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

II. BACKGROUND ................................................................................................................... 2

III. GENERAL REGULATORY APPROACHES................................................................... 3

A. Marketing Under OTC Drug Monograph Versus Approved NDA ..........................................4

B. CMC Information for Botanical Drug Products.........................................................................5

C. CMC and Toxicology Information to Support Initial Studies...................................................5

D. Applicability of Combination Drug Regulations.........................................................................6

IV. MARKETING A BOTANICAL DRUG UNDER AN OTC DRUG MONOGRAPH..... 6

V. MARKETING A BOTANICAL DRUG UNDER AN NDA.............................................. 7

VI. INDS FOR BOTANICAL DRUGS ..................................................................................... 7

A. IND Information for Different Categories of Botanicals............................................................7

B. Basic Format for INDs...................................................................................................................9

1. Cover Sheet (see § 312.23(a)(1)).....................................................................................................9

2. Table of Contents (see § 312.23(a)(2))............................................................................................9

3. Introductory Statement and General Investigational Plan (see § 312.23(a)(3)).............................9

4. Investigator′s Brochure (see § 312.23(a)(5))...................................................................................9

5. Protocols (§ 312.23(a)(6))...............................................................................................................9

6. Chemistry, Manufacturing, and Controls (§ 312.23(a)(7)) ...........................................................10

7. Pharmacological and Toxicological Information (§ 312.23(a)(8))...............................................13

8. Previous Human Experience With the Product (§ 312.23(a)(9)) ..................................................13

VII. INDS FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES OF LAWFULLY

MARKETED BOTANICAL PRODUCTS WITHOUT SAFETY CONCERNS.................. 13

A. Description of Product and Documentation of Human Use.....................................................13

1. Description of Botanicals Used (§ 312.23(a)(3)(i)).......................................................................14

2. History of Use (§ 312.23(a)(3)(ii),(a)(9)) ......................................................................................14

3. Current Marketed Use (§ 312.23(a)(3)(ii), (a)(9)) ........................................................................14

B. Chemistry, Manufacturing, and Controls .................................................................................14

1. Botanical Raw Material (§ 312.23(a)(7)(i)) ..................................................................................14

2. Botanical Drug Substance (§ 312.23(a)(7)(iv)(a)) ........................................................................15

3. Botanical Drug Product (§ 312.23(a)(7)(iv)(b)) ...........................................................................15

4. Animal Safety Test (§ 312.23(a)(8))...............................................................................................16

5. Placebo (§ 312.23(a)(7)(iv)(c)) .....................................................................................................16

6. Labeling (§ 312.23(a)(7)(iv)(d)) ....................................................................................................16

7. Environmental Assessment or Claim of Categorical Exclusion (§ 312.23(a)(7)(iv)(e))................17

C. Pharmacology/Toxicology Information .....................................................................................17

1. All Marketed Botanical Products...................................................................................................17

2. Foreign-Marketed Botanical Products ..........................................................................................18

D. Bioavailability...............................................................................................................................18

E. Clinical Considerations ...............................................................................................................18
VIII. INDS FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES FOR

NONMARKETED BOTANICAL PRODUCTS AND PRODUCTS WITH KNOWN

SAFETY CONCERNS ............................................................................................................... 19

A. Description of Product and Documentation of Human Use.....................................................19

1. Description of Botanicals Used (§ 312.23(a)(3)(i)).......................................................................19

2. History of Use (If Any) (§ 312.23(a)(3)(ii), (a)(9))........................................................................19

3. Current Investigational Use (If Any) (§ 312.23(a)(3)(ii), (a)(9)) ..................................................20

B. Chemistry, Manufacturing, and Controls .................................................................................20

1. Botanical Raw Material (§ 312.23(a)(7)(i)) ..................................................................................20

2. Botanical Drug Substance (§ 312.23(a)(7)(iv)(a)) ........................................................................21

3. Botanical Drug Product (§ 312.23(a)(7)(iv)(b)) ...........................................................................23

4. Placebo (see section VII.B.5).........................................................................................................25

5. Labeling (see section VII.B.6)........................................................................................................25

6. Environmental Assessment or Claim of Categorical Exclusion ....................................................25

C. Nonclinical Safety Assessment ....................................................................................................25

1. Traditional Preparations ...............................................................................................................25

2. Others.............................................................................................................................................26

3. Products with Known Safety Issues ...............................................................................................26

D. Bioavailability...............................................................................................................................26

E. Clinical Considerations ...............................................................................................................27

IX. INDS FOR PHASE 3 CLINICAL STUDIES OF ALL BOTANICAL PRODUCTS ... 27

A. Description of Product and Documentation of Human Experience........................................27

B. Chemistry, Manufacturing, and Controls .................................................................................28

1. Expanded Clinical Studies .............................................................................................................28

2. End-of-Phase 3 Clinical Studies and Pre-NDA Considerations....................................................32

C. Nonclinical Safety Assessment ....................................................................................................34

1. Repeat-Dose General Toxicity Studies ..........................................................................................35

2. Nonclinical Pharmacokinetic/Toxicokinetic Studies .....................................................................35

3. Reproductive Toxicology ...............................................................................................................36

4. Genotoxicity Studies.......................................................................................................................36

5. Carcinogenicity Studies .................................................................................................................36

6. Special Pharmacology/Toxicology Studies....................................................................................37

7. Regulatory Considerations ............................................................................................................37

D. Bioavailability and Clinical Pharmacology ...............................................................................37

E. Clinical Considerations ...............................................................................................................38

GLOSSARY................................................................................................................................. 39

QUESTIONS AND ANSWERS................................................................................................. 42

ATTACHMENT A: REGULATORY APPROACHES FOR MARKETING BOTANICAL

DRUG PRODUCTS.................................................................................................................... 47
Contains Nonbinding Recommendations

1

Guidance for Industry1

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

 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).
Contains Nonbinding Recommendations

2

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).

• 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).

• 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.

 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.
Contains Nonbinding Recommendations

3

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

 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. 
Contains Nonbinding Recommendations

4

drug must be marketed under an approved NDA6 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

 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).
Contains Nonbinding Recommendations

5

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
Contains Nonbinding Recommendations

6

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)).

 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.
Contains Nonbinding Recommendations

7

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)).
Contains Nonbinding Recommendations

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 WellCharacterized, Therapeutic, Biotechnology-derived Products (November 1995).
Contains Nonbinding Recommendations

9

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 doseresponse) (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, placebocontrolled trials should almost always be conducted because active control trials are

particularly difficult to interpret in such situations. Having a concurrent active treatment
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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 NonLife-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
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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
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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 (nonbotanical) 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.
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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
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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

• 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
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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, biotechnologyderived 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 

(8:1 powdered aqueous

extract)

250 mg 10.0 kg (equivalent to 80.0

kg of dried leaves)

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).
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Component Amount per tablet Amount per batch

Senna 250 mg (equivalent to 2000 mg

dried leaves)

10.0 kg (equivalent to 80.0 kg of dried

leaves)

Excipient 1 100 mg 4.0 kg

Excipient 2 10 mg 0.4 kg

Example for a multi-herb botanical drug product:

Component Amount per

tablet

Amount per

batch

A 5:1 powdered, aqueous extract from

1:1 mixture of Forsythia suspensa

Vahl. flowers and Lonicera japonica

Thunb. fruits

600 mg 24 kg 

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:
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• 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

• the individual botanical ingredients

• 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

• target organs or systems of toxicity
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• teratogenic, carcinogenic, or mutagenic potential of any botanical ingredient in the

product

• relationship of dosage and duration to toxic responses

• 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 caseby-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.
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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
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• 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
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• 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
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indicated. If more than one botanical raw material is introduced to produce a multiherb 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 stabilityindicating analytical methods and conduct stability studies as the IND progresses.
Contains Nonbinding Recommendations

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• 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:

− 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:

− 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.)

• 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.
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Example:

Component Amount per

tablet

Amount per

batch

Senna 250 mg (equivalent to

2000 mg dried leaves)

10.0 kg (equivalent to 80.0

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

• 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.)

• 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).
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• A description of the container/closure in which the drug product is to be packaged

• Available stability data on the drug product. The sponsor should develop stabilityindicating 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
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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 caseby-case basis to address those issues (see section VI.A).

D. Bioavailability

Pharmacokinetic and pharmacodynamic information is helpful in the design and
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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
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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.

• 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

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

• 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.

• 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
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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

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

material

• 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).

• 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.

• 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.

• A description of the manufacturing process for the botanical drug substance. 

The description should include the quantity of botanical raw material,
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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.

• 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
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– 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

• A description of the batch of botanical drug substance designated as the

reference standard for use in fingerprinting and other comparative tests

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

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

substance

• Sufficient stability data on the drug substance to support its safe use during

clinical studies; stability-indicating analytical methods

• 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)

• 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.

• 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.

• 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
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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

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

• A description of the container and closure used to package the finished

product

• 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.

• 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
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batch record should be available.

• 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.

• 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.

• 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. 

• 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
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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.

• 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. 

• 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
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(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
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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
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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)).
Contains Nonbinding Recommendations

38

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). 
Contains Nonbinding Recommendations

39

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,
Contains Nonbinding Recommendations

40

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))
Contains Nonbinding Recommendations

41

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.
Contains Nonbinding Recommendations

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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
Contains Nonbinding Recommendations

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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.
Contains Nonbinding Recommendations

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Q9: Intellectual property rights are a difficult issue for developing new drugs from wellknown 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
Contains Nonbinding Recommendations

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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.
Contains Nonbinding Recommendations

46

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.
Contains Nonbinding Recommendations

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ATTACHMENT A: REGULATORY APPROACHES FOR MARKETING BOTANICAL

DRUG PRODUCTS

Go to

Attachment B

Botanical

Product

Cosmetic Food

 Consumed for

 its taste, aroma,

 or nutritive value

 Applied to body for

 cleansing, beautifying,

 or altering appearance

What is

the intended

use?

 Drug

 To diagnose,

 cure, mitigate, or

 treat disease

Is

marketing

exclusivity

desired?

OTC

monograph

Is

 the proposed

 indication appropriate for

nonprescription

use?

Has it

 been marketed

 for a specific OTC 

 indication for a material 

 time and to a material

extent?

Does

available evidence

of safety and effectiveness

warrant inclusion

in an OTC

monograph? Is there

sufficient evidence

of safety and effectiveness

and adequate CMC

information to

support an

NDA?

NDA

application IND

Yes

Yes

Yes

No

No

Yes No

Yes

No

 To affect

 structure or

 function of body

Meets

dietary supplement

definition in 21

U.S.C. 321 (ff)?

 No

No

Authorized

 health 

 claim?

Conventional

 Food or 

 Dietary 

 Supplement

 Structure/

 function claims

comply with all 

requirements of

 21 U.S.C. 

 343(r)(6)?

 Dietary

 Supplement

 To

 prevent

 disease

Yes

Yes

Yes No

 No
Contains Nonbinding Recommendations

48

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

BOTANICAL DRUG 

 General principles; 

format and contents 

(Sec. VI) 

 

 _

 

Previous human experience

 may be sufficient

 to support safety

 (Sec. VIII.C.1)

No

Initial clinical trial of

a marketed botanical

product with no

known safety issues

(Sec. VII)

Documentation of use;

limited CMC information;

previous human experience

may be sufficient

to support safety

Yes

IND

for a

Botanical

Drug Product

Expanded clinical

trial of any

botanical product

(Sec. IX)

Initial clinical trial of a

nonmarketed botanical

product or a marketed

botanical product with

known safety issues

(Sec. VIII)

More documentation

of use and more

CMC information

than in Sec. VII

 Same documentation of

 use but more detailed

 CMC information than

 in Sec. VIII; standard

 nonclinical toxicology

 studies may be needed

Is the

product a

traditional

preparation?

If the product is marketed only

outside the U.S., additional CMC

and nonclinical safety information

may be needed

(Sec. VII.B.1, B.3.c, & C.2)

 Additional nonclinical

 safety information

 may be needed

 (Sec. VIII.C.2)