies and their timing relative to
> clinical development (see ICH *S1A The Need for Long-Term Rodent
> Carcinogenicity Studies of Pharmaceuticals* (March 1996)). Draft
> protocols for carcinogenicity studies should be submitted to the
> appropriate review division and the CDER Carcinogenicity Assessment
> Committee for review and concurrence prior to the initiation of such
> studies to ensure the acceptability of dose selection and study
> design. Study types should be in accordance with the ICH guidance *S1B
> Testing for Carcinogenicity of Pharmaceuticals* (February 1998). Doses
> used should be chosen according to the principles outlined in the ICH
> guidances *S1C Dose Selection for Carcinogenicity Studies of
> Pharmaceuticals* (March 1995) and *S1C(R) Dose Selection for
> Carcinogenicity Studies of Pharmaceuticals: Addendum on a Limit Dose
> and Related Notes* (December 1997).

### 6. Special Pharmacology/Toxicology Studies

> A general evaluation of the pharmacological effects of a drug on
> physiological functions (e.g., central nervous system, cardiovascular
> system) is often performed during new drug development. This
> evaluation can be accomplished using established in vitro and in vivo
> assays of broad specificity that screen for the modes and sites of
> action of the botanical drug. When significant and unique toxicities
> to certain organs and/or systems are evident, the sponsor should
> provide further explanation of the mechanism of toxic actions, if
> appropriate, by performing additional in vitro or in vivo studies.

### 7. Regulatory Considerations

> Nonclinical toxicity studies conducted as part of botanical drug
> development and intended to support safety must be in accordance with
> regulations governing good laboratory practices under 21 CFR part 58.
> Both the drug substance and the drug product should be made with
> batch-to-batch consistency. If changes occur in the drug substance or
> product during clinical development, bridging toxicity studies might
> be needed to comply with § 312.23(a)(8)(ii)(*a*).

## D. Bioavailability and Clinical Pharmacology

> The general requirements for in vivo bioavailability data in an NDA,
> described in § 320.21, are applicable to botanical drug products. The
> type of bioavailability study that is appropriate for a specific
> botanical drug product is based on the following: (1) information on
> the active constituent, if known; (2) the complexity of the drug
> substance; and (3) the availability of analytical methods. Because
> there could be more than one active constituent in a botanical drug or
> the active constituent may not be identified, it could be difficult or
> impossible to perform standard in vivo bioavailability and
> pharmacokinetic studies (e.g., by measuring, as a function of time,
> the concentration of the active moiety, active ingredients, or active
> metabolites in whole blood, plasma, serum, or other appropriate
> biological fluid, or by measuring the excretion of the active moiety
> or active metabolites in urine). In some cases, it may be possible
> to measure an acute pharmacological effect as a function of time using
> an appropriate biological assay method. If this is not possible, the
> bioavailability of a botanical drug could be based on clinical effects
> observed in well-controlled clinical trials.
>
> The general criteria for waiver of in vivo bioavailability data in an
> NDA, described in § 320.22, are applicable to botanical drug products.
> FDA may, for good cause, waive or defer the in vivo bioavailability
> study requirement if a waiver or deferral is compatible with the
> protection of the public health (§ 320.22(e)).
>
> Interactions between botanicals and other commonly used drugs and/or
> dietary supplements should be investigated. This may include
> characterization of the metabolic enzymes and/or pathway affected by
> the drug (see section VIII.D).
>
> Where possible, the effects of impaired clearance (renal or hepatic)
> on the drug's pharmacokinetics should be examined. This is easiest
> when the active substance(s) are known, but even if they are not,
> knowledge of the major constituents should make it possible to
> determine the effects of impaired clearance. Dose-response information
> may indicate the proper level of concern about impaired excretion.
>
> As with synthetic and/or highly purified drugs, pharmaceutical and
> biopharmaceutics studies for botanical drug products are important for
> product quality control, batch comparison, and linkage between
> different strengths. These studies may involve, for example, in vitro
> dissolution testing, in situ drug absorption testing, in vitro-in vivo
> correlation studies, or in vitro percutaneous absorption/penetration
> testing, depending on the indication and formulation of the botanical
> product.

## E. Clinical Considerations

> Expanded studies of botanicals have the same purpose as expanded
> studies of synthetic drugs, including further evaluation of
> dose-response for favorable and unfavorable effects and evaluation of
> long-term safety and effectiveness, different populations, different
> stages/severity of disease, and drug-drug interactions. Many general
> and therapy-specific guidances are available on CDER\'s Web page (see
> title page for URL).

# glossary

The following definitions are intended for use in this guidance only and
may not be appropriate in other contexts.

**Active Constituent**: The chemical constituent in a botanical raw
material, drug substance, or drug product that is responsible for the
intended pharmacological activity or therapeutic effect

**Botanical; Botanical Product:** A finished, labeled product that
contains vegetable matter, which may include plant materials (see
below), algae, macroscopic fungi, or combinations of these. Depending in
part on its intended use, a botanical product may be a food, drug,
medical device, or cosmetic.

**Botanical Drug Product; Botanical Drug**: A botanical product that is
intended for use as a drug; a drug product that is prepared from a
botanical drug substance. Botanical drug products are available in a
variety of dosage forms, such as solutions (e.g., teas), powders,
tablets, capsules, elixirs, and topicals.

**Botanical Drug Substance**: A drug substance derived from one or more
plants, algae, or macroscopic fungi. It is prepared from botanical raw
materials by one or more of the following processes: pulverization,
decoction, expression, aqueous extraction, ethanolic extraction, or
other similar process. It may be available in a variety of physical
forms, such as powder, paste, concentrated liquid, juice, gum, syrup, or
oil. A botanical drug substance can be made from one or more botanical
raw materials (see Single-Herb and Multi-Herb Botanical Drug Substance
or Product). A botanical drug substance does not include a highly
purified or chemically modified substance derived from natural sources.

**Botanical Ingredient**: A component of a botanical drug substance or
product that originates from a botanical raw material

**Botanical Raw Material:** Fresh or processed (e.g., cleaned, frozen,
dried, or sliced) part of a single species of plant or a fresh or
processed alga or macroscopic fungus

**Cosmetic**: An article intended to be rubbed, poured, sprinkled, or
sprayed on, introduced into, or otherwise applied to the human body or
any part thereof for cleansing, beautifying, promoting attractiveness,
or altering the appearance, or an article intended for use as a
component of any such article, except that such term does not include
soap (21 U.S.C. 321(i))

**Dietary Supplement**: The following definition is taken directly from
21 U.S.C. 321(ff).

The term *dietary supplement* 

"(1) means a product (other than tobacco) intended to supplement the
diet that bears or contains one or more of the following dietary
ingredients: (A) a vitamin; (B) a mineral; (C) an herb or other
botanical; (D) an amino acid; (E) a dietary substance for use by man to
supplement the diet by increasing the total dietary intake; or (F) a
concentrate, metabolite, constituent, extract, or combination of any
ingredient described in clause (A), (B), (C), (D), or (E);

\(2\) means a product that (A)(i) is intended for ingestion in a form
described in section 411(c)(1)(B)(i) \[of the Act\]; or (ii) complies
with section 411(c)(1)(B)(ii); (B) is not represented for use as a
conventional food or as a sole item of a meal or the diet; and (C) is
labeled as a dietary supplement; and

\(3\) does (A) include an article that is approved as a new drug under
section 505 \[of the Act\] or licensed as a biologic under section 351
of the Public Health Service Act (42 U.S.C. 262) and was, prior to such
approval, certification, or license, marketed as a dietary supplement or
as a food unless \[FDA\] has issued a regulation, after notice and
comment, finding that the article, when used as or in a dietary
supplement under the conditions of use and dosages set forth in the
labeling for such dietary supplement, is unlawful under section 402(f)
\[of the Act\]; and (B) not include (i) an article that is approved as a
new drug under section 505 \[of the Act\], certified as an antibiotic
under section 507 \[of the Act\], or licensed as a biologic under
section 351 of the Public Health Service Act (42 U.S.C. 262), or (ii) an
article authorized for investigation as a new drug, antibiotic, or
biological for which substantial clinical investigations have been
instituted and for which the existence of such investigations has been
made public, which was not before such approval, certification,
licensing, or authorization marketed as a dietary supplement or as a
food unless \[FDA\], in \[its\] discretion, has issued a regulation,
after notice and comment, finding that the article would be lawful under
this Act. Except for purposes of section 201(g), a dietary supplement
shall be deemed to be a food within the meaning of this Act."

**Dosage Form**: A pharmaceutical product type, for example, tablet,
capsule, solution, or cream, that contains a drug ingredient (substance)
generally, but not necessarily, in association with excipients

**Drug**: The following definition is taken directly from 21 U.S.C.
321(g)(1).

The term drug means "(A) articles recognized in the official United
States Pharmacopoeia, official Homeopathic Pharmacopeia of the United
States, or official National Formulary, or any supplement to any of
them; and (B) articles intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in man or other animals;
and (C) articles (other than food) intended to affect the structure or
any function of the body of man or other animals; and (D) articles
intended for use as a component of any articles specified in clause (A),
(B), or (C). A food or dietary supplement for which a claim, subject to
sections 403(r)(1)(B) and 403(r)(3) \[of the Act\] or sections
403(r)(1)(B) and (r)(5)(D), is made in accordance with the requirements
of section 403(r) is not a drug solely because the label or the labeling
contains such a claim. A food, dietary ingredient, or dietary supplement
for which a truthful and not misleading statement is made in accordance
with section 403(r)(6) is not a drug under clause (C) solely because the
label or the labeling contains such a statement."

**Drug Product**: A finished dosage form, for example, tablet, capsule,
solution, etc. (21 CFR 210.3 (b)(4))

**Drug Substance**: An active ingredient that is intended for use to
furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease or to
affect the structure or any function of the human body (21 CFR 314.3(b))

**Food**: The term *food* means (1) articles used for food or drink, (2)
chewing gum, and (3) articles used for components of such articles (21
U.S.C. 321(f)).

**Formulation**: A formula that lists the components (or ingredients)
and composition of the dosage form. The components and composition of a
multi-herb botanical drug substance should be part of the total
formulation.

**Marker**: A chemical constituent of a botanical raw material, drug
substance, or drug product that is used for identification and/or
quality control purposes, especially when the active constituents are
not known or identified.

**Multi-Herb (Botanical Drug) Substance or Product**: A botanical drug
substance or drug product that is derived from more than one botanical
raw material, each of which is considered a botanical ingredient. A
multi-herb botanical drug substance may be prepared by processing
together two or more botanical raw materials, or by combining two or
more single-herb botanical drug substances that have been individually
processed from their corresponding raw materials. In the latter case,
the individual single-herb botanical drug substances may be introduced
simultaneously or at different stages during the manufacturing process
of the dosage form.

**Plant Material**: A plant or plant part (e.g., bark, wood, leaves,
stems, roots, flowers, fruits, seeds, or parts thereof) as well as
exudates thereof.

**Single-Herb (Botanical Drug) Substance or Product**: A botanical drug
substance or drug product that is derived from one botanical raw
material. Therefore, a single-herb substance or product generally
contains only one botanical ingredient.

**Spectroscopic and/or Chromatographic Fingerprint**: A spectroscopic
and/or chromatographic profile of a botanical raw material, drug
substance, or drug product that is matched qualitatively and
quantitatively against that of a reference sample or standard to ensure
the identity and quality of a batch and consistency from batch to batch.

# QUESTIONS AND ANSWERS

***Q1: Are INDs required for clinical studies of botanical products that
are lawfully marketed as dietary supplements in the United States?***

> A1: It depends on what the botanical product is being studied for. If
> a lawfully marketed botanical dietary supplement is studied for a
> dietary supplement use, i.e., effect on the structure and/or a
> function of the body, an IND is not required (see final rule on
> "Structure and Function Claims for Dietary Supplements," 65 FR 1000,
> January 6, 2000). Although an IND is not legally required for such a
> study, CDER encourages sponsors to submit one. If you have questions
> on how to design such a study, FDA would be willing to review and
> provide advice on protocols. You may contact CDER's Botanical Review
> Team at 301-827-2250 or <BOTANICALTEAM@cder.fda.gov>. If a botanical
> preparation is being studied for its effects on a disease in the
> proposed investigation (i.e., to cure, treat, mitigate, prevent, or
> diagnose disease, including its associated symptoms), it is considered
> a new drug and will need to be studied under an IND (see § 312.2).

***Q2: Are INDs required for clinical studies on marketed dietary
supplements for research purposes only?***

A2: Again, it depends on the use. If the intent is to study the effect
of the product on the structure and/or a function of the body, no IND is
needed. If the study is to assess the effects on disease, an IND is
needed.

***Q3: Is there any other setting in which an IND is not required for
the botanical study?***

> A3: When a nonmarketed botanical preparation is studied in the United
> States for a dietary supplement use, an IND is not required. In
> addition, clinical studies conducted in foreign countries require no
> IND. However, FDA will accept an IND for either kind of study. In the
> absence of an IND, an investigational new drug intended for export for
> the purpose of clinical investigation must comply with the
> requirements set forth in § 312.110(b)(2) unless the new drug has been
> approved or authorized for export under section 802 of the Act (21
> U.S.C. 382).

***Q4: May a sponsor submit an IND for a phase 3 study of a botanical
product not previously studied under an IND?***

A4: Yes. Clinical data collected from phase 1 and phase 2 studies
conducted without an IND can be used to support a phase 3 study
involving the same drug substance if they are adequately designed and
conducted. The formulation/dosage form of the botanical product used in
the proposed phase 3 study ideally would be the same as that of the
product used in phase 1 and 2 studies as well as in the preclinical
(nonclinical) studies. If the product is different, additional studies
may be appropriate.

***Q5: For NDA approvals of botanical drug products, must all studies be
carried out under INDs?***

> A5: No. FDA does not require that all studies submitted in an NDA be
> conducted under an IND. Clinical studies need not necessarily be
> conducted under an IND (i.e., if they are carried out abroad). The
> clinical data generated from these studies conducted without an IND
> can be used to support an NDA if the studies were adequately designed
> and conducted under good clinical practices.
>
> Although an IND is not required by law in all cases, the sponsor is
> encouraged to go through the IND process. Compliance with the IND
> requirements will help to ensure that an adequate pharmaceutical
> product development program is in place so that the material will meet
> the quality standards not only for various phases of clinical trials
> but also for eventual marketing. It will also help to ensure that the
> clinical trials will be well designed so that data generated can be
> persuasive.

***Q6: It appears that the changes in regulatory approaches described in
the guidance on Botanical Drug Products concern only IND applications.
How will these changes be applied to the NDA requirements for botanical
drugs?***

> A6: To facilitate the clinical development of botanical drugs, FDA
> decided to focus initially on a guidance for INDs, especially the
> early phases of clinical study. The standards for the safety and
> efficacy required for marketing approval of a botanical drug are the
> same as those required for a conventional chemical drug for the same
> indication. However, the product quality standards for a botanical
> drug can be different from those for a purified chemical drug. The
> Botanical Drug Products guidance contains recommendations for
> establishing appropriate quality standards for botanical drugs.

***Q7: Some botanical preparations are not administered orally, e.g.,
intravenous, topical, and inhalation products. How are these nonoral
formulations considered in the guidance?***

> A7: The guidance applies to all dosage forms of botanical products.
> All parenteral, topical, inhalation, or other nonorally administered
> botanical products are considered to be drugs, not dietary
> supplements, and must be studied under an IND for any use (see section
> 201(ff) of the Act). Just as for purified chemical drugs, the type of
> quality testing varies from dosage form to dosage form. For example,
> all injectables are required to be sterile and pyrogen-free
> (211.165(b) and 211.167 and 314.50(d)(1)(ii)(b); oral tablets are not.
> In addition, dietary supplements are orally ingested and the human
> experience of an orally administered botanical dietary supplement may
> not be applicable to the same botanical product given through other
> routes.

***Q8: In terms of IND requirements and regulatory review by the Agency,
is there any difference between a commercial development program and an
academic research project?***

A8: No. The Agency applies the same standards to both commercial and
academic sponsors when evaluating the safety and quality of human
studies proposed in INDs.

***Q9: Intellectual property rights are a difficult issue for developing
new drugs from well-known botanical preparations. How does FDA protect
the confidentiality of a sponsor's submission? What kind of IND/NDA data
may FDA release without prior permission from the sponsor?***

A9: IND information generally is not publicly available (see §§ 312.130,
314.430). Once an NDA is approved, FDA may release certain safety and
efficacy information (§ 314.430(e)). Manufacturing information
(including information related to growers and suppliers) provided in an
NDA or a Drug Master File (DMF) is considered proprietary and may not be
released (21 U.S.C. 331(j); 21 CFR 20.61).

***Q10: How does FDA ensure that the new* Botanical Drug Products
*guidance will be implemented consistently across the different new drug
review divisions?***

A10: FDA will provide reviewers in all divisions with training on how to
implement the guidance.

***Q11: One of the major premises of the new guidance is that because
many botanical products have been used by a large population for a long
period of time, they are presumed to be safe enough to be studied in
clinical trials without first undergoing conventional nonclinical
studies. What kind of documentation should a sponsor submit to
demonstrate prior human experience with the sponsor's product?***

> A:11 The Agency recognizes that prior human experience with a
> botanical product can be documented in many different forms and
> sources, some of which may not meet the quality standards of modern
> scientific testing. The sponsor is encouraged to provide as much data
> as possible, and the review team for the botanical drug IND generally
> will accept all available information for regulatory consideration.
> FDA will assess the quality of the submitted data on a case-by-case
> basis. It should be emphasized that, in reviewing botanical drugs, the
> Agency does not lower or raise the safety and efficacy standards for
> marketing approval that apply to purified chemical drugs. The guidance
> simply recommends the use of different types of data for preliminary
> safety consideration of human trials (for example, large quantities of
> mostly anecdotal human data instead of animal studies).

***Q12: In many cases, botanical therapies are highly individualized
with variations in relative contents of multiple plant ingredients
tailored for each patient. Must a sponsor submit a separate IND for
every change in composition, if similar patients are being treated for
the same indication?***

A12: Studies can be designed to take into account individualized
treatments. Multiple formulations can be included in one IND if they are
being studied under a single clinical trial. It is important that the
IND provide the rationale for using multiple formulations and the
criteria used to assign patients to different treatment regimens.

***Q13: Many medicinal plants with therapeutical potential are quite
toxic. Does the new guidance address the study of such botanicals?***

A13: The guidance discusses this issue in the sections addressing
botanical drug products with known safety issues (e.g., section VI.A).
Well-known examples of safety issues concerning botanicals include the
nephrotoxicity associated with herbal preparations containing
aristolochic acid and the hepatotoxicity associated with comfrey
products containing pyrrolizidine alkaloid. Other examples include the
cardiovascular and central nervous system effects associated with
yohimbe and the hepatotoxicity associated with germander and chapparal.
In such cases, FDA will evaluate the known risk and the potential
benefit of an investigational drug for its intended use. When the
potential benefit of an investigational drug outweighs its risk in the
intended patient population, clinical trials may be allowed to proceed
under an IND (see § 312.42). For example, FDA will accept a relatively
higher level of toxicity of an investigational drug when studied to
treat terminally ill cancer patients. However, additional nonclinical
studies may be appropriate to adequately characterize the toxicity
(e.g., can a dose be identified that would not be expected to produce
toxicity?) and/or additional monitoring may be appropriate during the
clinical trial. Also, FDA may recommend against human studies (e.g.,
bioavailability, clinical pharmacology) in healthy volunteers.

***Q14: There is a concern that if a botanical is being studied under an
IND or is approved as a new drug in an NDA, its subsequent status as a
dietary supplement may be jeopardized. Is this true?***

> A14: No, it is generally not true for products already on the market
> before approval of an NDA. It is also generally not true for products
> marketed before authorization of an IND for which substantial clinical
> investigations have been instituted and the existence of such
> investigations has been made public (see section 201(ff)(3) of the
> Act).

***Q15: What is FDA's advice on the initial approach for sponsors not
familiar with new drug development and regulatory processes?***

A15: A sponsor should first consult the guidance. If there are questions
concerning the guidance document or other questions about the submission
of INDs for botanical drugs, consult the appropriate CDER review
division for the therapeutic class of the sponsor's product. CDER also
grants pre-IND meetings with sponsors.

***Q16: The guidance states that the submission of an NDA for a drug
derived from plants taken from the wild is an extraordinary circumstance
requiring the submission of an environmental assessment (EA) under
§ 25.21. Are plants maintained in their native setting on private land
considered wild?***

A16: Yes. Plants that are obtained from their native setting on either
public or private land are considered to be taken from the wild.
Cultivated plants are considered those that are grown collectively in
controlled settings such as plantations, farms, or greenhouses, i.e.,
purposely segregated from wildlife to the extent practicable.

***Q17: Is a drug made with a commercially available crude extract
viewed the same as a drug derived from plants taken from the wild for
purposes of determining the need for an EA?***

> A17: Yes. If an NDA is submitted for a drug made from a crude extract
> or intermediate from a plant taken from the wild, an EA is required
> under § 25.21. This is true whether or not the extract or intermediate
> is commercially available. As for an IND for a drug made from a crude
> extract or intermediate from a plant taken from the wild, FDA will
> decide on a case-by-case whether an EA is required.

***Q18: What is the GMP status of botanical raw materials (starting
materials) in terms of compliance and inspection?***

> A18: Starting materials of botanical origin that are used to produce a
> botanical drug substance should be evaluated for quality. The use of
> appropriate starting materials and the drug substance manufacturer's
> ability to control the source depend on appropriate specifications
> (tests, analytical procedures, and acceptance criteria). In addition
> to establishing specifications, manufacturers can achieve adequate
> quality control of starting materials by applying the principles
> outlined in FDA's botanical guidance and by following good
> agricultural and good collection practice for starting materials of
> herbal origin (e.g., European Medicines Evaluation Agency
> *HMPWP/31/99*). Upon receipt of the starting materials at a processing
> facility, it is the responsibility of the drug substance manufacturer
> to determine the suitability of these raw materials before use. This
> can be accomplished by examining and/or testing to ensure that the
> acceptance criteria are met and by documenting the quality control for
> the processing of the starting materials. FDA will review the
> inspection and examination of starting materials upon receipt when
> conducting a current good manufacturing practice (CGMP) inspection of
> a drug substance manufacturer.

***Q19: Will FDA assign the same level of priority to botanical drug
products as to other drugs with respect to meeting with IND sponsors and
NDA applicants?***

> A19: Yes, FDA treats botanical and purified chemical drugs the same.

####### 

####### 

####### 

#######  

# ATTACHMENT A: Regulatory Approaches FOR MARKETING BOTANICAL DRUG PRODUCTS

# 

**ATTACHMENT B: INFORMATION TO BE PROVIDED IN AN IND FOR A BOTANICAL
DRUG**

###### 

General principles;

format and contents

(Sec. VI)

[\_]{.underline}

####### 

[^1]: This guidance has been prepared by working groups in the Medical
    Policy, Pharmacology and Toxicology, and Complex Drug Substances
    Coordinating Committees in the Center for Drug Evaluation and
    Research (CDER) at the Food and Drug Administration (FDA).

[^2]: FDA has issued a draft guidance entitled *Drug Substance:
    Chemistry, Manufacturing, and Controls Information*, which, when
    finalized, will replace the 1987 guidance (see 69 FR 929, January 7,
    2004).

[^3]: *Botanical product* and other terms used in this guidance are
    defined in the Glossary for use in this guidance only; these
    definitions may not be appropriate in other contexts.

[^4]: The manufacturer must have substantiation that such statement is
    truthful and not misleading (section 403(r)(6)(B) of the Act) and
    must notify FDA that the statement is being used no later than 30
    days after the first marketing of the dietary supplement with the
    statement (section 403(r)(6) of the Act). In addition, the statement
    must be accompanied by the following disclaimer: "This statement has
    not been evaluated by the Food and Drug Administration. This product
    is not intended to diagnose, treat, cure, or prevent any disease"
    (section 403(r)(6)(C) of the Act). FDA regulations at 21 CFR
    101.93(b)-(e) prescribe the required format and placement of the
    disclaimer in dietary supplement labeling.

[^5]: ^?^FDA regulations at § 101.93(g) define *disease* for purposes of
    this provision and set forth what types of statements FDA will
    consider to be claims to diagnose, mitigate, treat, cure, or prevent
    disease.

[^6]: Under section 505(j) of the Act, a botanical drug product may also
    be marketed as a generic drug under an abbreviated new drug
    application (ANDA). The *generic* version of the previously approved
    drug would have to be both pharmaceutically equivalent and
    bioequivalent to such drug. For information on the submission of
    ANDAs, see FDA regulations in 21 CFR parts 314 and 320 as well as
    Agency guidance documents.

[^7]: FDA has issued a final rule that establishes criteria and
    procedures by which conditions may become eligible for inclusion in
    the OTC drug monograph system (67 FR 3060, January 23, 2002). Among
    other things, the final rule addresses how FDA considers *foreign*
    marketing data in determining whether a drug has been used under
    particular conditions to a material extent and for a material time
    (as required under section 201(p) of the Act) to qualify for
    inclusion in an OTC drug monograph.

[^8]: See 21 CFR 312.20 (concerning requirement for an IND).

[^9]: However, a botanical drug's conformance to the standards of the
    USP or any other official compendium does not establish that the
    botanical is safe, effective, and not misbranded for its intended
    use as a drug.