Botanical Drug 
Development 
Guidance for Industry 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2016 
Pharmaceutical Quality/CMC 
Revision 1
   
 
Botanical Drug 
Development 
Guidance for Industry 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2016 
Pharmaceutical Quality/CMC 
Revision 1
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL REGULATORY APPROACHES ............................................................... 2 
A.  Marketing of Botanical Drugs Under OTC Drug Monographs ................................................. 3 
B.  Marketing of Botanical Drugs Under NDAs ................................................................................ 4 
IV.  BOTANICAL DRUG DEVELOPMENT UNDER INDS ............................................. 4 
V.  INDS FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES ...................................... 5 
A.  Description of Product and Documentation of Prior Human Experience ................................ 6 
1. Description of Botanical Raw Materials Used and Known Active Constituents or Chemical 
Constituents ( 312.23(a)(3)(i))............................................................................................................ 6 
2. Prior Human Experience ( 312.23(a)(3)(ii),(a)(9))...................................................................... 7 
B.  Chemistry, Manufacturing, and Controls.................................................................................... 8 
1. Botanical Raw Materials ( 312.23(a)(7)(i)) ................................................................................... 8 
2. Botanical Drug Substance ( 312.23(a)(7)(iv)(a)) ........................................................................... 9 
3. Botanical Drug Product ( 312.23(a)(7)(iv)(b)) ............................................................................ 11 
4. Placebo ( 312.23(a)(7)(iv)(c)) ...................................................................................................... 12 
5. Environmental Assessment or Claim of Categorical Exclusion ( 312.23(a)(7)(iv)(e)) ................ 13 
C.  Nonclinical Pharmacology/Toxicology ....................................................................................... 13 
D.  Clinical Pharmacology ................................................................................................................. 14 
E.  Clinical Considerations ................................................................................................................ 15 
VI.  INDS FOR PHASE 3 CLINICAL STUDIES ............................................................... 15 
A.  General Regulatory Considerations in Late-Phase Development ............................................ 15 
B.  Description of Product and Documentation of Prior Human Experience .............................. 16 
C.  Chemistry, Manufacturing, and Controls.................................................................................. 17 
1. Botanical Raw Material ................................................................................................................. 17 
2. Botanical Drug Substance and Drug Product ............................................................................... 17 
D.  Nonclinical Safety Assessment .................................................................................................... 18 
1. General Pharmacology/Toxicology ............................................................................................... 18 
2. Nonclinical Pharmacokinetic/Toxicokinetic Studies ...................................................................... 18 
3. Reproductive Toxicology ................................................................................................................ 19 
4. Genotoxicity Studies ....................................................................................................................... 19 
5. Carcinogenicity Studies ................................................................................................................. 19 
6. Other Toxicity Studies .................................................................................................................... 20 
7. Regulatory Considerations ............................................................................................................. 20 
E.  Clinical Pharmacology ................................................................................................................. 20 
  Contains Nonbinding Recommendations 
 
F.  Clinical Considerations ................................................................................................................ 20 
1. Study Design for Multiple Batch Analyses ..................................................................................... 20 
2. Dose-Response Effect ..................................................................................................................... 21 
3. Clinical Studies of Botanical Drugs for Serious Conditions .......................................................... 22 
4. Other Study Design Issues.............................................................................................................. 22 
G.  Applicability of Combination Drug Regulations ....................................................................... 22 
VII.  NDAS FOR BOTANICAL DRUG PRODUCTS ......................................................... 23 
A.  Description of Product and Documentation of Prior Human Experience .............................. 23 
B.  Quality Control ............................................................................................................................ 24 
1. Botanical Raw Material ................................................................................................................. 24 
2.  Botanical Drug Substance and Drug Product ............................................................................... 24 
C.  Nonclinical Safety Assessment .................................................................................................... 28 
D.  Clinical Pharmacology ................................................................................................................. 28 
E.  Clinical Evidence of Efficacy and Safety ................................................................................... 28 
F.  Evidence To Ensure Therapeutic Consistency .......................................................................... 29 
1.   Raw Material Control ................................................................................................................... 29 
2.   Quality Control by Chemical Tests and Manufacturing Control .................................................. 29 
3. Biological Assay(s) and Clinical Data ........................................................................................... 29 
G.   Postmarketing Considerations .................................................................................................... 30 
  Contains Nonbinding Recommendations 
Botanical Drug Development 
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 
discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title 
page. 
 
 
 
I.  INTRODUCTION  
 
This guidance describes the Center for Drug Evaluation and Researchs (CDERs) current 
thinking on appropriate development plans for botanical drugs to be submitted in new drug 
applications (NDAs) and specific recommendations on submitting investigational new drug 
applications (INDs) in support of future NDA submissions for botanical drugs. In addition, this 
guidance provides general information on the over-the-counter (OTC) drug monograph system 
for botanical drugs. Although this guidance does not intend to provide recommendations specific 
to botanical drugs to be marketed under biologics license applications (BLAs), many scientific 
principles described in this guidance may also apply to these products. 
 
This guidance specifically discusses several areas in which, due to the unique nature of botanical 
drugs, the Agency finds it appropriate to apply regulatory policies that differ from those applied 
to nonbotanical drugs, such as synthetic, semi-synthetic, or otherwise highly purified or 
chemically modified drugs, including antibiotics derived from microorganisms. Because this 
guidance focuses on considerations unique to botanical drugs, policies and recommendations 
applicable to both botanical and nonbotanical drugs are generally not covered in this document; 
readers should refer to other FDA guidance documents for appropriate information.  
 
This guidance replaces the Guidance for Industry on Botanical Drug Products issued in June 
2004.2 The general approach to botanical drug development has remained unchanged since that 
time; however, based on improved understanding of botanical drugs and experience acquired in 
the reviews of NDAs and INDs for these drugs, specific recommendations have been modified 
and new sections have been added to better address late-phase development and NDA 
submission for botanical drugs.  
                                                 
1 This guidance has been prepared by a working group composed of staff from the Office of Pharmaceutical Quality, 
Office of New Drugs, Office of Translational Sciences, and Office of Medical Policy in the Center for Drug 
Evaluation and Research at the Food and Drug Administration.  
2 In the Federal Register of August 2015 (80 FR 49240), we issued and sought comment on a draft guidance that 
revised Botanical Drug Products. This guidance finalizes the August 2015 draft guidancealso entitled Botanical 
Drug Developmentand replaces the June 2004 final guidance. 
  1  Contains Nonbinding Recommendations 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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 
 
For the purposes of this document, the term botanicals means products that include plant 
materials, algae, macroscopic fungi, and combinations thereof. It does not include: 
 
  Products that contain animals or animal parts (e.g., insects and annelids) and/or minerals, 
except when these are a minor component in a traditional botanical preparation (e.g., 
traditional Chinese medicine, Ayurvedic medicine). 
 
  Materials derived from botanical species that are genetically modified with the intention 
of producing a single molecular entity (e.g., by recombinant DNA technology or cloning). 
 
  Products produced by fermentation of yeast, bacteria, plant cells, or other microscopic 
organisms, including plants used as substrates, if the objective of the fermentation process 
is to produce a single molecular entity (e.g., antibiotics, amino acids, and vitamins). 
 
  Highly purified substances, either derived from a naturally occurring source (e.g., 
paclitaxel) or chemically modified (e.g., estrogens synthesized from yam extracts). 
 
If the botanical material is derived from traditional cultivation or breeding techniques (e.g., not 
genetically modified), or if fermentation of a botanical raw material is part of the manufacturing 
process to produce a product that is a natural mixture consisting of multiple active constituents,3 
then appropriate provisions in this guidance will apply. 
 
When a drug product contains a botanical drug substance in combination with either a (1) 
synthetic or highly purified drug or (2) biotechnology-derived or other naturally derived drug, 
this guidance can generally be applied to the botanical portion of the product. 
 
III.  GENERAL REGULATORY APPROACHES 
 
A botanical product may be classified as a food (including a dietary supplement), drug (including 
a biological drug), medical device, or cosmetic under the Federal Food, Drug, and Cosmetic Act 
(FD&C Act). Whether an article is a food, drug, medical device, or cosmetic depends in large 
part on its intended use,4 though for some product types, other factors must also be considered.5 
                                                 
3 Active constituents are the chemical constituent(s) in a botanical drug substance that contribute significantly to a 
botanical drugs intended pharmacological activity or therapeutic effect. 
4 See 21 USC 321(f)(1), (g)(1)(B) and (C), (h)(2) and (3), (i), (ff). 
5 See, e.g., 21 USC 321(f), 321(ff). 
  2  Contains Nonbinding Recommendations 
Intended use is established by, among other things, the products labeling, advertising, and the 
circumstances surrounding its distribution.6  
 
A botanical product intended for use in diagnosing, curing, mitigating, or treating disease would 
meet the definition of a drug under section 201(g)(1)(B) of the FD&C Act and would be subject 
to regulation as such. A botanical product intended to prevent disease would also generally meet 
the definition of a drug under section 201(g)(1)(B) and be regulated as a drug. Under certain 
circumstances, however, an article that meets the definition of a drug would nevertheless be 
subject to a different regulatory scheme. For example, when a conventional food or dietary 
supplement bears a health claim about reducing the risk of a disease and the claim is made in 
accordance with an authorizing regulation issued under section 403(r)(1)(B) of the FD&C Act 
(21 USC 343(r)(1)(B)), such a product would not be regulated as a drug solely because its 
labeling contains such a claim. The recommendations in this guidance are only for botanical 
products that are subject to regulation as drugs. 
 
A.  Marketing of Botanical Drugs Under OTC Drug Monographs  
 
Any drug that does not fall within the definition of a prescription drug in section 503(b)(1) of the 
FD&C Act is a nonprescription or OTC drug. A botanical drug that has been marketed 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.7 Currently, several botanical drug substances 
(e.g., psyllium and senna) are included in the OTC drug review, and witch hazel is currently 
marketed under an OTC drug monograph. To be included in an OTC drug monograph, a 
botanical drug must generally be recognized as safe and effective based on the standards for 
safety and effectiveness set forth in 21 CFR 330.10(a)(4). 
 
A request to amend an OTC drug monograph to include a botanical drug substance may be 
submitted by a citizen petition in accordance with 21 CFR 10.30 and 330.10(a)(12) or a Time 
and Extent Application (TEA) in accordance with 21 CFR 330.14.8 To be included in an OTC 
drug monograph, a botanical drug substance must be recognized in an official United States 
Pharmacopeia and National Formulary (USP-NF) drug monograph that sets forth its standards of 
identity, strength, quality, and purity.9 Therefore, a request for a botanical drug substance to be 
included in an OTC drug monograph should include a reference to the applicable USP-NF drug 
monograph. In the absence of such a USP-NF drug monograph, the request should include a 
proposed standard for inclusion in an article to be recognized in an official USP-NF drug 
monograph, as described in 21 CFR 330.10(a)(2). Considering the complexity of botanical drugs, 
there are challenges to this approach. Interested parties (e.g., a botanical drug manufacturer) 
                                                 
6 See 21 CFR 201.128. 
7 See 21 CFR Part 330. 
8 21 CFR 330.14 sets forth criteria and procedures by which OTC drugs initially marketed in the United States after 
the OTC drug review began and OTC drugs without any U.S. marketing experience can be considered in the OTC 
drug monograph system. Basic information to be provided in the TEA includes a detailed description of the botanical 
drug substance, as set forth in 21 CFR 330.14(c)(1)(ii).  
9 See 21 CFR 330.10(a)(2) and 330.14(i). 
  3  Contains Nonbinding Recommendations 
should contact the Division of Nonprescription Drug Products in CDERs Office of New 
Drugs/Office of Drug Evaluation IV for additional information about the OTC drug monograph 
 
approach to marketing a botanical drug.
 
B.  Marketing of Botanical Drugs Under NDAs 
 
Any person who wishes to market a new drug in the United States must submit an NDA and 
obtain Agency approval prior to marketing the new drug product for the proposed use (see 
sections 201(p) and 505 of the FD&C Act). FDA may approve a drug product containing such a 
drug substance for OTC sale pursuant to an application submitted under section 505 of the 
FD&C Act. Accordingly, an applicant could seek marketing approval for a botanical drug under 
section 505 of the FD&C Act for either prescription or OTC use.10   
 
Because of the heterogeneous nature of a botanical drug and possible uncertainty about its active 
constituents, one of the critical issues for botanical drugs is ensuring that the therapeutic effect 
for marketed drug product batches is consistent. In general, therapeutic consistency can be 
supported by a totality of the evidence approach, including the following considerations: 
 
  Botanical raw material control (e.g., agricultural practice and collection). 
 
  Quality control by chemical test(s) (e.g., analytical tests such as spectroscopic and/or 
chromatographic methods that capture the active or chemical constituents of a botanical 
drug substance) and manufacturing control (e.g., process validation).  
 
  Biological assay (e.g., a biological assay that reflects the drugs known or intended 
mechanism of action) and clinical data (for details regarding use of clinical data in 
ensuring therapeutic consistency, see Section VI.F.1 of this guidance under Study Design 
for Multiple Batch Analyses and Section VI.F.2 of this guidance under Dose-Response 
Effect). 
 
Section VII of this guidance describes recommendations for submitting NDAs, including 
instructions for submitting information to support therapeutic consistency for botanical drug 
products, and discusses post-marketing issues for botanical drug products. 
 
IV.  BOTANICAL DRUG DEVELOPMENT UNDER INDS 
 
To develop information to support either an NDA or an OTC monograph for a botanical drug, 
interested parties may need to develop data by, among other things, conducting clinical 
investigations. 
 
Section 505(i) of the FD&C Act and 21 CFR Part 312 require clinical investigations in which a 
drug is administered to human subjects to be conducted under an IND (unless exempt under 
                                                 
10 See section 503(b)(1) of the FD&C Act. 
  4  Contains Nonbinding Recommendations 
 312.2(b)). To determine whether a proposed study would be exempt from the IND 
requirements, a sponsor11 (or sponsor-investigator of an individual investigator-initiated study) 
should consult the Guidance for Clinical Investigators, Sponsors, and Institutional Review 
Boards on Investigational New Drug Applications (INDs)Determining Whether Human 
Research Studies Can Be Conducted Without an IND.12 If a sponsor is uncertain, we recommend 
that the sponsor contact the appropriate Office of New Drugs (OND) review division for advice 
about whether the IND regulations apply.  
 
Pre-IND, end-of-phase 1, end-of-phase 2 and 2A, pre-phase 3, and pre-NDA consultations13 are 
strongly encouraged for the sponsor of a botanical drug to assess the adequacy of existing 
information for an IND submission or an NDA, obtain advice regarding the need for additional 
studies, ensure that clinical protocols are properly designed, and allow discussion of the initial or 
overall development plan. The sponsor should submit all available information to the appropriate 
OND review division in accordance with the content and format requirements outlined below. 
 
The format and content requirements for IND submissions are provided in  312.23 and 
discussed in several FDA guidance documents.14 In general, an IND must contain sufficient 
information to demonstrate that the drug is safe for testing in humans and that the clinical 
protocol(s) is properly designed for its intended objectives. While these general requirements are 
applicable to botanical drug INDs, botanical drugs have certain unique characteristics that may 
affect the information necessary to be provided in an IND. Botanical drugs are generally 
heterogeneous mixtures. As such, their chemical constituents often are not well defined; in some 
cases, their active constituents are not identified and their biological activities are not well 
characterized. However, certain botanical drugs may have been used in humans prior to 
submission, which may provide some indication of their safety. The unique characteristics of 
such botanical drugs could have significant impact on their development program (e.g., quality 
control and clinical study design). Sections V and VI below provide recommendations for IND 
submissions that consider these unique characteristics. 
 
V.  INDS FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES  
 
Under  312.22(b), the amount of information that must be submitted in an IND for a particular 
drug depends on several factors, including the extent of prior human experience and past clinical 
                                                 
11 In this guidance, sponsor refers to anyone who submits an IND and applicant refers to anyone who submits an 
NDA.  
12 CDER updates guidances periodically. To make sure you have the most recent version of a guidance, check the 
FDA Drugs guidance Web page at 
www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmwww.fda.gov/Drugs/Guidan
ceComplianceRegulatoryInformation/Guidances/default.htm. 
13 See the Guidance for Industry on Formal Meetings Between the FDA and Sponsors or Applicants and the 
Guidance for Industry on End-of-Phase 2A Meetings. 
14 Examples of related guidance documents include the Guidance for Industry on Content and Format of 
Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, 
Therapeutic, Biotechnology-derived Products and the Guidance for Industry on INDs for Phase 2 and Phase 3 
Studies Chemistry, Manufacturing, and Controls Information. 
  5  Contains Nonbinding Recommendations 
studies, the drugs known or suspected risks, and the developmental phase of the drug. For 
example, a botanical dietary supplement marketed under the Dietary Supplement Health and 
Education Act of 1994 (DSHEA) that has no known safety issues often would require less 
detailed information on chemistry, manufacturing, and controls (CMC) or toxicological data in 
an IND for early-phase studies than would a botanical product that is newly discovered, has not 
been marketed, or has known safety issues. For most botanical drugs, detailed CMC information 
(e.g., data on comprehensive characterization of the drug substance) may not be warranted for 
early-phase development (Phase 1 and Phase 2 clinical studies); however, gathering of CMC data 
should be initiated during these phases because such preliminary information should be 
submitted prior to initiating Phase 3 studies.  
 
Every botanical drug has unique considerations, and the Agency encourages a sponsor to seek 
input from the appropriate OND review division before formally submitting an IND. We 
recommend that the clinical development of a botanical drug take a stepwise approach so that 
raw material control considerations, analytical characterization data, and early-phase study results 
can assist in the design of late-phase studies. However, botanical drug substances used in various 
stages of development may differ in some characteristics (e.g., chemical composition), as there 
could be possible changes in agricultural practice and collection for botanical raw material(s) 
and/or manufacturing process conditions as a result of process optimization. Therefore, bridging 
studies may be needed to justify these differences. The sponsor should request input from the 
appropriate OND review division so the review division can evaluate any changes in the 
botanical drug substance during development and provide guidance (e.g., on the type of bridging 
studies that may be needed).  
 
To comply with the requirements outlined in 21 CFR 312.23, the sponsor should specifically 
address the following issues unique to botanical drugs in the IND submission. We recognize that 
some aspects of the following quality control strategy may not be completed until Phase 3 
studies; nonetheless, all available information should be provided:    
 
A.  Description of Product and Documentation of Prior Human Experience 
 
1.  Description of Botanical Raw Materials Used and Known Active Constituents or 
Chemical Constituents ( 312.23(a)(3)(i)) 
 
Provide the following general information for each of the botanical raw materials used as the 
source of the botanical drug substance in a botanical drug product: 
 
  Scientific name of the plant species according to international binomial nomenclature 
convention, including the genus name, the specific epithet, and the name of the botanist 
who initially described and nominated the species. 
 
  Synonyms, especially those used in recent publications of scientific studies related to the 
species. 
 
  Subspecific rank (subspecies, variety, and form) and cultivars, if applicable. 
 
  6  Contains Nonbinding Recommendations 
  Family name. 
 
  Botanical parts used (e.g., aerial parts, roots, rhizomes, flowers, and/or leaves) as the 
botanical raw material(s). 
 
  Common or usual names of the plant, alga, or macroscopic fungus in English and other 
languages (e.g., Chinese or Spanish), especially the languages of the region in which the 
species and the raw materials have medicinal or other significance. 
 
  Active constituents identified as individual compounds or chemical classes, if known. If 
active constituents are not known, chemical constituents that have been identified (e.g., 
those can be used as a characteristic profile for identification and quality control 
purposes).  
 
2.  Prior Human Experience ( 312.23(a)(3)(ii),(a)(9)) 
 
Under  312.23(a)(9), a sponsor must submit information about prior human experience with the 
investigational drug, if available. Many botanical drugs have been previously marketed or tested 
in clinical studies, including clinical studies reported in literature. Where clinical studies have 
been conducted, the study reports should be submitted in the IND with a critical review of the 
data quality and the datas relevance to the proposed use. The botanical drugs marketing history 
also should be described. In particular, it should include documentation of the annual sales 
volume, an estimate of the size of the exposure population, and rates of adverse effects, as well 
as provide references to compendia and publications (e.g., books of medical practice in 
Ayurveda, traditional Chinese medicine, Unani, Sidha, and other herbal medicine and 
pharmacognosy textbooks). For botanical drugs only available in foreign markets, the 
informations reliability and relevance to the proposed clinical study should be justified. A 
sponsor planning to support its IND with a well-designed and well-conducted foreign clinical 
study or studies not conducted under an IND should refer to  312.120 and related FDA guidance 
documents.15 Any literature that is submitted should be provided in English (and in its original 
language, if other than English).16    
 
In addition to a thorough review of the past human experience with the botanical drug and the 
drugs botanical raw material(s), the sponsor should also present information to bridge the past 
experience with the current proposed investigation. This information may include a: 
 
  Description of the amount of raw material or traditional preparation that is equivalent to 
the dose proposed in the IND study, 
 
  Comparison of the identity of the investigational botanical drug with traditional 
                                                 
15 Examples of related guidance documents include the Guidance for Industry and FDA Staff on FDA Acceptance of 
Foreign Clinical Studies Not Conducted Under an IND: Frequently Asked Questions and the Guidance for Industry 
on E5  Ethnic Factors in the Acceptability of Foreign Clinical Data: Questions and Answers. 
16 See  312.23(c). 
  7  Contains Nonbinding Recommendations 
preparations described in the literature, and/or 
 
  Comparison of the clinical settings in which the drugs have been used with the setting(s) 
in which they are proposed to be used. 
 
The Agency will determine the relevance of prior human experience with traditional preparations 
to the assessment of botanical drugs safety in clinical studies proposed under INDs on a case-by-
case basis. 
 
B.  Chemistry, Manufacturing, and Controls 
  
The amount of CMC information to support clinical studies conducted under an IND depends on 
a number of factors, including the botanical drugs marketing history and the phase of 
development. The use of botanical drugs in foreign markets may provide useful human 
experience; however, the relevance of such experience to determining the amount of CMC 
information needed for early-phase clinical studies depends on the integrity of the control 
measures and the quality of the foreign manufactured botanical drug. Provided below is an 
overview of the CMC information that is recommended to support early-phase clinical studies for 
a botanical drug. More detailed CMC information will be needed to proceed into late-phase 
clinical studies (see Section VI).  
 
1.  Botanical Raw Materials ( 312.23(a)(7)(i)) 
 
A botanical drug substance can be derived from one or more botanical raw materials of the same 
or different plant species. The following recommendations apply to each individual botanical raw 
material used. 
 
For raw material control, trained personnel should identify the plant species, plant parts, alga, or 
macroscopic fungus used via methods including organoleptic, macroscopic, and microscopic 
examination. This identification should be done against a voucher specimen (i.e., reference 
specimen). A genetic taxonomic method (e.g., DNA barcoding described in USP General 
Chapter <563>: Identification of Articles of Botanical Origin) may be developed at this stage. If 
more than one variety of a given species is used, each variety should be specified. The botanical 
raw material supplier and drug substance manufacturer for each batch should retain and store 
under appropriate conditions a sample of the plant, plant parts, or other botanical materials. 
These samples can be used to further verify identity, if needed. The sponsor should provide the 
following information: 
 
  Identification of the plant species, plant parts, alga, or macroscopic fungus used.  
 
  A certificate of authenticity. 
 
  Whether the plant species is: 
 
  Determined to be endangered or threatened under the Endangered Species Act or the 
  8  Contains Nonbinding Recommendations 
Convention on International Trade in Endangered Species of Wild Fauna and Flora,17 
 
  Entitled to protection under some other federal law or international treaty to which the 
United States is a party, and/or 
 
  In a critical habitat that has been determined to be endangered or threatened. 
 
  The following items for each grower and/or supplier, if available: 
 
  Name and address, 
 
  Description and characterization of the plant species, as well as varieties and cultivars 
(if applicable), and botanical identification (macroscopic and microscopic), 
 
  Harvest location (e.g., by global positioning system (GPS) coordinates), growth 
conditions, stage of plant growth at harvest, and harvest time/season, and  
 
  Post-harvest processing (e.g., washing, drying, and grinding procedures); control of 
foreign matter (i.e., inorganic and organic contaminants such as soil, insects, and 
algae/fungi); preservation procedures; handling, transportation, and storage 
conditions; tests for elemental impurities; microbial limits; tests for residual 
pesticides, including parent pesticides and their major toxic metabolites; and tests for 
adventitious toxins (e.g., aflatoxins), foreign materials, and adulterants. 
 
2.  Botanical Drug Substance ( 312.23(a)(7)(iv)(a)) 
 
The sponsor should provide the following information for the botanical drug substance, 
regardless of whether it is prepared from one or more botanical raw materials:  
 
  Qualitative description of the drug substance. It should include the name, appearance, 
active constituents, physicochemical properties, biological activity, and any prior clinical 
use of each botanical raw material used to prepare the drug substance. If the active 
constituents, biological activity, and/or prior clinical use are unknown, the application 
should clearly state this. For a multi-plant drug substance, the application should state 
whether the drug substance is prepared by combining individually processed botanical 
drug substances or processing combined botanical raw materials.  
 
  Quantitative description of the drug substance. The strength of a botanical drug substance 
should generally be expressed as the absolute dry weight of a processed botanical 
substance. The batch size and yield of the process relative to the botanical raw material 
should be provided. When the active constituents or other chemical constituents are 
known and measurable, the amount in which they are present in the botanical drug 
                                                 
17 See www.fws.gov/international/laws-treaties-agreements/us-conservation-laws/endangered-species-act.html. 
  9  Contains Nonbinding Recommendations 
substance should be declared. The composition of multi-plant drug substances, in terms 
of the relative ratio of the individually processed botanical drug substances or of the 
botanical raw materials before processing (as applicable), should be expressed.  
 
  Name and address of the drug substance manufacturer (i.e., processor). 
 
  Description of the manufacturing process. The description should include each process 
step (e.g., pulverization, decoction, expression, aqueous and/or ethanol extraction), the 
quantity of botanical raw material, solvents, temperature and time for extraction and/or 
drying, 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, should be indicated. 
If more than one botanical raw material is introduced to produce a multi-plant substance, 
the quantity of each raw material and the sequence of addition, mixing, grinding, and/or 
extraction should be provided. If a multi-plant substance is prepared by combining two or 
more individually processed botanical drug substances, a separate description of the 
process leading to each botanical drug substance should be provided. 
 
  Quality control tests performed on each batch of the drug substance, analytical procedures 
that were used, available test results, and proposed acceptance criteria. The quality 
control tests should include, but not be limited to, tests for the following attributes: 
 
  Appearance. 
 
  Strength by dry weight (equivalent to botanical raw material). 
 
  Chemical identification for the active constituents, if known, or the chemical 
constituents.18 In general, the sponsor should use the best available analytical 
technology to address the issue of analytical resolution. When the resolution is 
inadequate in one particular method, multiple methods should be used to provide 
complementary data for adequate chemical identification and quantification.  
 
  Quantification for the active constituents, if known, or the chemical constituents. If 
several botanical raw materials are combined to produce a multi-plant substance and a 
quantitative determination of each individual active or chemical constituent is 
infeasible, a joint determination can be made for several active or chemical 
constituents. When multiple active or chemical constituents are known, they should 
be chemically characterized and their relative amounts should be defined. 
   
                                                 
18 The characteristic profile of chemical constituents can be determined based on spectroscopic and/or 
chromatographic methods. Examples of spectroscopic methods include ultraviolet, infrared, Fourier transformed 
infrared, mass spectroscopy, and liquid chromatographymass spectrometry (LC-MS). Examples of chromatographic 
methods include high performance liquid chromatography (HPLC), gas chromatography (GC), thin layer 
chromatography (TLC), and capillary zone electrophoresis. 
 
  10  Contains Nonbinding Recommendations 
  Biological assay. If the active constituents are not known or quantifiable, a biological 
assay should be developed, prior to initiation of Phase 3 studies, to assess drug 
substance batch potency and activity relative to a reference standard (see Section 
VII.B.2.d).  
 
  Mass balance. Methods should be developed to quantify other classes of compounds 
(e.g., lipids or proteins) that contribute to the mass balance of the botanical substance, 
prior to initiation of Phase 3 studies (see Section VII.B.2.e).   
 
  Tests for residual pesticides as outlined in USP <561> and for any pesticides routinely 
used in the countries of origin of botanical raw materials.  
 
  Tests for elemental impurities, residual solvents, and radioisotope contamination, if 
applicable. 
 
  Tests for microbial limits. 
 
  Tests for adventitious toxins, such as aflatoxins. 
 
  Available stability data. The sponsor should develop stability-indicating analytical 
methods and conduct stability studies as the IND progresses. 
 
3.  Botanical Drug Product ( 312.23(a)(7)(iv)(b)) 
 
The sponsor should provide the following information for a botanical drug product: 
 
  Qualitative description of the drug product. It should include the dosage form, route of 
administration, names and functions of all ingredients (e.g., botanical drug substance, 
other drug substances, and excipients), and a statement declaring if the botanical drug 
substance is combined with other drug substances (e.g., a highly purified, biotechnology-
derived, or other naturally derived drug substance). 
 
  Composition or quantitative description of the drug product expressed in terms of amount 
per dosage unit and amount per batch. The sponsor should provide this information in 
tabular form (see example below). 
 
     
Component  Amount per Tablet  Amount per Batch 
     
A 5:1 powdered, aqueous extract  600 mg  24.0 kg 
from 1:1 mixture of Forsythia 
suspensa Vahl. fruits and Lonicera 
japonica Thunb. flowers 
     
Excipient 1  100 mg  4.0 kg 
     
Excipient 2  10 mg  0.4 kg 
  11  Contains Nonbinding Recommendations 
 
  Manufacturers certificate of analysis for the drug product or authorization for the Agency 
to cross-reference the manufacturers previous submission or drug master file (DMF) for 
the relevant CMC information. If this information is unavailable for a foreign-marketed 
product, the sponsor should perform quality testing on the drug product. In addition to 
those tests, elemental impurities analysis and, if applicable, an animal safety test, should 
be performed. The sponsor should provide these test methods and results in the IND. A 
product sample from each batch to be used in clinical studies should be retained for 
possible future testing by the Agency and/or sponsor. 
 
  Stability data to support the use of a botanical drug product for at least the length of the 
clinical study. As development continues, stability studies in line with International 
Council for Harmonisation (ICH) guidelines19 should continue to generate data in support 
of the proposed expiration dating period.   
 
Although generally discouraged, it may be permissible in unusual cases to augment levels of 
individual active constituents in a botanical drug product to achieve batch-to-batch consistency in 
the therapeutic effect. In general, this approach would only be appropriate in situations in which 
the active constituents in the drug substance are known and there is a substantial natural variation 
in the concentrations of these active constituents in the botanical raw material (e.g., due to 
changes in growing conditions over time that cannot be controlled). In such cases, limited 
amounts of the purified active constituents could be added to meet the specification for a 
benchmark drug substance. The target levels for active constituents should not exceed levels that 
occur naturally. The sponsor should consult with the Agency in advance concerning the 
appropriateness of augmenting levels of active constituents in a specific case and the process for 
determining the specification for the benchmark drug substance. 
 
4.  Placebo ( 312.23(a)(7)(iv)(c)) 
 
Use of certain botanical materials in the placebo to mask the identity of active drug may be 
necessary, but such botanical substances should not have any known pharmacological activity 
because that will make the clinical data difficult to interpret. The Agency understands that for 
some botanical drugs, it may be difficult to create a placebo with the identical taste, odor, and 
appearance of the active drug. It may be acceptable for these attributes in the placebo to be subtly 
different from those of the botanical drug if the investigators and study subjects cannot 
differentiate the active drug from the placebo and blinding of the clinical study can be 
maintained. The sponsor is encouraged to consult with the appropriate OND review division 
regarding the use of such a placebo in clinical studies.   
                                                 
19 See ICH Q1A(R2) Stability Testing of New Drug Substances and Products.  
  12  Contains Nonbinding Recommendations 
 
5.  Environmental Assessment or Claim of Categorical Exclusion 
( 312.23(a)(7)(iv)(e)) 
 
A claim of categorical exclusion from the requirement for preparation of an environmental 
assessment (EA) can ordinarily be made for an IND (21 CFR 25.31(e)); however, additional 
information should be provided in the IND to support a claim for a categorical exclusion for a 
botanical drug product.20 
 
C.  Nonclinical Pharmacology/Toxicology  
 
The amount of nonclinical information recommended to support Phase 1 and Phase 2 clinical 
studies with botanical products will depend on the extent of previous human use and the design 
of the proposed clinical studies. Examples are provided below: 
 
  For a botanical drug that is currently lawfully marketed in the United States as a dietary 
supplement, initial clinical studies may be allowed to proceed without further nonclinical 
pharmacological/toxicological testing provided that the previous use is similar to the 
proposed use. Nevertheless, literature and other available information related to the safety 
of the drug should be provided. 
   
  For a botanical drug that is not currently lawfully marketed in the United States, if it is 
administered using the route (e.g., topically or orally) and prepared, processed, and used 
according to methodologies for which there is extensive prior human experience, 
sufficient information may be available to support initial clinical studies without 
additional nonclinical pharmacological/toxicological testing. Literature and other 
available information related to the safety of the drug should be provided. 
 
  Regardless of whether a botanical drug is currently lawfully marketed in the United 
States, if the anticipated exposure in the proposed clinical studies exceeds that in the prior 
human use (e.g., higher doses or a longer duration), a nonclinical 
pharmacological/toxicological assessment is warranted to adequately address the 
difference between the prior human use and the proposed clinical studies. 
  
  For nontraditional routes of administration of a botanical drug (e.g., if a drug traditionally 
has been used only topically and the sponsor is proposing it be used orally), additional 
nonclinical pharmacological/toxicological information may be warranted to support this 
difference before initial clinical studies may be allowed to proceed. 
 
  For a new botanical drug for which extensive prior human use is not available, a more 
extensive nonclinical pharmacological/toxicological assessment is warranted. This 
                                                 
20 See the Guidance for Industry on Environmental Assessment of Human Drug and Biologics Applications 
(Environmental Assessment Guidance). 
  13  Contains Nonbinding Recommendations 
assessment should be similar to that for nonbotanical drugs (e.g., synthetic drugs), and 
recommendations should follow appropriate ICH and FDA guidances. 
 
If formal, nonclinical studies have not been performed for the IND submission, the sponsor 
should conduct a literature search to identify any publicly available information pertaining to the 
safety of the following: 
 
  Final formulation of the intended commercial botanical drug product, 
  Botanical substance(s) of the drug product, and 
  Known active or chemical constituents of the botanical substance. 
 
Under  312.23(a)(8)(ii), an integrated summary of available data from medical and toxicological 
literature (e.g., Medline and Toxline) should be submitted for review. The following issues 
should be addressed in the original IND for review: 
 
  General toxicity, 
  Target organs or systems of toxicity, 
  All data suggesting adverse genetic or reproductive effects of any constituents of the 
botanical substance,   
  Relationship of dosage and duration to toxic responses, and 
  Pharmacologic effects reported for the whole botanical substance and its individual active 
constituents. 
 
For botanical drugs that have been previously marketed only outside of the United States, the 
sponsor should provide additional data to verify and document the safety of prior human use. 
  
D.  Clinical Pharmacology 
 
Pharmacokinetic and pharmacodynamic information is helpful in the design and interpretation of 
clinical studies. The Agency recognizes the technical challenges in determining standard 
pharmacokinetic measurements of systemic exposure because a botanical drug product often 
consists of more than one chemical constituent and the active constituents may not be identified. 
However, if the major active constituent(s) in a botanical product is known, the sponsor should 
attempt to measure the blood levels of the active constituent(s) using a sensitive analytical 
method to achieve the same objectives of clinical pharmacology studies for nonbotanical drugs. 
Examples of these objectives are provided below:  
 
  Assess drug absorption, distribution, metabolism, and excretion, 
 
  Assess the dose-response or exposure-response relationship for desirable and undesirable 
effects, 
  
  Address pharmacokinetics in specific populations (e.g., the elderly or patients with 
hepatic or renal impairments), and 
  
  14  Contains Nonbinding Recommendations 
  Provide information from in vitro studies to evaluate the potential for interactions with 
drugs or other botanicals (e.g., contribution of enzymes and transporters to drug 
disposition, inhibition, and induction potential on drug metabolizing enzymes), and 
evaluate potential for QT interval prolongation.  
 
An approach based on a pharmacodynamic or clinical endpoint may be appropriate if no 
quantifiable active constituents are available for in vivo pharmacokinetic or in vitro studies. 
 
E.  Clinical Considerations 
 
The clinical evaluation of botanical drugs in early-phase clinical studies does not differ 
significantly from that of synthetic or highly purified drugs in such studies (see 21 CFR 314.126). 
Botanical drug products currently marketed as dietary supplements under DSHEA generally 
would not require typical Phase 1 tolerability studies if sponsors can provide adequate 
justification for the relevance of the prior human use. The sponsors of such drug products are 
strongly encouraged to initiate well-controlled and more definitive clinical studies in order to 
explore the therapeutic effect early in the development program. If there is uncertainty about the 
dose selection, a clinical dose-response study may be necessary to determine the optimal dose for 
Phase 3 clinical studies. As is generally the case with all drugs, safety data should be collected 
during these early-phase clinical studies.   
 
If an IND of a botanical drug product includes only foreign marketing experience, no prior human 
experience, or known safety issues, the sponsor should provide additional early-phase clinical 
data before initiating larger-scale, late-phase clinical studies. To mimic the use in traditional 
practice, when the preparation is simple (e.g., decoction), botanical raw materials are sometimes 
dispensed at clinical study centers and subsequently prepared by patients at home. This practice 
should be applied cautiously in clinical studies because it may introduce potential variability to 
safety and efficacy data. The sponsor is encouraged to discuss this issue with the appropriate 
OND review division.   
 
VI.  INDS FOR PHASE 3 CLINICAL STUDIES 
 
A.  General Regulatory Considerations in Late-Phase Development  
 
During the Phase 3 development, further ongoing characterization of the botanical drug product 
will ensure drug substance quality and, therefore, the validity and reliability of the clinical data 
that are generated. Given the more extensive exposure in late-phase clinical studies, additional 
toxicology data are warranted to support safe human use and facilitate the design of clinical 
safety evaluations. This additional information should be provided regardless of prior marketing 
history. 
 
Batch-to-batch variations (e.g., a variation in chemical composition) are known to exist in 
different batches of the botanical drug substances. Therefore, it would be of both scientific and 
regulatory interest to learn the impact of such variations on the therapeutic effect of botanical 
drug products. The sponsor should consider what evidence will be needed to support that the 
  15  Contains Nonbinding Recommendations 
variations observed in botanical drug substance batches do not cause any meaningful differences 
in the therapeutic effect. One approach is to use multiple batches of the botanical drug product 
(i.e., each manufactured by using a different batch of the drug substance) in the Phase 3 clinical 
studies and to examine the clinical effects across these drug product batches (see Section VI.F for 
further discussion). This type of investigation would help the sponsor better understand which 
variations are clinically relevant, and, if clinically relevant, what range of variability can be 
tolerated to consistently maintain a botanical drug products identity, efficacy, and safety. Such 
an improved understanding would aid in setting acceptance criteria for a clinically relevant 
specification. 
 
If previously available nonclinical and/or clinical data in the earlier phases of development are 
provided or referenced in the IND, the sponsor should provide a comparison of the 
investigational botanical drug product to be used in the IND and the botanical drug product(s) 
used in the referenced studies (e.g., chemical identification and quantification of active or 
chemical constituents in the drug substance, drug product composition and formulation). 
Likewise, when the source and manufacturing process of the botanical raw material, drug 
substance, or drug product are changed during development, the sponsor should provide a 
comparison of the previous and new sources and manufacturing processes, because seemingly 
minor changes in the source and/or process may result in a meaningful difference in the clinical 
effects and raise the question about the applicability of earlier pharmacological, nonclinical, and 
clinical data.  
 
If there is uncertainty about whether different batches of the drug substance are similar, bridging 
studies (e.g., chemical identification and quantification of active or chemical constituents in the 
drug substance, biological assay, and/or other nonclinical studies) may be warranted to 
demonstrate that the drug substances used in various stages of development are sufficiently 
similar to justify reliance on previous nonclinical and clinical testing results. Sufficient quantities 
of the botanical raw material and drug substance from the different batches should be retained for 
future chemical characterization and/or pharmacological/toxicological testing.   
 
The sponsor should also refer to Section VI.G below regarding the applicability of the fixed-dose 
combination rule to the investigational botanical drug.   
 
Phase 3 studies should provide pivotal support for an NDA submission. Thus, it is important that 
the sponsor reviews sections VI and VII of this guidance regarding the information recommended 
for botanical-specific contents in an NDA submission to ensure that the necessary information 
will be collected with appropriate technologies and well-designed studies during this phase. 
 
B.  Description of Product and Documentation of Prior Human Experience 
 
This information should have been submitted to the IND in support of Phase 1 and Phase 2 
clinical studies in accordance with  312.23. See Section V.A of this guidance for details. 
 
  16  Contains Nonbinding Recommendations 
C.  Chemistry, Manufacturing, and Controls 
 
To support Phase 3 clinical studies of a botanical drug product, the sponsor should provide 
information under the same categories outlined in Section V.B in accordance with  312.23; 
however, more detailed information should be provided to support these studies, as described 
below.  
 
1.  Botanical Raw Material 
 
To assess quality and therapeutic consistency, it is important to select representative raw material 
batches (i.e., raw material from three or more representative cultivation sites or farms) for the 
manufacturing of the clinical drug substance for multiple batch Phase 3 studies. The sponsor 
should establish large growing regions with three or more cultivation sites or farms whose 
locations are purposefully selected to be representative of the regions for each of the botanical 
raw materials following the principles of Good Agricultural and Collection Practices (GACP).21 
This will help reduce the likelihood of an insufficient supply of the botanical raw material post-
NDA approval.  
 
The sponsor should provide information on additional work performed to characterize the 
botanical raw material(s) (e.g., chemical identification of each botanical raw material by a 
spectroscopic or chromatographic method, and authentication of each botanical raw material by a 
DNA fingerprinting method as necessary), updates on the quality control tests and analytical 
procedures applied by the botanical raw material supplier, and the proposed acceptance criteria, 
with the goal of working toward final development in preparation for an NDA submission.   
 
2.  Botanical Drug Substance and Drug Product 
 
For the drug substance and drug product, the sponsor should provide updates (as necessary) on 
additional work conducted to improve characterization of the botanical drug and its active 
constituents. The sponsor should establish specifications (with interim acceptance criteria) that 
can be finalized during the NDA review based on the results of Phase 3 clinical studies. In 
addition, pharmaceutical development of the drug substance and drug product should be well 
advanced so that no significant changes of the botanical raw material(s) and manufacturing 
processes will be needed during Phase 3 clinical studies to support the marketing application. For 
example, a robust manufacturing process for the drug substance and drug product should be 
established and demonstrated to ensure that the clinical study materials and the to-be-marketed 
materials are consistent, so bridging studies may not be necessary to support the marketing 
application (see Section V). 
 
                                                 
21 See the World Health Organizations WHO guidelines on good agricultural and collection practices 
(GACP) for medicinal plants at http://whqlibdoc.who.int/publications/2003/9241546271.pdf and 
the European Medicines Agencys Guideline on Good Agricultural and Collection Practice (GACP) for Starting 
Materials of Herbal Origin at  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003362.pdf. 
  17  Contains Nonbinding Recommendations 
D.  Nonclinical Safety Assessment  
 
Toxicity data from standard toxicology studies in animals should generally be provided to 
support late-phase clinical studies.22 A botanical drug product in Phase 3 clinical studies will 
generally be assessed with the same overall nonclinical review standards as any other new drug 
under development in accordance with  312.23(a)(8).  
 
Certain changes in formulation could affect whether previously performed pharmacology or 
toxicology studies are applicable to the new formulation, and in some cases may warrant the 
submission of nonclinical bridging studies. The sponsor should discuss all proposed formulation 
changes with the appropriate OND review division to determine whether the changes would 
warrant bridging or other types of studies.  
 
The sponsor should consider the following points when preparing a nonclinical 
pharmacology/toxicology development plan for a botanical drug product that is intended to be 
used in Phase 3 clinical studies. If questions arise during any stage of botanical drug product 
development, the sponsor is encouraged to consult the appropriate OND review division. 
 
1.  General Pharmacology/Toxicology 
 
In general, for late-phase clinical studies, the recommendations for general 
pharmacology/toxicology assessment of botanical drugs are no different from those for 
nonbotanical drugs.23 Doses used in toxicology studies should follow the principles in ICH 
M3(R2). 
 
The sponsor should reach agreement with the appropriate OND review division about the 
methods it plans to use for arriving at acceptable dose levels in safety pharmacology (see ICH 
S7A and S7B)24 and toxicology studies. In principle, the highest dose used in toxicology studies 
should produce some measurable toxicity. This toxicity information can be used to inform safety 
monitoring during human studies. 
  
2.  Nonclinical Pharmacokinetic/Toxicokinetic Studies 
 
Because a botanical drug product usually consists of more than one chemical constituent, it may 
be technically challenging to use standard pharmacokinetic measurements to substantiate the 
systemic exposure of a botanical drug in animals. Monitoring representative chemical 
constituent(s) in a botanical drug product using a sensitive analytical method can provide 
                                                 
22 See the ICH joint safety and efficacy guidances at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065006.htm and the ICH 
safety guidances at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065007.htm.  
23 See ICH M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals. 
24 See ICH S7A Safety Pharmacology Studies for Human Pharmaceuticals and S7B Nonclinical Evaluation of the 
Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. 
  18  Contains Nonbinding Recommendations 
information regarding systemic exposure. If feasible, chemical constituents of a drug product that 
contribute to toxicity or pharmacology should be assessed in the pharmacokinetic/toxicokinetic 
studies. The sponsor should also attempt to determine the metabolic fates of these chemical 
constituents. Pharmacokinetic/toxicokinetic information collected during the toxicity studies may 
help the sponsor to interpret the outcome of the studies performed.25  
 
3.  Reproductive Toxicology 
 
For most botanical drug products, prior human experience may be a less reliable indicator of 
reproductive safety than are specialized animal toxicology studies. In the absence of documented 
reproductive safety data in humans or animals, reproductive toxicology studies are normally 
conducted per recommendations provided in ICH guidelines (same as for nonbotanical drugs).26   
 
4.  Genotoxicity Studies 
 
A complete assessment of genetic toxicity may be warranted prior to Phase 3 clinical studies if 
these assessments have not been conducted earlier. See ICH S2(R1) for the definition of a 
standard battery of genotoxicity tests.27 Interpretation of the results of this standard battery of 
tests and the determination of the need for additional tests should be no different for botanical 
and nonbotanical drugs.28  
 
5.  Carcinogenicity Studies 
 
Carcinogenicity studies are typically submitted with an NDA for chronic use indications. To 
meet this goal, dose range finding studies and the carcinogenicity studies should generally be 
conducted during the IND phase. The indication and duration of the intended use of the botanical 
drug product will influence the need for carcinogenicity studies and their timing relative to 
clinical development.29 Protocols for carcinogenicity studies should be submitted to the Agency 
for review under Special Protocol Assessment30 and for concurrence prior to the initiation of 
such studies to ensure that the dose selection and study design are acceptable. In particular, these 
protocols should identify the rationale for selecting the high dose for the carcinogenicity study.31  
 
                                                 
25 See ICH S3A Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies and S3B 
Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies.  
26 See ICH S5A Detection of Toxicity to Reproduction for Medicinal Products, S5B Detection of Toxicity to 
Reproduction for Medicinal Products: Addendum on Toxicity to Male Fertility, and ICH M3(R2), supra note 23. 
27 See ICH S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use. 
28 See  312.23(a)(8)(ii)(a). 
29 See Environmental Assessment Guidance, supra note 20. Also, see ICH S1A The Need for Long-Term Rodent 
Carcinogenicity Studies of Pharmaceuticals and S1B Testing for Carcinogenicity in Pharmaceuticals. 
30 See the Guidance for Industry on Special Protocol Assessment. 
31 See ICH S1C(R2) Dose Selection for Carcinogenicity Studies of Pharmaceuticals.  
  19  Contains Nonbinding Recommendations 
6.  Other Toxicity Studies 
 
In general, recommendations for special pharmacological/toxicological studies (e.g., studies that 
are used to identify potential biomarkers or provide mechanistic understanding) for botanical 
drugs are not different from those for nonbotanical drugs.   
 
7.  Regulatory Considerations 
 
Nonclinical pharmacological and toxicological studies that the sponsor conducts as part of 
botanical drug development and to support safety should generally be performed in accordance 
with regulations governing good laboratory practices under 21 CFR Part 58. Both the botanical 
drug substance and drug product should be manufactured to achieve adequate batch-to-batch 
consistency as outlined in this guidances CMC sections. If changes occur in the botanical drug 
substance or botanical drug product during clinical development, nonclinical bridging studies 
may be needed to comply with 21 CFR 312.23(a)(8)(ii)(a). 
 
E.  Clinical Pharmacology 
 
To support Phase 3 clinical studies of a botanical drug product, regardless of its marketing 
experience in the United States or other countries, the sponsor should provide the dose selection 
rationale (including a description of the human pharmacokinetic and pharmacodynamic 
relationships for both efficacy and safety, if available). This information should be provided in 
addition to the information recommended in Section V.D. It may be useful for the sponsor to 
perform clinical trial simulations prior to conducting Phase 3 clinical studies, if feasible. The 
sponsor is encouraged to meet with the Agency to reach agreement on the sponsors planned 
clinical pharmacology development programs prior to Phase 3. 
 
F.  Clinical Considerations 
 
Phase 3 clinical studies of botanical drugs have the same purpose as Phase 3 clinical studies of 
nonbotanical drugs. Many general and therapeutic area-specific guidance documents are 
available on the FDA Drugs guidance web page.32 Special considerations for Phase 3 clinical 
studies of botanical drugs are summarized as follows: 
 
1.  Study Design for Multiple Batch Analyses  
 
Analyses of batch effects on clinical endpoints (i.e., batch effect analyses) should be considered 
when drug product batches exhibit variations (e.g., a variation in chemical composition), 
potentially affecting clinical outcomes. These are additional analyses beyond the standard 
primary efficacy analyses usually performed. Standard analyses involve comparing a control 
group to a treatment group composed of subjects pooled across different batches. The batches 
that are chosen should be representative of the marketing batches and should not be too 
                                                 
32 See www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
  20  Contains Nonbinding Recommendations 
homogenous. The goal of these analyses is to quantify potential heterogeneity in clinical 
outcomes for subjects who receive different batches in the study. This is in principle similar to 
other types of subgroup analyses.33  
 
If batch effect analyses are warranted, the sponsor should design clinical studies to facilitate these 
analyses, pre-specify in the protocols how these analyses will be carried out, discuss with the 
appropriate OND review division the pre-planned models for these analyses, and present the 
results of these analyses in the clinical study report. Batch effect analyses are usually exploratory, 
with no formal requirement of control of the Type I error rate. The remainder of this section 
provides more details on our recommendations for clinical study design, as well as modeling and 
presentation of clinical study results, to accommodate batch effect analyses. 
 
Randomization of subjects to different batches in each site is highly recommended to facilitate 
batch effect analyses. For instance, a study of three different batches is conceptually similar to a 
study with three different randomized dosage groups and one control group. If subjects are not 
randomized to different batches, a direct comparison of clinical outcomes in different batches can 
be confounded by other effects. For example, if drug products supplied to any given site are only 
from one batch rather than from multiple batches, then a direct comparison of clinical outcomes 
in different batches is confounded with site effects on clinical outcomes.  
 
The sponsor should also ensure that subjects randomized to a certain batch group receive study 
drug from the same batch for the duration of the study. In situations where this may not be 
possible, the batch effect analyses may only be able to estimate a batch sequence effect.   
 
With regard to modeling and presentation of results from batch effect analyses, the sponsor 
should include summary tables and/or forest plots displaying estimates and confidence intervals 
of clinical outcomes or treatment effect by batch, describe the pre-planned models used to 
generate these results, assess possible heterogeneity of clinical outcomes in subjects that receive 
different batches, and describe the statistical measures of heterogeneity and statistical tests of 
homogeneity used. In addition, the sponsor should provide a summary of the subjects baseline 
characteristics by batch to explore possible imbalances in the subjects baseline characteristics 
between batches and identify possible confounders of batch effect on clinical outcomes.  
 
2.  Dose-Response Effect 
 
Another approach to show that clinical response to a botanical drug will not be affected by 
variations of different batches is to demonstrate that the drugs effect on clinical outcomes is not 
sensitive to dose, while also demonstrating that the studied doses are more effective than placebo 
or control, or not inferior to active treatment. If a randomized, multiple-dose, parallel group 
design, Phase 3 study demonstrates a similar treatment effect across multiple doses, concerns 
about the impact of variability in chemical composition across batches may be diminished. 
Therefore, to facilitate the Agencys evaluation of the effects of doses on clinical outcomes, the 
                                                 
33 See Section 5.7 of ICH E9 Statistical Principles for Clinical Trials.   
  21  Contains Nonbinding Recommendations 
sponsor should summarize the results of different doses on clinical outcomes, including estimates 
and confidence intervals of treatment effects by dose displayed in tables and/or forest plots, in the 
clinical study report. 
 
3.  Clinical Studies of Botanical Drugs for Serious Conditions 
 
While extensive anecdotal human experience for some botanical drugs may exist, not knowing 
the active constituent(s) and/or mechanisms of action may cast doubt on the drugs presumed 
efficacy. Lack of scientifically reliable and relevant data to support efficacy may raise ethical 
concerns for clinical studies evaluating the botanical drug alone, especially for serious 
conditions. In these cases, an add-on to standard care versus standard care design is preferred 
to a stand-alone versus control design in clinical studies for serious conditions. However, add-
on designs present the possibility of an adverse interaction between the standard of care and the 
botanical drug. If such an interaction is possible and strong evidence is available to support the 
presumed efficacy of the botanical drug alone, alternative designs (e.g., adding a third arm of 
botanical drug alone) should be considered. 
 
4.  Other Study Design Issues 
 
When the rationale for developing certain botanical drug products is based on prior clinical 
experience in alternative medical systems (e.g., Ayurveda, traditional Chinese medicine, Unani, 
Sidha, and other herbal medicine and pharmacognosy textbooks), the sponsor may propose to 
incorporate traditional practices into their clinical protocols. For example, patients may be 
selected or grouped based on alternative medical theory or practice and treated with specific 
botanical regimens accordingly, or the final dosage form may be prepared by individual patients 
according to traditional Chinese or Indian methods. 
 
These unconventional measures should be considered individually and could be acceptable if 
they will help ensure or enhance the therapeutic effect for an acceptable indication and can be 
described and translated into practical instructions for use in the labeling for patients and 
healthcare providers in the United States. The sponsor contemplating such approaches should 
consult with the appropriate OND review division. 
 
G.  Applicability of Combination Drug Regulations  
 
Fixed dose drug combinations (FDCs) are combinations of two or more active drugs in a single 
dosage form, as defined under the Fixed-Combination regulations (21 CFR 300.50 and 
330.10(a)(4)(iv)). Current regulations require demonstration of the contribution toward overall 
efficacy and safety of each component of a combination drug product; however, the applicability 
of this regulation to a botanical drug product is dependent on the type of mixture from which the 
drug is derived. For example, a botanical drug product derived from a single source (e.g., 
American ginseng root) would not be considered a fixed combination drug product under the 
Fixed-Combination regulations because the entire botanical mixture generally is considered to be 
the active ingredient. The Agency recognizes that demonstrating each botanical raw materials 
contribution to safety and efficacy in a product with multiple botanical raw materials may not 
  22  Contains Nonbinding Recommendations 
always be feasible. In addition, the Agency believes that it is desirable to facilitate the 
development of natural source products that have been used in humans, thus the Agency has 
proposed revisions to the current Fixed-Combination regulations that would allow FDA to waive 
the combination rule requirements in certain situations.34 For example, the proposed rule 
envisions that botanical drug products composed of multiple botanical raw materials in fixed 
ratios (e.g., from multiple parts of the same plant or from parts of different plant species) could 
be considered for waiver, provided that there is prior human experience for the clinical use of 
such a combination. Until a final rule is issued, sponsors are encouraged to discuss such 
approaches for a botanical drug product candidate composed of multiple botanical raw materials 
with the appropriate OND review division.  
 
VII.  NDAS FOR BOTANICAL DRUG PRODUCTS 
 
The pre-NDA meeting is of particular importance for botanical drug products, given their unique 
characteristics and considerations. The pre-NDA meeting should be held sufficiently in advance 
of (e.g., more than 2 months before) the planned NDA submission to allow the applicant enough 
time to meaningfully respond to the Agencys feedback. In accordance with the Prescription 
Drug User Fee Act (PDUFA V) performance goals,35 the Agency and applicant will agree on the 
content of a complete application for the proposed indication(s) at the pre-NDA meeting. 
Agreements and discussions will be summarized at the conclusion of the meeting and reflected in 
the Agencys meeting minutes. 
 
Submission requirements for an NDA for a botanical drug product are generally no different 
from those for other drug products. For instructions and advice on submitting NDAs (applicable 
to all drug products), the applicant should refer to existing Agency regulations and FDA 
guidances. The applicant should submit an NDA for a botanical drug product in the Electronic 
Common Technical Document (eCTD) format.36 Issues specific to NDAs for botanical drug 
products are discussed in this section. Refer to previous sections of this guidance for details on 
data to be acquired and the studies to be conducted to collect such data during the IND process.   
 
A.  Description of Product and Documentation of Prior Human Experience 
 
All information provided in the IND should be submitted in the NDA. Refer to Sections V.A.1 
and 2. If more recent human experience exists for the botanical drug (e.g., based on a similar 
drug product marketed in foreign countries), an updated summary also should be provided in the 
NDA.   
   
                                                 
34 See the proposed rule Fixed-Combination and Co-Packaged Drugs: Applications for Approval and Combinations 
of Active Ingredients Under Consideration for Inclusion in an Over-the-Counter Monograph (80 FR 79776, 
December 23, 2015). 
35 See PDUFA Reauthorization Performance Goals and Procedures for Fiscal Years 2013 through 2017 at 
http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm270412.pdf.  
36 For information about a Common Technical Document (CTD), see the Guidance for Industry on M4: 
Organization of the CTD. For information about an Electronic Common Technical Document, see the FDA web 
page eCTD Basics and Getting Started. 
  23  Contains Nonbinding Recommendations 
B.  Quality Control 
 
Because the drug substances active constituents may not be unequivocally identified, the 
technical challenges for quality control are to determine a botanical drugs identity and ensure its 
consistency of strength. A botanical drug products quality control should consider a totality-of-
the-evidence approach as outlined in Sections III.B and VII.F. It should extend to the raw 
material(s) and may require additional measures such as biological assays and/or information on 
the effect of variations on clinical outcomes from a multiple batch clinical study. 
 
1.  Botanical Raw Material 
 
A botanical drug products quality control should start with the raw material(s) and should be 
described in the NDA. Specific information on medicinal plants (e.g., verification of authenticity 
with morphology, macroscopic and microscopic analysis, and chemical analysis), agricultural 
practices (e.g., growing, harvesting, and storage conditions), geographic locations, and collection 
and processing methods should be identified. The applicant should establish GACP and 
summarize the related procedures for each of the botanical raw materials when submitting an 
NDA. The general GACP principles established by the World Health Organization (WHO), 
European Medicines Agency (EMA), or the regulatory body of the botanical raw material 
growing region should be referenced. DNA fingerprinting may be warranted in cases of 
complicated taxonomy and when identification issues related to the botanical raw material exist. 
For example, if multiple related plant species have been used to produce a particular botanical 
raw material, the DNA fingerprint may provide more plant-specific characteristics for 
identification than would other methods. In addition, the applicant should describe approaches 
used to minimize contamination, deterioration, and variations. The same methods should be used 
to collect and process the raw material(s) for manufacturing the botanical drug substance tested 
during early-phase clinical studies and the drug substance tested during late-phase clinical 
studies. Making changes to these collection and processing methods during clinical development 
could change the chemical profile of the drug substance in the resulting botanical drug product 
and may warrant bridging studies to justify reliance of previous clinical testing results. Also see 
Sections V.A.1 and B.1. 
 
2.   Botanical Drug Substance and Drug Product 
 
a.   Identity 
 
Because of inherent difficulties in characterizing all chemical constituents in botanical drugs, 
establishing their identity relies not only on chemical characterization of molecules in the 
mixture, but also on other aspects, including control of the raw material(s) at the medicinal plant 
level, characterization of relative potency and activity by a biological assay, and/or clinically 
relevant specifications based on results of the multiple batch clinical studies. Nevertheless, the 
applicant should evaluate the current and emerging technologies and develop orthogonal 
analytical methods to provide adequate identification and quantification of the active or chemical 
constituents in a botanical drug. When the active constituents are not known and the botanical 
mixture cannot be fully characterized, the applicant may then select a characteristic profile of 
  24  Contains Nonbinding Recommendations 
chemical constituents (which shows sensitivity to changes in the quality of the raw material(s) 
and/or manufacturing conditions for drug substance and product) for identity testing.   
 
b.   Chemical characterization 
 
The multiple analytical methodologies used for chemical characterization of the botanical drug 
should be fully described in the NDA. The NDA should include all chemical tests performed to 
qualitatively and quantitatively characterize active or chemical constituents, as well as provide 
data to address mass balance.   
 
c.  Manufacturing processes 
 
The applicant should provide information about all of the sites that will be used to manufacture 
the drug substance and drug product for commercial distribution. Changes in the drug 
substances manufacturing sites should be avoided, especially during late-phase clinical 
development. The NDA should include full manufacturing information, including manufacturing 
equipment used, in-process controls, and testing. 
 
The drug substance and drug product manufacturing processes should be finalized, and in-
process controls and testing should be established.  
 
d.  Biological assay 
 
In cases where chemical testing alone may not be sufficient to ensure quality and thus therapeutic 
consistency, the applicant should include a biological assay in the release specifications and 
stability protocols for the botanical drug substance and/or drug product. A biological assay that 
reflects the drugs known or intended mechanism of action is preferred. 
 
Because results from a biological assay are inherently more variable than most of the chemical 
assays, the batch potency and activity should be measured relative to a suitable reference 
standard or material; results should be expressed in units of activity calibrated against the 
reference standard or material. The applicant should incorporate system suitability criteria and 
quality controls to ensure that the assay will perform in a reproducible and predictable manner. 
 
At the time of the NDA submission, the applicant should appropriately validate the biological 
assay. At a minimum, the validation should demonstrate accuracy, precision, specificity, 
linearity, and range.  
 
When the same botanical drug product is intended for multiple indications, the applicant should 
consult with the appropriate OND review division regarding whether it is necessary to develop a 
separate biological assay for each indication.37  
                                                 
37 See ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products 
and USP Biological Assays <1032>: Design and Development of Biological Assays and USP <1033>: Biological 
Assay Validation. 
  25  Contains Nonbinding Recommendations 
 
e.  Specifications 
 
The experience and data accumulated during the development of a botanical drug should form 
the basis for setting clinically relevant specifications. Analytical procedures should be properly 
validated. In addition, when multiple orthogonal methods are used, the totality of the data from 
all analytical procedures 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. Analytical methods should also be sensitive to detect any 
differences in critical quality attributes among multiple batches.  
 
The following tests on the drug substance should be included, if possible (see  314.50(d)(1)): 
 
  Amount by weight of each known chemical constituent and total amount of constituents 
in the same class,  
  Area percentage of each unknown peak, 
  Relative Retention Time (RRT) of each unknown quantifiable peak,  
  Amounts by weight of total lipids and individual fatty acids, 
  Amounts by weight of total amino acids and individual amino acids, 
  Total amount by weight of simple carbohydrates, 
  Total amount by weight of complex carbohydrates,  
  Amounts by weight of total vitamins and individual vitamins, and 
  Ash content (see USP <561 >, Articles of Botanical Origin). 
 
If a biological assay is needed for quality control, the mass balance should be evaluated in 
conjunction with the biological assay.  
 
f.  Stability 
 
The applicant should develop, validate, and use stability-indicating analytical methods and/or a 
biological assay to monitor the stability of the botanical drug substance and drug product. The 
applicant also should perform stress stability studies to identify degradation products in the drug 
substance and drug product, assess the potential toxicity, and provide adequate control of these 
degradation products. A retest period for a drug substance and an expiration dating period for a 
botanical drug product should be established based on data from stability studies designed 
according to the scientific principles described in ICH Q1A(R2).38      
 
g.  Drug master file  
 
CMC information about the botanical raw material and/or drug substance may be submitted as 
part of the IND, NDA, or a drug master file (DMF). However, if the applicant relies on 
information in a DMF, the applicant should have adequate acceptance testing (e.g., chemical 
                                                 
38 See ICH Q1A(R2), supra note 19. 
  26  Contains Nonbinding Recommendations 
identification test, content, biological assay) before accepting the raw materials and/or drug 
substance received from the DMF holder for further processing or for direct use in humans. 
 
h.  Naming consideration 
 
Regulation at 21 CFR  299.4(d) encourages the applicant to contact the United States Adopted 
Name (USAN) Council for designation of an established name. When deriving an established 
name for the botanical drug substance, the USAN Council will base its consideration on a 
common similar pharmacological action or common structural type for the active or chemical 
constituents in the mixture.39   
 
The corresponding International Nomenclature body (the INN Expert Committee) does not grant 
INNs for mixtures, so a botanical drug substance will not be granted an INN.  
 
i.  Current good manufacturing practices 
 
Because of a botanical drugs heterogeneous nature and uncertainty in its defined active 
constituents, control of botanical raw materialsincluding their storage conditions and 
processing methodsis of particular importance in the manufacture of a botanical drug 
substance. The applicant should provide sufficient information about the quality of the starting 
material in the application and should not rely solely on quality control of the finished product 
for a botanical drug product. The manufacturing of botanical drug substance should be in 
compliance with current good manufacturing practices (CGMPs). In some cases, compliance 
with both GACP and CGMPs may be warranted to cover the way in which the botanical raw 
material is grown, collected, processed, and stored. The applicant should designate and document 
the rationale for the point at which production of the drug substance begins and is encouraged to 
contact the appropriate review division in the Office of Pharmaceutical Quality to reach 
agreement on this aspect. 
 
j.  Environmental assessment 
 
Environmental assessment (EA) requirements for NDA approval are described in 21 CFR  
25.30, 25.31, and 25.40. 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.40  
                                                 
39 If a drug substance submitted to the USAN Council for naming is closely related to a compendial article (i.e., 
USP/National Formulary (NF)), compliant with the current USP/NF monograph, or purified to a different extent than 
required in the monograph, the USAN Council has three basic options in naming the substance: 
1)  Vote No USAN, stating that the substance is already compendial and has a compendial name; 
2)  Vote to adopt the compendial name as USAN (in some cases, the name is NF and the monograph concerns use as an 
inactive ingredient), and the USAN would provide an official name for the substance for use as an active drug 
substance; or 
3)  Vote to adopt a name different from the compendial name. This might be done if the origin of the botanical raw 
material or level of purification or manufacturing results in a different mode of action, clinical indication, or safety, 
efficacy, or pharmacokinetics profile. 
 
40 See Environmental Assessment Guidance, supra note 20.  
  27  Contains Nonbinding Recommendations 
   
C.  Nonclinical Safety Assessment 
 
Pharmacology and toxicology requirements for an NDA for a botanical drug are anticipated to be 
the same as those for a nonbotanical drug. Standard guidance documents are available on the 
FDA Drugs guidance web page.41 The applicant should work closely with the Agency on all 
regulatory issues relating to pharmacology and toxicology studies needed during the IND 
process. Possible exceptions to normal drug development recommendations should have been 
initially discussed with the Agency by the end of Phase 2, and general agreements should be 
reached by the end of Phase 3 studies and captured in pre-NDA meeting minutes in accordance 
with PDUFA V performance goals. 
 
D.  Clinical Pharmacology 
 
The general requirements for in vivo bioavailability data in an NDA (described in  320.21) are 
applicable to botanical drugs (see Sections V.D and VI.E). The type of bioavailability study that 
is appropriate for a specific botanical drug product is based on the following: (1) information on 
the active constituents, if known; (2) the complexity of the drug substance; and (3) the 
availability of sensitive analytical methods. Because there could likely be more than one 
chemical constituent in a botanical drug or the active constituents may not be identified, standard 
in vivo bioavailability and pharmacokinetic studies that measure the blood or urine concentration 
of the active moieties or active metabolites may be difficult or impossible to perform. 
Documentation of the methods evaluated and the reason for their abandonment should be 
provided. As an alternative, it may be reasonable to measure an acute pharmacological effect as a 
function of time using an appropriate biological assay method. Well-controlled clinical studies 
that establish the botanical drugs safety and efficacy may be considered acceptable for 
measuring bioavailability when other methods are not possible. 
 
The general criteria for granting a waiver of in vivo bioavailability data in an NDA, described in 
 320.22, are applicable to botanical drug products. The Agency 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 (see  320.22(e)). 
 
The applicant should refer to existing regulations and FDA guidance documents for further 
instructions on the format and content of the clinical pharmacology sections of NDAs. 
 
E.  Clinical Evidence of Efficacy and Safety 
 
The overall requirements for demonstrating a botanical drug products efficacy and safety are the 
same as those for other drug products. The applicant should refer to existing regulations and 
FDA guidance documents for further instructions on the format and content of the clinical 
sections of NDAs. See also Sections VI.F and G.   
                                                 
41 See www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  28  Contains Nonbinding Recommendations 
 
F.  Evidence To Ensure Therapeutic Consistency 
 
One of the key challenges for manufacturers of a botanical drug product is to ensure that different 
marketing batches, with their variations, have the therapeutic effect consistent with those of the 
batches used in the Phase 3 clinical studies. Given the heterogeneous nature of botanical drug 
products, chemical testing alone may not be sufficient for quality control and therefore for 
ensuring therapeutic consistency. As outlined in Section III.B, quality control of botanical drug 
products should take into consideration the three following aspects: (1) botanical raw material 
control, (2) quality control by chemical tests and manufacturing control, and (3) biological assay 
and clinical data. These different aspects of the quality control should be viewed collectively. For 
example, the amount of data needed from (1) and/or (3) (biological assay) could depend on the 
extent to which the molecules in a botanical mixture are characterized based on the chemical 
testing in (2). The applicant should provide an integrated assessment of the above three quality 
control aspects to demonstrate that the commercial botanical drug product batches will have the 
therapeutic effect consistent with those observed in the pre-marketing clinical testing. 
 
The quality information should be collected from the clinical studies conducted during drug 
development, as discussed under different sections earlier in this guidance. All available data 
should be summarized and an integrated evaluation should be presented in the NDA in a 
botanical drug-specific section entitled Assurance of Therapeutic Consistency under Module 
2.3.P.2 (Pharmaceutical Development).   
 
1.    Raw Material Control  
     
Refer to Section VII.B.1. 
 
2.    Quality Control by Chemical Tests and Manufacturing Control  
   
Refer to Section VII.B.2. 
 
3.  Biological Assay(s) and Clinical Data  
   
While the raw material control and other CMC measures will help establish the identity and 
ensure the quality of the botanical drug products, information on correlations between such 
quality parameters and the pharmacological activity or clinical effect may be warranted in certain 
cases to ensure that variations in raw materials and drug substance will not affect a botanical 
drug products therapeutic consistency. Examples of such information are as follows: 
 
a.  Biological assay 
 
As noted above, a biological assay is an important method by which to measure a botanical 
drugs potency and activity. While the biological assay should be as closely related to the drugs 
presumed mechanism of action as possible, other less relevant assays may also be considered and 
evaluated in individual cases. Also see Section VII.B.2. 
  29  Contains Nonbinding Recommendations 
 
b.  Clinical data 
 
Dose-response data (see Section VI.F.2): If the clinical effects are not sensitive to dose (but are 
still superior to the placebo control group), it can reasonably be assumed that the variations 
within the established specifications probably will not affect the therapeutic consistency of drug 
products. 
 
Multiple batch clinical data (see Section VI.F.1): Clinical studies in which subjects are 
randomized to receive different drug product batches can be used to assess treatment-by-batch 
interactions. Lack of significant interaction could provide confidence that therapeutic effects will 
be independent of drug batches within the established specification.   
 
G.   Postmarketing Considerations 
 
Because of the importance of having a stable source of the botanical raw material and consistent 
manufacturing process for the botanical drug substance, any changes made post-approval (e.g., 
change in agricultural sites, agricultural and collection practice, and/or processing methods) 
should be assessed carefully to determine if drug product batches produced after such a proposed 
change would be sufficiently similar (pharmacologically and/or therapeutically) to batches 
produced before such a change. For botanical drug products, the effect of changes may not be 
easily evident. Additional studies (e.g., assessment of potency and activity using biological 
assays and/or other in vivo bridging studies) may be necessary. The Agency will determine the 
amount of data required on a case-by-case basis, taking into consideration a number of factors 
including, for example, the nature and extent of the changes and the extent of characterization of 
the active or chemical constituents in the mixture. 
  30