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Guidance for Industry
Botanical Drug Products
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
June 2004
Chemistry
[PDF
version of this document]
Copies of this Guidance are available from:
Division of Drug Information (HFD-240),
Office of Training and Communications,
Center for Drug Evaluation and Research (CDER),
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857, (Tel) 301-827-4573
Internet at
http://www.fda.gov/cder/guidance/index.htm
TABLE OF CONTENTS
I. INTRODUCTION
II. BACKGROUND
III. GENERAL REGULATORY APPROACHES
A. Marketing Under OTC Drug Monograph
Versus Approved NDA
B. CMC Information for Botanical Drug
Products
C. CMC and Toxicology Information to
Support Initial Studies
D. Applicability of Combination Drug
Regulations
IV. MARKETING A BOTANICAL DRUG UNDER AN
OTC DRUG MONOGRAPH
V. MARKETING A BOTANICAL DRUG UNDER AN
NDA
VI. INDs FOR BOTANICAL DRUGS
A. IND Information for Different
Categories of Botanicals
B. Basic Format for INDs
1. Cover Sheet (see § 312.23(a)(1))
2. Table of Contents (see
§ 312.23(a)(2))
3. Introductory Statement and General
Investigational Plan (see § 312.23(a)(3))
4. Investigator¢
s Brochure (see § 312.23(a)(5))
5. Protocols (§ 312.23(a)(6))
6. Chemistry, Manufacturing, and
Controls (§ 312.23(a)(7))
7. Pharmacological and Toxicological
Information (§ 312.23(a)(8))
8. Previous Human Experience With the
Product (§ 312.23(a)(9))
VII. INDs FOR PHASE 1 AND PHASE 2
CLINICAL STUDIES OF LAWFULLY MARKETED BOTANICAL PRODUCTS WITHOUT
SAFETY CONCERNS
A. Description of Product and
Documentation of Human Use
1. Description of Botanicals Used
(§ 312.23(a)(3)(i))
2. History of Use
(§ 312.23(a)(3)(ii),(a)(9))
3. Current Marketed Use
(§ 312.23(a)(3)(ii), (a)(9))
B. Chemistry, Manufacturing, and
Controls
1. Botanical Raw Material
(§ 312.23(a)(7)(i))
2. Botanical Drug Substance
(§ 312.23(a)(7)(iv)(a))
3. Botanical Drug Product
(§ 312.23(a)(7)(iv)(b))
4. Animal Safety Test (§ 312.23(a)(8))
5. Placebo (§ 312.23(a)(7)(iv)(c))
6. Labeling (§ 312.23(a)(7)(iv)(d))
7. Environmental Assessment or Claim of
Categorical Exclusion (§ 312.23(a)(7)(iv)(e))
C. Pharmacology/Toxicology Information
1. All Marketed Botanical Products
2. Foreign-Marketed Botanical Products
D. Bioavailability
E. Clinical Considerations
VIII. INDs FOR PHASE 1 and PHASE 2
CLINICAL STUDIES FOR NONMARKETED BOTANICAL PRODUCTS and Products
with known safety concerns
A. Description of Product and
Documentation of Human Use
1. Description of Botanicals Used
(§ 312.23(a)(3)(i))
2. History of Use (If Any)
(§ 312.23(a)(3)(ii), (a)(9))
3. Current Investigational Use (If Any)
(§ 312.23(a)(3)(ii), (a)(9))
B. Chemistry, Manufacturing, and
Controls
1. Botanical Raw Material
(§ 312.23(a)(7)(i))
2. Botanical Drug Substance
(§ 312.23(a)(7)(iv)(a))
3. Botanical Drug Product
(§ 312.23(a)(7)(iv)(b))
4. Placebo (see section VII.B.5)
5. Labeling (see section VII.B.6)
6. Environmental Assessment or Claim of
Categorical Exclusion
C. Nonclinical Safety Assessment
1. Traditional Preparations
2. Others
3. Products with Known Safety Issues
D. Bioavailability
E. Clinical Considerations
IX. INDs FOR PHASE 3 CLINICAL STUDIES OF
ALL BOTANICAL PRODUCTS
A. Description of Product and
Documentation of Human Experience
B. Chemistry, Manufacturing, and
Controls
1. Expanded Clinical Studies
2. End-of-Phase 3 Clinical Studies and
Pre-NDA Considerations
C. Nonclinical Safety Assessment
1. Repeat-Dose General Toxicity Studies
2. Nonclinical
Pharmacokinetic/Toxicokinetic Studies
3. Reproductive Toxicology
4. Genotoxicity Studies
5. Carcinogenicity Studies
6. Special Pharmacology/Toxicology
Studies
7. Regulatory Considerations
D. Bioavailability and Clinical
Pharmacology
E. Clinical Considerations
glossary
QUESTIONS AND ANSWERS
ATTACHMENT A: Regulatory Approaches FOR
MARKETING BOTANICAL DRUG PRODUCTS
Guidance for Industry
Botanical Drug Products
This guidance represents the Food and Drug Administration's
(FDA's) current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA or
the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact
the FDA staff responsible for implementing this guidance. If you
cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance. |
I. INTRODUCTION
This guidance explains when a botanical drug may be marketed
under an over-the-counter (OTC) drug monograph and when FDA
regulations require approval for marketing of a new drug application
(NDA), submitted under section 505(b) of the Federal Food, Drug, and
Cosmetic Act (the Act), 21 U.S.C. 355(b). In addition, this document
provides sponsors with guidance on submitting investigational new
drug applications (INDs) for botanical drug products, including
those botanical products (or botanicals) currently lawfully
marketed as foods (including conventional foods and dietary
supplements) in the United States.
This guidance also discusses several areas in which, because of
the unique nature of botanicals, FDA finds it appropriate to apply
regulatory policies that differ from those applied to synthetic,
semisynthetic, or otherwise highly purified or chemically modified
drugs (including antibiotics derived from microorganisms). This
latter group of drug substances is referred to in this guidance as
synthetic or highly purified drugs. Therefore, when the
recommendations on a specific topic discussed in this guidance
differ from those in other existing guidances (e.g., Submitting
Supporting Documentation in Drug Applications for the Manufacture of
Drug Substances, 1987), this guidance takes
precedence. In particular, this guidance states that applicants may
submit reduced documentation of nonclinical (preclinical) safety and
of chemistry, manufacturing, and controls (CMC) to support an IND
for initial clinical studies of botanicals that have been legally
marketed in the United States and/or a foreign country as dietary
supplements without any known safety concerns.
FDA's guidance documents, including this guidance, do not
establish legally enforceable responsibilities. Instead, guidances
describe the Agency's current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or
statutory requirements are cited. The use of the word should
in Agency guidances means that something is suggested or
recommended, but not required.
II. BACKGROUND
Botanical products are finished, labeled products that
contain vegetable matter as ingredients. A botanical product may be
a food (including a dietary supplement), a drug (including a
biological drug), a medical device (e.g., gutta-percha), or a
cosmetic under the Act. An article is generally a food if it is used
for food (21 U.S.C. 312(f)(1)). Whether an article is a drug,
medical device, or cosmetic under the Act turns on its "intended
use" (21 U.S.C. 312(g)(1)(B) and (C), (h)(2) and (3), (i)).
"Intended use" is created by claims made by or on behalf of a
manufacturer or distributor of the article to prospective
purchasers, such as in advertising, labeling, or oral statements.
For the purposes of this document, the term botanicals
includes plant materials, algae, macroscopic fungi, and combinations
thereof. It does not include:
- Materials derived from genetically modified botanical species
(i.e., by recombinant DNA technology or cloning).
- Fermentation products (i.e., products produced by
fermentation of yeast, bacteria, and other microscopic
organisms, including when plants are used as a substrate, and
products produced by fermentation of plant cells), even if such
products are previously approved for drug use or accepted for
food use in the United States (e.g., antibiotics, amino acids,
and vitamins).
- Highly purified substances (e.g., paclitaxel) or chemically
modified substances (e.g., estrogens synthesized from yam
extracts) derived from botanical sources.
This guidance addresses all botanical drug products (in all
dosage forms) that are regulated under the Act, except those also
regulated under section 351 of the Public Health Service Act (42
U.S.C. 262). Although this guidance does not address drugs that
contain animals or animal parts (e.g., insects, annelids, shark
cartilage) and/or minerals, either alone or in combination with
botanicals, many scientific principles described in this guidance
may also apply to those products. When a drug product contains
botanical ingredients in combination with either (1) a synthetic or
highly purified drug or (2) a biotechnology derived or other
naturally derived drug, this guidance only applies to the botanical
portion of the product.
III. GENERAL REGULATORY APPROACHES
Many botanical products are used widely in the United States.
Depending on its labeling and intended use, a botanical product can
be a food, a dietary supplement, and/or a drug. Botanicals used for
food and consumed primarily for their taste, aroma, or nutritive
value (e.g., lettuce, herbs used as seasonings) are regulated as
foods. Botanicals can also be dietary supplements if they are
labeled as dietary supplements and otherwise meet the dietary
supplement definition in section 201(ff) of the Act (21 U.S.C.
321(ff)).
If a botanical product is intended for use in diagnosing,
mitigating, treating, or curing disease, it is a drug under section
201(g)(1)(B) of the Act and is subject to regulation as such. If a
botanical product is intended to prevent disease, it is also a drug
under section 201(g)(1)(B), except that a product that bears a
health claim authorized in accordance with section 403(r) of the Act
(21 U.S.C. 343(r)) is not a drug solely because its labeling
contains such a claim. If the intended use of a botanical product is
to affect the structure or function of the human body, it may be
regulated either as a dietary supplement or as a drug, depending on
the circumstances.
Under the Dietary Supplement Health and Education Act of 1994 (DSHEA),
an orally ingested product that meets the definition of a "dietary
supplement" under section 201(ff) of the Act may be lawfully
marketed with a statement that (1) claims a benefit related to a
classical nutrient deficiency disease (and discloses the prevalence
of the disease in the United States), (2) describes how the product
is intended to affect the structure or function of the human body,
(3) characterizes the documented mechanism by which the product acts
to maintain such structure or function, or (4) describes general
well-being from consumption of the product (section 403(r)(6)(A) of
the Act). A dietary supplement statement of the type described above
may not claim to diagnose, mitigate, treat, cure, or prevent a
specific disease or class of diseases (section 403(r)(6) of the
Act).
If a botanical product is intended to affect the structure or
function of the body but does not meet the definition of a dietary
supplement, or does not meet the requirements for making a
structure/function claim under section 403(r)(6) of the Act, it is
subject to regulation as a drug under section 201(g)(1)(C) of the
Act. As noted above, a botanical product is subject to regulation as
a drug under section 201(g)(1)(B) of the Act if it is intended for
use in diagnosing, mitigating, treating, curing, or preventing
disease (except for a product marketed with certain health claims
authorized under section 403(r) of the Act). Under section 505(b) of
the Act, a drug must be marketed under an approved NDA unless the
product is excluded from the definition of a new drug under section
201(p) of the Act. Certain products that FDA determines are
generally recognized as safe and effective in accordance with
section 201(p) may be marketed under FDA¢
s OTC drug monograph system.
A. Marketing Under OTC Drug Monograph
Versus Approved NDA
A botanical drug product may be marketed in the United States
under (1) an OTC drug monograph or (2) an approved NDA or ANDA.
A botanical product that has been marketed in the United States
for a material time and to a material extent for a specific OTC
drug indication may be eligible for inclusion in an OTC drug
monograph codified in
21 CFR parts 331-358. The manufacturer would need to submit a
petition in accordance with 21 CFR 10.30 to amend the monograph
to add the botanical substance as a new active ingredient.
Under current regulations, if there is no marketing history
in the United States or a foreign country for a botanical drug
product, if available evidence of safety and effectiveness does
not warrant inclusion of the product in an OTC drug monograph,
or if the proposed indication would not be appropriate for
nonprescription use, the manufacturer must submit an NDA to
obtain FDA approval to market the product for the proposed use
(sections 201(p) and 505 of the Act). An NDA for a botanical
drug could seek approval for either prescription or OTC use,
depending on the indication and characteristics of the product
and whether it is safe for use outside of the supervision of a
practitioner licensed by law to administer it. If existing
information on the safety and effectiveness of a botanical drug
product is insufficient to support an NDA, we recommend that new
clinical studies be conducted to demonstrate safety and
effectiveness.
When a final OTC drug monograph is published for a specific
use of a botanical drug, any person may market a product
containing the same substance and for the same use, provided the
labeling and other active ingredients (if present) are in accord
with all relevant monographs and other applicable regulations.
In contrast, when a product is approved under an NDA, the
approval is specific to the drug product that is the subject of
the application (the applicant’s drug product), and the
applicant may be eligible for marketing exclusivity for either 5
years (if it is a new chemical entity) or 3 years from the time
of approval, even in the absence of patent protection. A new
botanical drug (containing multiple chemical constituents) may
qualify as a new chemical entity under § 314.108(a). If a
product qualifies as a new chemical entity, during the period of
exclusivity, FDA will not approve, or in some cases even review,
certain competitor products unless the second sponsor conducts
all studies necessary to demonstrate the safety and
effectiveness of its product and submits a 505(b)(1)
application. Therefore, if a person wishing to market a
botanical drug product that is not included in an existing OTC
drug monograph desires marketing exclusivity for the product,
the person should seek approval of an NDA rather than petition
the Agency to amend a monograph. Attachment A contains a
schematic showing different regulatory approaches that can be
taken for marketing botanical drug products in the United
States, including OTC drug monograph and NDA procedures.
B. CMC Information for Botanical Drug
Products
Botanical drug products have certain unique characteristics
that should be taken into account in the application of FDA
regulations and guidance. Botanical drugs are derived from
vegetable matter and are usually prepared as complex mixtures.
Their chemical constituents are not always well defined. In many
cases, the active constituent in a botanical drug is not
identified, nor is its biological activity well characterized.
Therefore, the CMC documentation that should be provided for
botanical drugs will often be different from that for synthetic
or highly purified drugs, whose active constituents can be more
readily chemically identified and quantified. For example, FDA
would expect an NDA for a synthetic or highly purified drug to
identify the active ingredient. However, it would not be
essential for the sponsor of a botanical drug to identify the
active constituents (although FDA recommends that this be done
if feasible). Even if the sponsor were to eventually identify
the active constituents in the NDA, the active constituents
might not be identified during the IND stage.
Because of the complex nature of a typical botanical drug and
the lack of knowledge of its active constituent(s), FDA may rely
on a combination of tests and controls to ensure the identity,
purity, quality, strength, potency, and consistency of botanical
drugs. These tests and controls include (1) multiple tests for
drug substance and drug product (e.g., spectroscopic and/or
chromatographic fingerprints, chemical assay of characteristic
markers, and biological assay), (2) raw material and process
controls (e.g., strict quality controls for the botanical raw
materials and adequate in-process controls), and (3) process
validation (especially for the drug substance).
C. CMC and Toxicology Information to Su
pport Initial Studies
Many botanical products are legally available in the United
States as dietary supplements. Given the wide availability of
such products outside of clinical trials, it is important to
assess the effectiveness of such products. To support initial
clinical trials, the nonclinical pharmacology and toxicology
information that must be provided under 21 CFR 312.22(b) for
legally available botanical products with no known safety issues
(see section VI.A) may be markedly reduced compared to that
expected for synthetic or highly purified new drugs that are not
legally marketed and for which there is no prior human
experience. In most cases, additional toxicology and CMC data
will not be required for such initial trials.
D. Applicability of Combination Drug
Regulations
Botanical drug products that are derived from a single part
of a plant (e.g., leaves, stems, roots, or seeds), or from a
single species of alga or macroscopic fungus (e.g., a mushroom),
are not considered to be fixed-combination drugs within the
meaning of 21 CFR 300.50 and 330.10(a)(4)(iv). Consequently,
they do not have to meet the requirements for combination drugs,
principally the need to demonstrate that each component or
active ingredient makes a contribution to claimed effects.
Botanical drugs composed of multiple parts of a single
species of plant, alga, or macroscopic fungus, or of parts from
different species of plants algae, or macroscopic fungi,
currently are subject to the combination drug requirements.
However, FDA is considering revising its regulations to allow
for the exemption of such botanical drugs from application of
the combination drug requirements under certain circumstances.
IV. MARKETING A BOTANICAL DRUG UNDER AN OTC
DRUG MONOGRAPH
A botanical product that has been marketed in the United States
for a material time and to a material extent for a specific OTC
indication may be eligible for consideration in the OTC drug
monograph system. Currently, there are several botanical drugs,
including cascara, psyllium, and senna, that are included in the OTC
drug review. For a botanical drug substance to be included in an OTC
drug monograph, there must be published data establishing general
recognition of safety and effectiveness, usually including results
of adequate and well-controlled clinical studies (see §§ 314.126(b)
and 330.10). Requirements related to safety, effectiveness, and
labeling for drugs to be included in an OTC drug monograph are set
forth in 21 CFR part 330.
A request to amend an OTC drug monograph to include a botanical
substance must be submitted by citizen petition in accordance with
§§ 10.30 and 330.10(a)(12). There should be publicly available
quality standards for such a botanical drug substance in the drug
section (i.e., not in the National Formulary or other nondrug
sections) of the United States Pharmacopeia (USP). In the
absence of a USP drug monograph, the
petitioner should include suitable quality standards for the
botanical drug substance in its citizen petition and simultaneously
propose adoption of those standards in the USP. Additional criteria
and procedures by which a botanical drug substance may become
eligible for inclusion in the OTC drug monograph system are set
forth in § 330.14. FDA regulations on current good manufacturing
practices (CGMPs) apply to all OTC drug monograph products,
including any listed botanical drug products (see § 330.1(a)).
For further information on the OTC drug monograph approach to
marketing a botanical drug product, sponsors are encouraged to
contact CDER¢ s Division of
Over-the-Counter Drug Products (HFD-560).
V. MARKETING A BOTANICAL DRUG UNDER AN NDA
A botanical drug product that is not generally recognized as safe
and effective for its therapeutic claims is considered a new drug
under section 201(p) of the Act. Section 505(a) of the Act requires
any person wishing to market a botanical drug product that is a new
drug to obtain FDA approval of an NDA or ANDA for that product.
According to section 505(d) of the Act and § 314.50, an NDA must
contain substantial evidence of effectiveness derived from adequate
and well-controlled clinical studies, evidence of safety, and
adequate CMC information. The format of an NDA submission and the
requirements for its various sections are set forth in part 314 and
discussed in several CDER guidance documents.
VI. INDs FOR BOTANICAL DRUGS
If available information is insufficient to support an NDA for a
botanical drug, the sponsor will need to develop further data. An
IND is required under section 505(i) of the Act and
21 CFR part 312 (unless exempt under § 312.2(b)) when a botanical
product is studied in the United States for a drug use (see section
201(g) of the Act), even if such study is intended solely for
research purposes. Under § 312.22, an IND must contain sufficient
information to demonstrate that the drug product is safe for testing
in humans and that the clinical protocol is properly designed for
its intended objectives.
A. IND
Information for Different Categories of Botanicals
Under § 312.22(b), the amount of information that must be
submitted in an IND for a particular drug product depends on,
among other things, the novelty of the drug, the extent to which
it has been studied previously, the drug product¢
s known or suspected risks, and the developmental phase of the
drug. Sections VII and VIII of this guidance describe the
information that we recommend a sponsor provide in meeting the
requirements in § 312.23 for an IND for initial (i.e., phase 1
and phase 2) clinical studies of a botanical drug. As noted
above, for botanicals legally marketed under the DSHEA, there
will often be very little new CMC or toxicological data needed
to initiate such trials, as long as there are no known safety
issues associated with the product and it is to be used at
approximately the same doses as those currently or traditionally
used or recommended. A botanical drug is considered to have a
known safety issue when FDA has evidence that it produces
serious and/or possibly life-threatening effects. Nonclinical
evaluation to characterize toxicities may be appropriate for
products with known safety issues. For example, nonclinical data
may be appropriate to help establish safe doses and to determine
ways to better monitor potential toxicities in humans. Such
nonclinical studies may be needed early in development (see
§ 312.23(a)(8)).
Properly conducted early clinical investigations, including
controlled effectiveness trials in phase 2, will allow a
determination of whether there is a clinical effect worth
pursuing and will provide a more systematic evaluation of safety
than previously available. If a botanical drug product shows
promise of effectiveness in such early trials, the potential for
wider use for particular purposes will create a need for greater
assurance of product quality and consistency and for expanded
(i.e., phase 3) clinical studies of safety and effectiveness
(§ 312.22(b)). IND information appropriate for expanded clinical
studies of botanical drugs is discussed in section IX.
Under § 312.22(b), the IND sponsor of a botanical product
that has been previously marketed but not in the United
States must provide sufficient additional information to assist
FDA in determining the safety of the product for use in initial
clinical studies (section VII). Such additional information is
appropriate under that regulation because these products are not
already marketed in the United States and evidence of safety
should be provided before patients are exposed to them.
This guidance also addresses the type of information that
should be provided under § 312.22 in INDs for initial studies on
botanical products that have not been lawfully marketed anywhere
or have known safety issues (section VIII). In contrast to
botanical products that have been marketed in some form,
considerably less information may be available on the safety of
a new botanical product that has not been marketed anywhere as a
food or dietary supplement and has not been tested as a drug in
humans. Consequently, it is appropriate that, under § 312.22(b),
sponsors of INDs for initial trials of botanical products that
have not previously been lawfully marketed anywhere, or for
which there are known safety issues, provide certain additional
information to FDA.
The information to be provided in an IND for a botanical drug
product is illustrated schematically in Attachment B and
discussed in this section and sections VII-IX below. FDA
encourages sponsors of INDs for initial studies of botanical
drugs to seek input from CDER review divisions (organized based
on the therapeutic classes of the drugs) to ensure that the
appropriate information is submitted and that the clinical
protocols are well designed. Many guidance documents specific to
particular indications or dosage forms are also available from
the respective review divisions.
FDA may place an IND for initial studies of a botanical drug
on clinical hold (i.e., an order issued by the Agency to delay a
proposed clinical study) if it finds that the IND does not
contain sufficient information required under § 312.23 to assess
the risk to subjects of the proposed studies
(§ 312.42(b)(1)(iv)). However, the lack of any specific item of
information listed in § 312.23 for a phase 1 study will not
necessarily justify imposing a clinical hold. Possible grounds
for a clinical hold are set forth in § 312.42(b) and discussed
in CDER¢ s guidance for industry on
Content and Format of Investigational New Drug Applications (INDs)
for Phase 1 Studies of Drugs, Including Well-Characterized,
Therapeutic, Biotechnology-derived Products (November 1995).
B. Basic Format
for INDs
The format and general requirements for IND submissions are
stated in § 312.23 and discussed in several CDER guidance
documents, including the phase 1 guidance referenced
above. These requirements are summarized below, with guidance on
the specific types of information that we recommend sponsors of
botanical drug products provide to meet these requirements:
1. Cover Sheet (see § 312.23(a)(1))
2. Table of Contents (see
§ 312.23(a)(2))
3. Introductory Statement and General
Investigational Plan (see § 312.23(a)(3))
4. Investigator¢
s Brochure (see § 312.23(a)(5))
5. Protocols (§ 312.23(a)(6))
Section 312.23(a)(6) requires information on protocols for
planned studies. In general, clinical evaluation of botanical
drug products for safety and effectiveness does not differ
significantly from evaluation of synthetic or highly purified
drugs. For study results to be interpretable, clinical studies
must be well designed and carefully executed (see § 314.126). A
sponsor need not differentiate the clinical effects of each
molecular entity in a botanical product derived from a single
part of a plant (see section III.D, Applicability of Combination
Drug Regulations). Even where the components of a combination
product must be studied under § 300.50, initial controlled
studies could be used to evaluate the entire combination
product. For additional information on the clinical development
of new drugs, see the CDER guidance Format and Content of the
Clinical and Statistical Sections of an Application (July
1988) and other guidances related to the submission of
applications involving specific drug classes and diseases.
Clinical studies of botanical products may pose special
problems associated with the incorporation of traditional
methodologies, such as selection of doses and addition of new
botanical ingredients based on response, that will need to be
resolved. In almost all cases, credible studies will be
randomized, double blind, and placebo-controlled (or
dose-response) (see § 314.126). Studies with only active
controls may be appropriate when it is unethical to use a
placebo, as would be the case in serious and life-threatening
conditions for which there is established effective therapy.
However, active studies pose special difficulties in
interpretation and should be used only when a placebo cannot be
used and there is good reason to expect the botanical treatment
to be effective. With respect to serious illnesses for which
there is established effective therapy, we generally encourage
sponsors to use an "add-on" design for the initial trials: The
botanical product would be compared to a placebo, each being
added to the standard treatment. For symptomatic disorders where
the use of a placebo poses no ethical problem,
placebo-controlled trials should almost always be conducted
because active control trials are particularly difficult to
interpret in such situations. Having a concurrent active
treatment group in addition to placebo control (e.g., a
three-armed study) is advisable in certain cases (as in
psychiatric trials) to verify the assay sensitivity of the
study. The sponsor is encouraged to consult International
Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) guidance
E10 Choice of Control Group and Related Issues in Clinical
Trials (May 2000).
For botanical as well as for synthetic or highly purified
drugs, absolute safety does not exist for any therapeutic
intervention, and FDA must assess risks in light of potential
clinical benefits (see § 312.22). For more comprehensive
information on safety evaluations, see other CDER guidance
documents. As is the case for synthetic or highly purified
drugs, the best safety data on newly developed botanicals will
be derived from controlled efficacy trials, but for chronic
indications, long-term, open-label extensions also will be
important. For chronic conditions, exposures of at least 6-12
months’ duration are usually appropriate (see ICH guidance
E1A The Extent of Population Exposure to Assess Clinical Safety:
For Drugs Intended for Long-term Treatment of
Non-Life-Threatening Conditions (March 1995)).
Section VII.E of this guidance provides recommendations on
the protocol design of initial clinical trials for botanical
products legally marketed under the DSHEA. Sections VIII.E and
IX.E provide information on the design of initial clinical
trials for nonmarketed botanical drug products and for expanded
studies on all botanical drug products, respectively.
As with any clinical study, appropriate human research
subject protections must be followed, including submission of
the protocol to an institutional review board (IRB) and
obtaining proper informed consent (see 21 CFR parts 56 and 50).
Pursuant to § 50.25, the consent form should describe any
procedures that are experimental along with a description of the
risks, benefits, and alternatives of taking the product. We
recommend that the consent form acknowledge any lack of
additional chemical or toxicological characterization.
6. Chemistry, Manufacturing, and
Controls (§ 312.23(a)(7))
The requirements for the content and format of the CMC
section of an IND are stated in § 312.23(a)(7)(iv)(a)-(e).
These regulations require documentation of the drug substance,
drug product, placebo, labeling, and an environmental analysis.
Plant materials used in the production of botanical drug
products often are not completely characterized and defined or
are prone to contamination, deterioration, and variation in
composition and properties. In many cases, the active
constituent in a botanical drug is not identified, nor is its
biological activity well characterized. Therefore, in contrast
to the situation with synthetic or highly purified drug
products, it may be difficult to ensure the quality of a
botanical drug by controlling only the corresponding drug
substance and drug product. To ensure that a botanical drug
product used in clinical trials is of consistently good quality,
and that sufficient information exists to meet the requirements
of § 312.23(a)(7)(iv), the sponsor should have, in addition to
final product testing, appropriate quality controls for the
botanical raw materials. The manufacturing process should be
well defined, with adequate in-process controls, especially for
the drug substance.
As noted in section III.C, sponsors of initial clinical
trials on botanical products that have been legally marketed as
dietary supplements and that do not have safety issues can
submit less CMC information than must be provided under
§§ 312.22(b) and 312.23(a)(7)) for later studies or for studies
on products not previously marketed. Section VII.B describes the
CMC information that generally will be necessary under
§ 312.23(a)(7) for initial trials on previously marketed
botanicals without safety issues.
To comply with §§ 312.22(b) and 312.23(a)(7), sponsors must
submit additional CMC information for initial studies of
nonmarketed botanical products and marketed botanicals with
safety issues (see section VIII.B) and for expanded trials on
all botanical products (see section IX.B). Additional guidance
(not specific to botanical drugs) on the submission of CMC
information in INDs and marketing applications can be found in
other CDER guidance documents.
In the initial stage of clinical studies of a botanical drug,
it is generally not necessary to identify the active
constituents or other biological markers or to have a chemical
identification and assay for a particular constituent or marker.
Identification by spectroscopic and/or chromatographic
fingerprinting and strength by dry weight (weight minus water or
solvents) can be acceptable alternatives. Attributes for lot or
batch release testing should be determined as the clinical study
progresses, although appropriate acceptance criteria for batch
release need not be established until later in phase 3 studies.
Batch analyses on clinical batches should be submitted as they
become available, to demonstrate batch-to-batch consistency and
to help establish appropriate acceptance criteria for
fingerprinting. Identification of active constituents is helpful
in optimizing manufacturing procedures, ensuring batch
consistency, and contributing to an understanding of the
clinical effects of the botanical product. Therefore, when
feasible, active constituents should be identified during phase
3 studies.
A single formulation (i.e., one in which the components or
ingredients and composition of the drug substance and drug
product are kept constant) and a single dosage form should be
used throughout the different stages of the clinical trials
unless this proves impossible. Screening of a number of
sources/batches for product quality is recommended to ensure
that the material used in initial trials will yield
interpretable results that can be used to guide later
development. Once a batch or source of acceptable quality is
identified, sufficient quantities should be obtained to sustain
the initial clinical trials. This is especially important if the
sponsor does not have access to the manufacturing and controls
information on the botanical drug substance and finished
product. In addition, sufficient quantities of the botanical raw
material and drug substance from the same batch should be
retained for future chemical characterization and/or
pharmacological/toxicological testing. It is also important to
obtain the botanical drug product from a source willing to
provide FDA with detailed manufacturing and controls information
when needed, or as clinical evaluation of the product
progresses. These factors are crucial if the sponsor intends to
pursue FDA approval for a new drug application for the botanical
product.
Consistency should be maintained when multiple batches are
used in the nonclinical and clinical trials. It also is
important that the material used in phase 1/2 trials be verified
for its authenticity (see VIII.B.1 below). Samples from phase
1/2 studies should be retained for comparison with batches to be
used in the phase 3 trials to ensure consistency. Bridging
studies (clinical and/or nonclinical) should be performed if the
use of batches with different characteristics in different
phases cannot be avoided.
Botanical raw materials may sometimes be dispensed at clinics
on an as needed or by prescription basis and subsequently
prepared by patients themselves at home. We recommend avoiding
these practices during clinical trials if at all possible
because data related to such use may not be reliable because of
variability in preparation by patients. When absolutely
necessary, dispensing in such a manner may be considered for
initial clinical studies. But as clinical trials are expanded,
the botanical drug product should be produced in a controlled
manner by an established manufacturer to ensure the validity and
reliability of data.
If previously available nonclinical and/or clinical data are
provided or referenced in the IND, a comparison should be made
of the botanical drug products used in the referenced studies,
the products to be used in the proposed trials, and (if
appropriate) the products intended for marketing (including
their corresponding botanical raw materials, drug substances,
and formulations).
If a synthetic or highly purified drug or a biotechnology- or
other naturally derived (non-botanical) drug is added to a
botanical drug product, the CMC data for this added substance
should be described or cross-referenced according to § 312.23(b)
and guidances. Under § 312.23(a)(7), animal parts (e.g.,
insects, annelids, shark cartilage) or minerals that are
combined with a botanical in a drug product, must be accompanied
by additional manufacturing and controls information specific to
these materials because they are part of the drug substance
being studied.
CMC information on a botanical raw material, drug substance,
and/or drug product may be submitted by the sponsor as part of
the IND or by the manufacturer (if different from the sponsor)
in a drug master file (DMF). A DMF is a submission from a
manufacturer to FDA that may be used to provide confidential
information on a human drug (§ 314.420(a)). The information
contained in a DMF may be cross-referenced to support an IND or
NDA and is reviewed and used by FDA only when authorized by the
manufacturer. However, the sponsor relying on information in a
DMF should have adequate acceptance testing (e.g.,
identification test, assay) before accepting the raw material,
drug substance, or drug product received from the DMF holder for
further processing or for use in humans directly.
7. Pharmacological and Toxicological
Information (§ 312.23(a)(8))
The content and format for pharmacological and toxicological
information to be provided in an IND are described in
§ 312.23(a)(8). Nonclinical pharmacology and toxicology studies
are useful in guiding early clinical studies and in predicting
the potential toxicity of a new drug.
Ordinarily, less nonclinical information will be required to
support the initial clinical trials of currently marketed orally
ingested botanical products than is expected for synthetic or
highly purified drugs. For a botanical product that is not
currently lawfully marketed in the United States, but is
administered orally and prepared, processed, and used according
to methodologies for which there is prior human experience,
sufficient information may be available to support initial
clinical studies without standard nonclinical testing. However,
for a botanical drug with a route of administration other than
oral, additional pharmacology/toxicology information may be
necessary before initial clinical studies.
After initial clinical studies, further pharmacology and
toxicology studies of a botanical drug generally would be needed
before later phases of clinical development and before approval
for marketing. Sections VII.C, VIII.C, and IX.C provide details
on the pharmacological and toxicological information that should
be provided for clinical trials on botanical drugs.
8. Previous Human Experience With the
Product (§ 312.23(a)(9))
Under § 312.23(a)(9), an IND sponsor must submit information
about previous human experience with an investigational drug.
Many botanical products have been marketed or tested in clinical
studies (often involving few patients). When such studies have
been conducted, data from the studies must be included in an IND
for a botanical drug to assist FDA in its overall safety
assessment. Sections VII.A, VIII.A, and IX.A of this guidance
provide additional recommendations on the submission of
information on previous human experience with a botanical
product.
VII. INDs FOR PHASE 1 AND PHASE 2
CLINICAL STUDIES OF LAWFULLY MARKETED BOTANICAL PRODUCTS
WITHOUT SAFETY CONCERNS
This section provides more detailed guidance on the submission of
certain types of information for INDs for initial clinical studies
on botanical products that have been lawfully marketed and that do
not raise safety issues (for drugs with known safety concerns, see
section VIII). This section also notes where additional information
must be provided under § 312.22(b) when an IND is for a botanical
product that has been marketed in one or more foreign countries but
not the United States.
A. Description of Product and
Documentation of Human Use
1. Description of Botanicals Used
(§ 312.23(a)(3)(i))
The following information should be provided for each
of the botanical raw materials used as ingredients in a
botanical drug product:
Common or usual names of the plant, alga, or
macroscopic fungus
Synonyms (e.g., Latin, Greek, English, Spanish,
Chinese)
Name of variety, species, genus, and family, including
the name of the botanist who first described the species
or variety, if known
Chemical class of the active constituent (the chemical
constituent that is responsible for the claimed
pharmacological activity or therapeutic effect) or
characteristic marker (a chemical constituent used for
identification and/or quality control purposes), if known
2. History of Use (§ 312.23(a)(3)(ii),(a)(9))
The sponsor should include information found in historical
sources (e.g., books of medical practice in Ayurveda,
traditional Chinese medicine, Unani, Sida) and scientific
literature about the prior human use of the botanical product,
and each of its ingredients, in traditional foods and drugs. Any
literature submitted must be provided in English (and in its
original language, if other than English) (§ 312.23(c)).
3. Current Marketed Use
(§ 312.23(a)(3)(ii), (a)(9))
The sponsor must include information about the nature and
extent of the current worldwide use of the botanical product,
and each of its ingredients, in foods and drugs, including
evidence concerning its marketing experience in the United
States and/or foreign countries. For a foreign-marketed
botanical product, the sponsor should provide data that verify
its safe human use, including proof of the annual sales volume,
an estimate of the size of the exposure population, and the rate
of adverse effects.
B. Chemistry, Manufacturing, and Controls
Outlined below is the CMC information that we recommend you
submit, in meeting the requirements of § 312.23(a)(7), in an IND
to support a phase 1 or phase 2 clinical trial on a botanical
product that is currently lawfully marketed without any known
safety issues in the United States and/or a foreign country.
Literature references and relevant official compendia or
published standards should be provided whenever possible.
1. Botanical Raw Material
(§ 312.23(a)(7)(i))
The information discussed in section VII.A.1 should be
provided for all currently lawfully marketed products. It is
important for the safe conduct of clinical trials to ensure the
proper identity of botanical raw materials used in the trials.
Since there is no history of U.S. experience for botanical raw
materials marketed only outside the United States, a certificate
of authenticity of the plant and plant parts should be provided
for such materials. A trained professional who is competent to
determine authenticity should sign this certificate. This
information also should be provided, if available, for a
botanical raw material marketed in the United States.
2. Botanical Drug Substance
(§ 312.23(a)(7)(iv)(a))
The general method of preparation (e.g., pulverization,
decoction, expression, aqueous extraction, or ethanolic
extraction) must be provided under § 312.23(a)(7)(iv)(a).
This is especially important where more than one process exists
in the literature on which the safety of the botanical drug
substance is based.
3. Botanical Drug Product
(§ 312.23(a)(7)(iv)(b))
A botanical drug product is manufactured from a botanical
drug substance by adding one or more excipients, mixing,
blending, granulating, tableting, encapsulating, or performing
other dosage-form-specific procedures, followed by packaging.
When packaged without further processing, a botanical drug
substance is considered the drug product. We recommend that the
following information be provided for a botanical drug product:
- A qualitative description of the finished product,
including the dosage form, route of administration, names of
all ingredients (i.e., botanical drug substance and excipients),
and a statement that the product is not adulterated with
potent, toxic, or addictive botanical substances, synthetic or
highly purified drugs, biotechnology-derived drugs, or other
naturally derived drugs.
- The composition or quantitative description of the finished
product (i.e., the quantity of the botanical drug substance
and each excipient, if any) expressed in terms of amount per
dosage unit. We recommend that sponsors provide this
information in tabular form.
Example for a single-herb botanical drug product
Component
|
Amount per tablet
|
Amount per batch
|
Senna leaf extract
(8:1 powdered aqueous extract) |
250 mg |
10.0 kg
(equivalent to 80.0 kg of dried leaves) |
Excipient 1 |
100 mg |
4.0 kg |
Excipient 2 |
10 mg |
0.4 kg |
The amount may also be expressed on the basis of amount of
botanical raw material (e.g., weight of dried leaves).
Component |
Amount per tablet
|
Amount per batch
|
Senna |
250 mg (equivalent to 2000
mg dried leaves) |
10.0 kg (equivalent to 80.0 kg of
dried leaves) |
Excipient 1 |
100 mg |
4.0 kg |
Excipient 2 |
10 mg |
0.4 kg |
Example for a multi-herb botanical drug product:
Component |
Amount per tablet |
Amount per batch |
A 5:1 powdered, aqueous extract
from 1:1 mixture of Forsythia suspensa Vahl. flowers and
Lonicera japonica Thunb. fruits |
600 mg |
24 kg |
Excipient 1 |
100 mg |
4.0 kg |
Excipient 2 |
10 mg |
0.4 kg |
- The manufacturer¢ s
certificate of analysis for the study product or, if none is
available, authorization to allow FDA to
cross-reference the manufacturer’s previous submission
for the relevant CMC information. If this information is
unavailable for a foreign-marketed product, the sponsor should
perform quality testing on the product according to the
recommendations listed under section VIII.B.3. In addition to
those tests, heavy metal analysis, and an animal safety test
(see below), if applicable, should be performed. The test
methods and results should be provided in the IND. The study
product should be from a single source and, where feasible,
from a single batch. A product sample from the batch to be
used in the clinical study should be retained for possible
future testing by FDA and/or the sponsor.
4. Animal Safety Test (§ 312.23(a)(8))
An animal safety test (different from the rabbit pyrogen
test, USP <151>) is an acute animal toxicity test applied only
to injectable drug products. We recommend that this test be
performed for crude extracts from natural sources, especially
when the raw material, process, and final product cannot be
fully characterized and controlled.
5. Placebo (§ 312.23(a)(7)(iv)(c))
The components of any placebo used must be described.
6. Labeling (§ 312.23(a)(7)(iv)(d))
The following labeling information must be provided:
- A copy of the container label and the immediate outer
carton label of the marketed product to be used in the
clinical study.
- A mock or printed representation of the proposed container
label that will be provided to the investigators in the
proposed clinical study. It should contain the following
information: protocol number; patient number; sponsor¢
s name; product name or code number; strength and/or potency;
recommended storage conditions; lot number; and (as required
under § 312.6) the statement, "Caution: New drug -- Limited by
Federal law to investigational use." In a placebo-controlled
clinical trial, both the study drug and the placebo should be
properly labeled to protect the integrity of the blinded
study.
7. Environmental Assessment or
Claim of Categorical Exclusion (§ 312.23(a)(7)(iv)(e))
A claim for categorical exclusion from the requirement for
preparation of an environmental assessment (EA) ordinarily can
be made for an IND (21 CFR 25.31(e)).
C.
Pharmacology/Toxicology Information
1. All Marketed Botanical Products
Under § 312.23(a)(8), previous human experience and available
animal toxicity data concerning the clinical formulation and the
individual botanical ingredients within the formulation must be
provided to support initial clinical trials (phase 1 and phase
2) of a botanical drug product for the proposed use. As noted in
section VI.A, initial studies for botanical products with no
known safety concerns and that have been marketed in the United
States as dietary supplements may generally be conducted without
further pharmacologic/toxicologic testing. Nevertheless,
available information should be provided. A database search
should be conducted, when feasible, to identify information
relevant to the safety and effectiveness of the following:
- the final formulation of the intended commercial botanical
drug product
- the individual botanical ingredients
- the known chemical constituents of the botanical
ingredients.
Under § 312.23(a)(8)(ii), an integrated summary of available
data from medical and toxicological databases (e.g., Medline,
Toxline, TOMES, RTEC) must be submitted for review. Using the
information gathered from this literature, the sponsor should
address, as appropriate for the proposed study, the following
issues concerning the botanical drug product:
- general toxicity
- target organs or systems of toxicity
- teratogenic, carcinogenic, or mutagenic potential of any
botanical ingredient in the product
- relationship of dosage and duration to toxic responses
- pharmacological activity.
2. Foreign-Marketed Botanical Products
For the reasons discussed in section VI, additional
information must be provided in accordance with § 312.22(b) for
a botanical product that has been previously marketed but not in
the United States. In addition to the information listed above,
the sponsor should provide data that support safe human use and
should include the annual sales volume, an estimate of the size
of the exposure population, and available data on the rate of
adverse effects. The nature of nonclinical
pharmacology/toxicology information needed before a sponsor
conducts an initial clinical study will be determined on a
case-by-case basis, depending on the indications, proposed dose,
duration and size of study, and available data supporting safe
human experience.
D.
Bioavailability
Pharmacokinetic and pharmacodynamic information is helpful in
the design and interpretation of clinical studies. Since
botanical products often consist of more than one chemical
constituent and the active constituents are often unknown,
standard pharmacokinetic measurements to demonstrate systemic
exposure to a product in animals and/or humans may be difficult
to obtain. However, when feasible, sponsors are encouraged to
monitor the blood levels of known active constituents,
representative markers, or major chemical constituents in a
botanical drug product (see section IX.D).
E. Clinical
Considerations
The initial clinical trial for a botanical product currently
marketed under the DSHEA will ordinarily be a well-controlled
study capable of demonstrating effectiveness. Because the
product is marketed and the dose that is thought to be
appropriate and well tolerated is known, there should be little
need for pilot or typical phase 1 studies, and uncontrolled
observations are unlikely to be useful. Sponsors are therefore
strongly encouraged to initiate more definitive trials early in
the development program to determine whether a botanical product
has efficacy for one or more claimed indications. Safety data
should be collected during the trials. If there is doubt about
the best dose of the product tested, a randomized, parallel,
fixed-dose, dose-response study may be particularly useful as an
initial trial.
Regarding the safety of the drug, a botanical preparation
lawfully marketed in the United States will generally be
considered acceptable for at least short-term (e.g., up to
several months) use in clinical trials. For foreign-marketed
botanical products, safety considerations will be based on
available CMC, pharmacology, and toxicology information, as well
as indications, proposed doses, duration and size of the study,
and available data supporting safe human use.
VIII. INDs FOR PHASE 1 and PHASE 2
CLINICAL STUDIES FOR NONMARKETED BOTANICAL PRODUCTS and
Products with known safety concerns
This section discusses the type of information that we recommend
be provided in meeting the requirements for INDs for initial trials
of botanicals that (1) have not previously been lawfully marketed in
the United States or elsewhere or (2) that have been marketed and
have known safety issues.
A. Description
of Product and Documentation of Human Use
In addition to the information outlined in section VII.A.1-2,
the following should be provided in accordance with the listed
subsections of § 312.23 for each raw material contained in a
botanical product not lawfully marketed in either the United
States or other countries:
1. Description of Botanicals Used
(§ 312.23(a)(3)(i))
- Morphological and anatomical description (including
gender, if applicable) and a photograph of the plant or plant
part, alga, or macroscopic fungus used
- Natural habitat and geographical distribution of the
plant, alga, or macroscopic fungus
- Current sources of the plant, alga, or macroscopic fungus,
including its geographical location and whether it is
cultivated or harvested from the wild
- A statement indicating whether the species is any of the
following:
- Determined to be endangered or
threatened under the Endangered Species Act or the Convention
on International Trade in Endangered Species of Wild Fauna and
Flora;
- Entitled to special protection
under some other Federal law or international treaty to which
the United States is a party;
- The critical habitat of a
species that has been determined to be endangered or
threatened
2. History of Use (If Any)
(§ 312.23(a)(3)(ii), (a)(9))
- Method of preparation, processing, and formulation
- Routes, schedules, and doses of administration
- Medical claims
- Contraindications and adverse events associated with use
in humans and animals
- Traditional geographical areas and populations in which
such use occurred
- A description of the similarities and/or differences
between the traditional preparation and the proposed clinical
formulation
3. Current Investigational Use (If
Any) (§ 312.23(a)(3)(ii), (a)(9))
- Proposed therapeutic claim and dose regimen (mg/kg/dose
and dose/day)
- All available information in the literature that addresses
the proposed therapeutic claim, including both positive and
negative studies
B. Chemistry,
Manufacturing, and Controls
Outlined below is the CMC information that should be
submitted, in meeting the requirements of § 312.23(a)(7), in an
IND to support a phase 1 or phase 2 clinical trial using a
botanical product that is not currently lawfully marketed in the
United States or a foreign country, or for which there are known
safety issues.
1. Botanical Raw Material
(§ 312.23(a)(7)(i))
A botanical drug substance can be derived from one or more
botanical raw materials. The following recommendations apply to
each individual botanical raw material used.
The botanical raw material should be described as outlined in
sections VII.A.1 and VIII.A.1. If the botanical raw material has
no documented history of use, the IND sponsor should so
indicate. The following information should be provided:
- Identification by trained personnel of the plant, plant
parts, alga, or macroscopic fungus used, including
organoleptic, macroscopic, and microscopic examination. The
identification should be done against a voucher specimen
(reference specimen). If more than one variety of a given
species is used, each should be specified. A sample of the
plant, plant parts, or other botanical materials should be
retained and stored under appropriate conditions by the raw
material supplier and botanical drug substance manufacturer
for each batch. These samples will be used for verification of
identity, if needed.
- A certificate of authenticity
- A list of all grower(s) and/or supplier(s) (including
names and addresses). The following items should be provided
for each grower/supplier, if available:
- Harvest location
- Growth conditions
- Stage of plant growth at
harvest
- Harvest time
- Collection, washing, drying,
and preservation procedures
- Handling, transportation, and
storage conditions
2. Botanical Drug Substance
(§ 312.23(a)(7)(iv)(a))
The following information should be provided for all
botanical drug substances, regardless of whether they are
prepared from one or more botanical raw materials:
A qualitative description of the drug substance, including
the name, appearance, physical and chemical properties, active
constituent (if known), biological activity (if known), and
clinical indication (if known) of each botanical raw material.
If the active constituent, biological activity, and/or clinical
indication is unknown, the IND sponsor should clearly so state.
In the case of a multi-herb substance, the sponsor should state
whether the drug substance is prepared by combining individually
processed botanical drug substances or by processing combined
botanical raw materials.
The quantitative description (strength) of the drug
substance. Historically, the strength of a botanical drug
substance is expressed simply as the absolute dry weight of the
processed substance. The batch size and the yield of the
process, relative to the botanical raw material, also should be
indicated. Furthermore, where the active constituents or other
chemical markers are known and measurable, the amount in which
they are present in the botanical drug substance should be
declared. For a multi-herb substance, its composition should be
expressed in terms of the relative ratio of the individually
processed botanical drug substances or of the botanical raw
materials before processing, whichever is appropriate.
The name and address of the drug substance
manufacturer (processor).
A description of the manufacturing process for the botanical
drug substance. The description should include the quantity of
botanical raw material, solvents, extraction and/or drying, and
yield. The yield of the process, expressed as the amount of the
original botanical raw material relative to the amount of the
extract, also should be indicated. If more than one botanical
raw material is introduced to produce a multi-herb substance,
the quantity of each raw material and the sequence of addition,
mixing, grinding, and/or extraction should be provided. If a
multi-herb substance is prepared by combining two or more
individually processed botanical drug substances, the process
leading to each botanical drug substance should be described
separately.
The quality control tests performed on each batch of
the drug substance, the analytical procedures used, and the
available test results. These tests should include, but need not
be limited to, the following attributes:
– Appearance
– Chemical identification by spectroscopic and/or
chromatographic fingerprints. Examples of spectroscopic
methods include ultraviolet, infrared, Fourier transformed
infrared, and mass spectroscopy. Examples of chromatographic
methods include high performance liquid chromatography (HPLC),
HPLC with diode array detection, thin layer chromatography
(TLC), 2-dimensional-TLC, and gas chromatography.
– Chemical assay (i.e., assay) for active constituents or
characteristic markers. If several botanical raw materials are
combined to produce a multi-herb substance and a quantitative
determination of each individual active constituent or marker
is infeasible, a joint determination can be made for several
active constituents or markers. When multiple active
constituents or markers are known, they should be chemically
characterized and their relative amounts should be defined.
– Biological assay (when the active chemical constituent(s)
are not known or quantifiable), if available. If the botanical
drug substance is considered potent (i.e., highly active),
toxic, addictive, or has abuse potential (e.g., ephedra or
marijuana), an assay for biological activity and/or a chemical
assay for the active constituent(s) should be performed.
– Strength by dry weight (equivalent to botanical raw
material)
– Heavy metals
– Microbial limits
– Animal safety test, if applicable
A description of the container/closure in which the
botanical drug substance is to be stored and/or shipped.
Available stability data on the drug substance. The sponsor
should develop stability-indicating analytical methods and
conduct stability studies as the IND progresses.
The container label, which should reflect the qualitative
and quantitative description of the botanical drug substance, as
discussed above, and recommended storage conditions. Examples of
labeling for single-herb and multi-herb substances are shown
below:
Single-herb substance:
- Expressed in terms of yield:
Senna, 10 kg, equivalent to 80 kg of dried leaves
or
Senna, 10 kg, 8:1 (w/w) powdered extract of dried leaves
- Expressed in terms of active
constituents:
Senna, 10 kg extract, containing 2 kg of
hydroxyanthracene glycosides (sennosides), calculated as
sennoside B
- Expressed in terms of chemical
markers:
Valerian, 10 kg extract, containing 0.1 kg valerinic acid
Multi-herb substance:
- Prepared by combining individually processed botanical
drug substances:
Lonicera japonica Thunb. and Forsythia suspensa Vahl., 6 kg,
containing 3 kg of Lonicera japonica Thunb. 4:1 solid extract
and 3 kg of Forsythia suspensa Vahl. 6:1 solid extract
- Prepared by processing combined botanical raw
materials:Lonicera japonica Thunb. and Forsythia suspensa Vahl.,
6 kg, a 5:1 powdered extract prepared from 15 kg of Lonicera
japonica Thunb. and 15 kg of Forsythia suspensa Vahl
3. Botanical Drug Product
(§ 312.23(a)(7)(iv)(b))
The following information should be provided:
A qualitative description of the finished product (see
section VII.B.3.)
The composition, or quantitative description, of the
finished product (i.e., the name and quantity of the botanical
drug substance and of each excipient (if any), expressed in
terms of amount per dosage unit and amount per batch). This
information should be provided in tabular form. A quantitative
description of the drug substance should be provided as
described in section VIII.B.2.
Example:
Component |
Amount per tablet
|
Amount per batch
|
Senna |
250 mg (equivalent to 2000
mg dried leaves) |
10.0 kg (equivalent to 80.0 kg of
dried leaves) |
Excipient 1 |
100 mg |
4.0 kg |
Excipient 2 |
10 mg |
0.4 kg |
- The name and address of the manufacturer of the finished
drug product
- A description of the manufacturing process. (If the
botanical drug substance is filled and packaged directly as
the finished product without the addition of excipients and
further processing, this item and items listed in the
immediately preceding two bullets will not apply.)
- A list of the quality control tests performed on each
batch of the drug product, and the analytical procedures used
and the available test results. These tests should include,
but need not be limited to, the following attributes:
– Appearance
– Chemical identification by spectroscopic and/or
chromatographic fingerprints
– Assay for active constituents or characteristic markers,
if available. If several botanical raw materials are combined
to produce a multi-herb substance and a quantitative
determination of each individual active constituent or marker
is infeasible, a joint determination can be carried out for
several active constituents or markers. When multiple active
constituents or markers are known, they should be chemically
characterized and their relative amounts should be defined.
– Biological assay (when the active chemical constituent(s)
are not known or quantifiable), if available. If the botanical
drug substance is considered potent (i.e., highly active),
toxic, addictive, or has abuse potential (e.g., ephedra or
marijuana), an assay for biological activity and/or a chemical
assay for the active constituent(s) should be performed.
– Strength by dry weight (of drug substance)
– Microbial limits
– Other attributes specific to the dosage form of interest
(e.g., dissolution for solid oral dosage forms, sterility and
nonpyrogenicity for parenterals, animal safety test for
parenterals, when appropriate).
- A description of the container/closure in which the drug
product is to be packaged
- Available stability data on the drug product. The sponsor
should develop stability-indicating analytical methods (using
markers when feasible) and conduct stability studies as the IND
progresses.
4. Placebo (see section VII.B.5)
5. Labeling (see section VII.B.6)
Additionally, a quantitative description of the drug
substance per dosage unit (as described in section VIII.B.2.h
and 3.b) should be provided. An example of a quantitative
description for a multi-herb botanical drug product is shown
below:
BRAND X. 100 tablets. Each 1-gram tablet contains:
300 mg of Lonicera japonica Thunb.4:1 solid
extract and
300 mg of Forsythia suspensa Vahl. 6:1 solid
extract
6. Environmental Assessment or Claim
of Categorical Exclusion
A claim for categorical exclusion from the requirement for
preparation of an EA ordinarily can be made for an IND
(§ 25.31(e)). However, FDA will require at least an EA for any
specific action that ordinarily would be excluded if
extraordinary circumstances indicate that the specific proposed
action may significantly affect the quality of the human
environment (21 CFR 25.21; 40 CFR 1508.4). CDER will evaluate
INDs on a case-by-case basis when the drug or biological product
is derived from wild plants or animals to determine whether the
extraordinary circumstance provision in § 25.21 is applicable.
FDA encourages early consultation with the Agency on
environment-related aspects of a requested action, especially
one that involves harvesting a wild species, to ensure that
planning and decisions reflect environmental values, avoid
delays later in the process, and avoid potential conflicts
(§ 25.10(b) and (c)). For additional information, see 21 CFR
part 25, 40 CFR parts 1500-08, and the CDER/CBER guidance for
industry on Environmental Assessment of Human Drug and
Biologics Applications (July 1998). An environmental
assessment or a claim for categorical exclusion must be provided
as required under § 25.15(a).
C. Nonclinical Safety Assessment
1. Traditional Preparations
Nonclinical pharmacology and toxicology studies are
particularly important in establishing the safety of a new
botanical drug for which there is no current marketing
experience. The information is used for assessing the botanical
drug's risk-to-benefit ratio, guiding early clinical studies,
and predicting potential toxicity.
Because of their extensive use in humans, there may be
sufficient information on traditional herbal medicines to
support initial clinical studies without standard nonclinical
testing. Therefore, such products may require fewer nonclinical
safety studies under § 312.23(a)(8) than would be expected for
synthetic or highly purified drugs with which there is little
experience.
A traditional herbal preparation, which may have evolved over
time, generally has the following characteristics:
- It meets official compendia or other published standards
in terms of the botanical identity and plant part used for
each botanical raw material.
- In the case of a multi-herb substance, it is composed of
the same formulation as a historical formula, with the amount
of each botanical ingredient falling within the range of
traditional usage.
- It is prepared by the same processing methodology as
traditionally used.
- It is used in the traditional manner in terms of
therapeutic indication, route and schedule of administration,
and quantities or doses.
For initial clinical studies on a botanical drug product that
is not currently lawfully marketed in the United States or
elsewhere but is prepared, processed, and used by humans
according to an established methodology, sufficient information
might be available to support the studies without standard
nonclinical testing. In general, the considerations listed under
section VII.C are applicable. When the initial clinical study
for such a drug shows promising results and further clinical
development of the drug is intended, pharmacology and toxicology
studies carried out prior to the later phases of the clinical
trials may be needed to support a risk-benefit assessment and to
identify potential toxicities not readily detected in clinical
studies (see section IX.C below).
2. Others
For a botanical product that is not prepared according to a
traditional methodology, the extent of variation from the
traditional formulation, preparation, or processing should be
described in full detail. The nature of nonclinical
pharmacology/toxicology information needed before conducting an
initial clinical study (in addition to that described under
section VII.C) will be determined on a case-by-case basis,
depending on the indications, extent of safe human experience,
and safety concerns about the new formulation, preparation, or
processing methodology used.
3. Products with Known Safety Issues
For those botanical drugs for which there are known safety
issues, the nature of the nonclinical pharmacology/toxicology
information needed will be determined on a case-by-case basis to
address those issues (see section VI.A).
D. Bioavailability
Pharmacokinetic and pharmacodynamic information is helpful in
the design and interpretation of clinical studies. As stated in
section VII.D, a botanical product’s active constituents may be
unknown, and standard pharmacokinetic measurements to
demonstrate systemic exposure to a product in animals and/or
humans may be infeasible due to the complexity of the botanical
drug. However, when feasible, a sponsor is encouraged to monitor
the blood levels of known active constituents, representative
markers, or other major chemical constituents in a botanical
drug product. Because there is less human use experience with
botanical products that have never been lawfully marketed than
with those that have been, a sponsor of a drug that has not been
lawfully marketed should consult FDA’s guidances Drug
Metabolism/Drug Interaction Studies in the Drug Development
Process: Studies In Vitro (April 1997) and In Vivo Drug
Metabolism/Drug Interaction Studies—Design, Data Analysis, and
Recommendations for Dosing and Labeling (November 1999) to
assess potential drug-drug interaction when a clinical study
includes co-administration with another drug (see section IX.D).
For a botanical product that is prepared according to
traditional methodology, the nature of clinical pharmacology
information needed should be determined on a case-by-case basis,
depending on the indications, extent of human experience, target
patient population, and projected length of clinical use.
E. Clinical
Considerations
In general, initial clinical investigations of nonmarketed
botanical preparations should be similar to those of marketed
products (see section VII.E). Because of the lack of current
marketing experience, however, greater concerns could exist
about toxicity. Therefore, FDA will seek greater assurance of
the safety of the product for initial clinical trials in the
United States. Such assurance may be provided in the form of
additional chemical analysis and/or additional toxicology data.
It may also be helpful to provide documentation of the product¢
s previous safe human use by referencing literature and/or
pharmacopoeias.
IX. INDs FOR
PHASE 3 CLINICAL STUDIES OF ALL BOTANICAL PRODUCTS
When conducting expanded (i.e., phase 3) clinical studies on a
botanical drug product, an IND sponsor is expected to provide more
detailed information on CMC and nonclinical safety than when
conducting a phase 1 or phase 2 study (§ 312.22(b), 312.23(a)(7)(i)
and (8)). The better definition of the product will ensure an
ability to apply data from trials to a well-controlled, reproducible
substance. The additional toxicology data are needed to support
wider use. This additional information should be provided regardless
of whether the product is currently lawfully marketed in the United
States or elsewhere as a dietary supplement.
For phase 3 clinical studies of a botanical product, the
following information should be provided in meeting the requirements
of § 312.23:
A. Description
of Product and Documentation of Human Experience
See sections VII.A and VIII.A for guidance on how to describe
the botanical product and human experience with it.
B. Chemistry,
Manufacturing, and Controls
To support phase 3 clinical trials of a botanical product,
regardless of its marketing experience in the United States or
other countries, the following CMC information should be
provided in accordance with § 312.23(a)(7) unless already
submitted in the IND for phase 1/phase 2 studies on the product:
1. Expanded Clinical Studies
a. Botanical raw material
A description of the botanical raw material as outlined in
sections VII.A.1 and VIII.A.1. If the botanical has no
documented history of use, this should be indicated. Proper
identification by trained personnel of the plant, plant parts,
alga, or macroscopic fungus used, including organoleptic,
macroscopic, and microscopic examination, should be provided.
The identification should be done against a voucher specimen
(reference specimen). If more than one variety or source of a
given species is used, they should be blended in a fixed
proportion in a consistent manner. A sample of the plant,
plant parts, or other botanical materials should be retained
for every batch by the raw material supplier and drug
substance manufacturer, and stored under appropriate
conditions for future verification of identity. In addition, a
certificate of authenticity and information on the grower
and/or supplier, growing conditions (including pesticides
used), harvest location, harvest time (including stage of
plant growth at harvest), handling, and shipping should be
provided.
A spectroscopic and/or chromatographic fingerprint of each
botanical raw material and the chemical identity of the active
constituents or characteristic markers in the botanical raw
material
The name and address of the botanical raw material
manufacturer (processor)
A description of the preparation of the botanical
raw material, including collection, washing, drying,
preservation, and/or detoxification and preservation
procedures. Equipment and quantity used, temperature employed,
processing time, in-process controls, and yield should be
specified.
The quality control tests and analytical procedures
applied by the botanical raw material supplier, and the
proposed acceptance criteria. These tests should include, but
need not be limited to, the following attributes:
– Botanical identification
– Chemical identification by spectroscopic and/or
chromatographic fingerprint
– Chemical identification for active constituents or
characteristic markers if active constituents are not known
– Assay for active constituents or characteristic markers
if active constituents are not known
– Biological assay (when the active chemical constituents
are not known or quantifiable), if available
– Heavy metals
– Microbial limits
– Residual pesticides, including parent pesticides and
their major toxic metabolites
– Adventitious toxins (e.g., aflatoxins)
– Foreign materials and adulterants
In some cases (e.g., when the botanical raw material
undergoes further processing to prepare the botanical drug
substance), reduced testing may be appropriate for certain
assays (e.g., heavy metals), if these assays are routinely
performed on the botanical drug substance. If some of these
tests cannot be performed by the raw material supplier, the
botanical drug substance manufacturer should perform the tests
upon receipt of the botanical raw material.
A photocopy of the voucher specimen (reference specimen)
of the botanical raw material used in identification,
fingerprinting, and other comparative and noncomparative tests
A certificate of analysis for representative batch(es) of
the botanical raw material
A description of the storage conditions, including
the container/closure system and temperature
b. Botanical drug substance (§ 312.23(a)(7)(iv)(a))
A qualitative and quantitative description of the
drug substance and the name and address of the
manufacturer (see section VIII.B.2).
A chemical identification for the active constituents or
characteristic markers in the drug substance, if possible. If
the chemical identity is unknown, a representative
spectroscopic and/or chromatographic fingerprint may suffice.
Appropriate acceptance specifications (tests, test
procedures, and acceptance criteria) for the botanical raw
material, similar to the list of quality control
specifications in section IX.B.1.a, established by the
botanical drug substance manufacturer. Upon receipt of each
batch of the raw material and its certificate of analysis, the
manufacturer should, at a minimum, conduct an identification
test and assay.
A description of the manufacturing process for the
botanical drug substance. The description should include the
quantity of botanical raw material, equipment, solvents,
temperature/time for mixing, grinding, extraction and/or
drying, yield, and in-process controls. The yield of the
process, expressed as the amount of the original botanical raw
material relative to the amount of the extract, also should be
indicated. If more than one botanical raw material is
introduced to produce a multi-herb substance, the quantity of
each raw material and the sequence of addition, mixing,
grinding, and/or extraction should be provided. If a
multi-herb substance is prepared by combining two or more
individually processed botanical drug substances, the process
leading to each botanical drug substance should be described
separately.
The quality control tests performed on each batch of drug
substance, the analytical procedures used, and the proposed
acceptance criteria. These tests should include, but need not
be limited to, the following attributes:
– Appearance
– Chemical identification by spectroscopic and/or
chromatographic fingerprints
– Chemical identification for the active constituents or,
if unknown, the characteristic markers
– Chemical assay for the active constituents, or the
characteristic markers if the active constituents cannot be
determined. If several botanical raw materials are combined
to produce a multi-herb substance and a quantitative
determination of each individual active constituent or
marker is infeasible, a joint determination can be made for
several active constituents or markers. When multiple active
constituents or markers are known, they should be chemically
characterized and their relative amounts should be defined.
– Biological assay (when the active chemical constituents
are not known or quantifiable), if available. If the
botanical drug substance is considered potent (i.e., highly
active), toxic, or addictive, or has abuse potential (e.g.,
ephedra or marijuana), an assay for biological activity
and/or a chemical assay for the active constituent(s) should
be performed.
– Strength by dry weight
– Residue on ignition
– Water content
– Residual solvents
– Heavy metals
– Microbial limits
– Animal safety test, if applicable
– Residual pesticides
– Radioisotope contaminants, if applicable
– Adventitious toxins (e.g., aflatoxins)
– Endogenous toxins (e.g., pyrrolizidine alkaloids)
– Other attributes specific to the botanical raw
materials from which the drug substance is derived
Validation reports of all analytical procedures, where
appropriate
A description of the batch of botanical drug substance
designated as the reference standard for use in
fingerprinting and other comparative tests
Batch analysis (i.e., test results for representative
batches)
A description of the container and closure used to package
the botanical drug substance
Sufficient stability data on the drug substance to support
its safe use during clinical studies; stability-indicating
analytical methods
Information on the container label as described in section
VIII.B.2
c. Botanical drug product (§ 312.23(a)(7)(iv)(b))
- A qualitative description and the composition of the dosage
form and the name and address of the manufacturer
(see section VIII.B.3)
- Appropriate acceptance specifications established by the
botanical drug product manufacturer for the botanical drug
substance, similar to the quality control tests in section
IX.B.1.b. Upon receipt of each batch of the drug substance and
its certificate of analysis, the manufacturer should, at a
minimum, conduct an identification test and assay.
- A description of the manufacturing process, without the
actual batch record. The description should include weighing,
mixing, blending, sieving, in-process controls, and other
processes, as appropriate.
- The quality control tests performed on each batch of drug
product, the analytical procedures used, and the proposed
acceptance criteria. These tests should include, but need not be
limited to, the following attributes:
– Appearance
– Chemical identification by spectroscopic and/or
chromatographic fingerprints
– Chemical identification for the active constituents or,
if unknown, the characteristic markers
– Chemical assay for active constituents or, if unknown,
the characteristic markers. If several botanical raw materials
are combined to produce a multi-herb substance and a
quantitative determination of each individual active
constituent or marker is infeasible, a joint determination can
be made for several active constituents or markers. When
multiple active constituents or markers are known, they should
be chemically characterized and their relative amounts should
be defined.
– Biological assay (when the active chemical constituent(s)
are not known or quantifiable), if available. If the botanical
drug substance is considered potent (i.e., highly active),
toxic, addictive, or has abuse potential (e.g., ephedra or
marijuana), an assay for biological activity and/or a chemical
assay for the active constituent(s) should be performed.
– Strength by dry weight (of drug substance)
– Residual solvents
– Microbial limits
– Adventitious toxins (e.g., aflatoxins)
– Other attributes specific to the dosage form of interest
(e.g., dissolution for solid oral dosage forms, sterility for
parenterals, animal safety test for parenterals, when
appropriate).
- Validation reports of all analytical procedures, where
appropriate
- Batch analysis (i.e., test results for representative
batches)
- A description of the container and closure used to package
the finished product
- Sufficient stability data on the drug substance to support
its safe use during clinical studies. Stability-indicating
analytical methods should be established.
d. Placebo (see section VII.B.5)
e. Labeling (see sections VII.B.6 for investigational labels
and VIII.B.5 for
quantitative description)
f. An EA or a claim of categorical exclusion (see section
VIII.B.7)
2. End-of-Phase 3 Clinical Studies and
Pre-NDA Considerations
Sponsors must continue to characterize the drug substance and
the drug product throughout the entire clinical development
program (§ 312.23(a)(7)). By the end of the phase 3 clinical
trial, as the sponsor prepares to submit an NDA, the following
objectives should be reached:
- Adequate controls for botanical raw materials should be
established.
- The manufacturing processes of the drug substance and the
drug product should be finalized and validated, and in-process
controls should be established. An executed batch record
should be available.
- Batch-to-batch consistency should be demonstrated for the
botanical drug substance and drug product based on results
from all chemical, physical, and biological tests on all
relevant batches. To achieve this goal, multiple fingerprints,
using a combination of analytical methods with different
separation principles and test methods, can be useful. All
chemical constituents detected by spectroscopic and/or
chromatographic fingerprinting should be qualitatively and
quantitatively comparable from batch to batch.
- Appropriate specifications (i.e., tests, analytical
procedures, and acceptance criteria), including identification
and assay for active constituents, identification and assay
for characteristic markers, and/or biological assay (when the
active chemical constituent(s) are not known or quantifiable),
should be established to control the quality of the drug
substance and product. Both the active constituents and the
biological assay should be clinically relevant. If the
identity of the active constituents is not known or a suitable
assay cannot be developed, the characteristic markers should
be demonstrated to be clinically relevant by direct or
indirect correlation to the clinical outcome.
- Analytical procedures should be properly validated.
Analytical procedures used for fingerprinting should be
verified for specificity and should be capable of detecting as
many chemical classes (e.g., proteins, carbohydrates, fatty
acids, small organic compounds) present and as many individual
chemical constituents as possible. Additionally, when multiple
fingerprints are used, the analytical procedures in
combination should be able to demonstrate the mass balance in
the test sample, on the basis of the different classes of
chemicals and, if appropriate, among the individual
constituents detected within a chemical class.
- A suitable voucher specimen (reference specimen) for each
of the botanical raw materials should be established, along
with a reference standard for the drug substance and drug
product.
- Stability-indicating analytical methods should be
developed to monitor the stability of the drug substance and
drug product. The stability of a botanical drug substance or
product generally should not be based entirely on the assay of
the active constituents, assay of the characteristic markers,
or biological assay, because degradants formed during storage
from other chemical constituents in the botanical drug
substance or product should also be controlled. An analytical
method capable of detecting these degradants (such as a
spectroscopic and/or chromatographic fingerprint) should be
established through exploratory studies by subjecting the drug
substance and drug product to stress conditions.
- A biological assay, when used for characterization and
quality control of a drug substance and drug product, should
be properly validated. The ICH Guideline Q6B
Specifications: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products (August 1999) and the
USP XXV Biological Tests <111>: Design and Analysis of
Biological Assays provide useful information on biological
assays. Performing a biological assay calls for the use of a
suitable reference standard and, frequently, positive and
negative controls. Because biological assays are usually more
variable than chemical assays, a relatively higher coefficient
of variation is generally justifiable.
- A comparison of the similarities and/or differences in CMC
among the nonclinical, clinical, and intended commercial
products should be made regarding raw materials, drug
substance, and drug product.
- The manufacturing, processing, and controls (receipt,
identification, storage, handling, sampling, testing, and
approval or rejection of components, drug products, and
container closures) for botanical drug products must be in
conformance with CGMP as set forth in 21 CFR parts 210 and
211. In addition, the manufacturing, processing, and controls
for the botanical drug substance (starting from the botanical
raw material) should be in conformance with CGMP because these
elements can affect the quality, safety, and efficacy of the
drug product. A satisfactory inspection is necessary for NDA
approval.
- A sponsor should be preparing the submission in the NDA of
either an EA or a claim for categorical exclusion from the
requirement for preparation of an EA (§ 25.15(a)). Classes of
NDAs that are categorically excluded and, therefore,
ordinarily do not require preparation of an EA are listed in
§ 25.31. However, FDA will require at least an EA for any
specific action that ordinarily would be excluded if
extraordinary circumstances indicate that the specific
proposed action may significantly affect the quality of the
human environment (§ 25.21; 40 CFR 1508.4). The Agency regards
the submission of an NDA for a drug derived from plants taken
from the wild as an extraordinary circumstance requiring the
submission of an EA. See section VIII.B.6 for additional
information.
Applicants are encouraged to discuss with the review division
any CMC issues regarding a botanical drug prior to the
preparation and submission of an NDA.
C. Nonclinical
Safety Assessment
To support safety for expanded clinical studies or to support
marketing approval of a botanical drug product, toxicity data
from standard toxicology studies in animals may be needed in
accordance with § 312.23(a)(8). A botanical product submitted
for marketing approval as a drug will be treated like any other
new drug under development. Safety data from previous clinical
trials conducted in foreign countries will be considered in
determining the need for nonclinical studies. However, previous
human experience may be insufficient to demonstrate the safety
of a botanical drug product, especially when it is indicated for
chronic therapy. Systematic toxicological evaluations could be
needed to supplement available knowledge on the general
toxicity, teratogenicity, mutagenicity, and carcinogenicity of
the final botanical drug product. Depending on the indication
(e.g., target patient population, disease to be treated), route
of administration, and duration of recommended drug exposure,
the timing of these animal studies in relation to concurrent
clinical trials and other requirements for nonclinical animal
studies can vary.
In general, animal studies should, as much as possible, be
conducted using the same drug substance prepared and processed
in the same manner as the drug substance used in clinical
trials.
The following are points to consider in preparing a
nonclinical pharmacology/toxicology development plan for a
botanical drug product that is intended to be used in
large-scale human trials or to support an NDA. If questions
arise during any stage of the clinical development of a
botanical drug, sponsors are encouraged to consult the
appropriate review division in CDER.
1. Repeat-Dose General Toxicity
Studies
The primary objective of long-term, repeat-dose toxicity
studies in animals is to identify the organs and/or systems that
are the targets of the drug’s toxicity and the threshold doses
for producing toxic effects. The studies provide information
valuable for designing long-term clinical studies at safe doses,
with appropriate monitoring for predicted adverse reactions.
Existing literature on the animal toxicity of a botanical drug
is often limited to single-dose (acute) studies. These studies
would be inadequate to support long-term use.
To support expanded clinical trials, repeat-dose toxicity of
a botanical drug should usually be evaluated in two
mammalian species (one of which is a nonrodent) by employing
sufficiently high doses to produce a toxic effect or by using a
maximum feasible dose. If possible, the drug should be tested
using the same route of administration as proposed for clinical
use. Animal studies should be of a duration at least equal to
that of the clinical trial (usually a minimum of 2 weeks).
Routinely, general animal toxicity studies need not exceed 6
months of testing in a rodent species and 9 months of testing in
a nonrodent species. For additional information on the timing of
animal toxicity studies in relation to clinical trials, see the
ICH guidance M3 Nonclinical Safety Studies for the
Conduct of Human Clinical Trials for Pharmaceuticals
(November 1997).
2. Nonclinical Pharmacokinetic/Toxicokinetic
Studies
In the development of a new drug that is a single molecular
entity, it is often useful to compare pharmacokinetics in
animals and humans and to relate exposure levels to toxicities
in both animals and humans. Because botanical drugs
usually consist of more than one chemical constituent, standard
pharmacokinetic measurements to substantiate the systemic
exposure of a botanical drug product in animals may be
technically infeasible. However, monitoring representative
chemical constituents in a botanical drug can provide valuable
information regarding systemic exposure. Depending on the
complexity of the botanical drug product to be studied,
pharmacokinetics could be helpful in the design and
interpretation of toxicity studies. For additional information
on toxicokinetic evaluations, see the ICH guidances
S3A Toxicokinetics: The Assessment of Systemic Exposure in
Toxicity Studies (March 1995) and S3B Pharmacokinetics:
Guidance for Repeated Dose Tissue Distribution Studies
(March 1995).
3. Reproductive Toxicology
Reproductive toxicology studies, such as those on
fertility/reproductive performance, teratology, and prenatal/perinatal
development in animals, provide information on the potential of
a botanical drug for producing toxicity during the different
stages of reproductive and developmental processes. In the
absence of documented data on reproductive toxicity in humans or
animals, these tests should be conducted prior to expanded
clinical trials. For detailed information regarding reproductive
toxicology, sponsors should refer to the ICH guidances
S5A Detection of Toxicity to Reproduction for Medicinal Products
(September 1994) and S5B Detection of Toxicity to
Reproduction for Medicinal Products: Addendum on Toxicity to
Male Fertility (April 1996).
4. Genotoxicity Studies
We recommend that information on the potential of a botanical
drug to produce genetic toxicity be obtained as early as
possible, preferably before the initiation of human clinical
trials (see ICH M3 Nonclinical Safety Studies for the Conduct
of Human Clinical Trials for Pharmaceuticals (November
1997)). A complete assessment of genetic toxicity may be needed
before expanded clinical trials. A standard battery of tests is
defined in the ICH guidances S2A Specific Aspects of
Regulatory Genotoxicity Tests for Pharmaceuticals (April
1996) and S2B Genotoxicity: A Standard Battery for
Genotoxicity Testing of Pharmaceuticals (November 1997).
If the standard battery of tests chosen indicate that a drug
is devoid of genetic toxicity, additional genotoxicity studies
may not be needed to comply with § 312.23(a)(8)(ii)(a).
If one or more test results are positive, the sponsor may need
to carry out additional genotoxicity tests to comply with this
provision, in consultation with the appropriate CDER review
division.
5. Carcinogenicity Studies
Carcinogenicity studies may be needed to comply with
§ 312.23(a)(8)(ii)(a) to support marketing approval of a
botanical drug, depending on the duration of therapy or any
specific cause for concern. The toxicity profile of the
botanical drug and the indication and duration of the intended
use may influence the need under this regulation for
carcinogenicity studies and their timing relative to clinical
development (see ICH S1A The Need for Long-Term Rodent
Carcinogenicity Studies of Pharmaceuticals (March 1996)).
Draft protocols for carcinogenicity studies should be submitted
to the appropriate review division and the CDER Carcinogenicity
Assessment Committee for review and concurrence prior to the
initiation of such studies to ensure the acceptability of dose
selection and study design. Study types should be in accordance
with the ICH guidance S1B Testing for Carcinogenicity of
Pharmaceuticals (February 1998). Doses used should be chosen
according to the principles outlined in the ICH guidances
S1C Dose Selection for Carcinogenicity Studies of
Pharmaceuticals (March 1995) and S1C(R) Dose Selection
for Carcinogenicity Studies of Pharmaceuticals: Addendum on a
Limit Dose and Related Notes (December 1997).
6. Special Pharmacology/Toxicology
Studies
A general evaluation of the pharmacological effects of a drug
on physiological functions (e.g., central nervous system,
cardiovascular system) is often performed during new drug
development. This evaluation can be accomplished using
established in vitro and in vivo assays of broad specificity
that screen for the modes and sites of action of the botanical
drug. When significant and unique toxicities to certain organs
and/or systems are evident, the sponsor should provide further
explanation of the mechanism of toxic actions, if appropriate,
by performing additional in vitro or in vivo studies.
7. Regulatory Considerations
Nonclinical toxicity studies conducted as part of botanical
drug development and intended to support safety must be in
accordance with regulations governing good laboratory practices
under 21 CFR part 58. Both the drug substance and the drug
product should be made with batch-to-batch consistency. If
changes occur in the drug substance or product during clinical
development, bridging toxicity studies might be needed to comply
with § 312.23(a)(8)(ii)(a).
D.
Bioavailability and Clinical Pharmacology
The general requirements for in vivo bioavailability data in
an NDA, described in § 320.21, are applicable to botanical drug
products. The type of bioavailability study that is appropriate
for a specific botanical drug product is based on the following:
(1) information on the active constituent, if known; (2) the
complexity of the drug substance; and (3) the availability of
analytical methods. Because there could be more than one active
constituent in a botanical drug or the active constituent may
not be identified, it could be difficult or impossible to
perform standard in vivo bioavailability and pharmacokinetic
studies (e.g., by measuring, as a function of time, the
concentration of the active moiety, active ingredients, or
active metabolites in whole blood, plasma, serum, or other
appropriate biological fluid, or by measuring the excretion of
the active moiety or active metabolites in urine). In some
cases, it may be possible to measure an acute pharmacological
effect as a function of time using an appropriate biological
assay method. If this is not possible, the bioavailability of a
botanical drug could be based on clinical effects observed in
well-controlled clinical trials.
The general criteria for waiver of in vivo bioavailability
data in an NDA, described in § 320.22, are applicable to
botanical drug products. FDA may, for good cause, waive or defer
the in vivo bioavailability study requirement if a waiver or
deferral is compatible with the protection of the public health
(§ 320.22(e)).
Interactions between botanicals and other commonly used drugs
and/or dietary supplements should be investigated. This may
include characterization of the metabolic enzymes and/or pathway
affected by the drug (see section VIII.D).
Where possible, the effects of impaired clearance (renal or
hepatic) on the drug’s pharmacokinetics should be examined. This
is easiest when the active substance(s) are known, but even if
they are not, knowledge of the major constituents should make it
possible to determine the effects of impaired clearance.
Dose-response information may indicate the proper level of
concern about impaired excretion.
As with synthetic and/or highly purified drugs,
pharmaceutical and biopharmaceutics studies for botanical drug
products are important for product quality control, batch
comparison, and linkage between different strengths. These
studies may involve, for example, in vitro dissolution testing,
in situ drug absorption testing, in vitro-in vivo correlation
studies, or in vitro percutaneous absorption/penetration
testing, depending on the indication and formulation of the
botanical product.
E. Clinical
Considerations
Expanded studies of botanicals have the same purpose as
expanded studies of synthetic drugs, including further
evaluation of dose-response for favorable and unfavorable
effects and evaluation of long-term safety and effectiveness,
different populations, different stages/severity of disease, and
drug-drug interactions. Many general and therapy-specific
guidances are available on CDER's Web page (see title page for
URL).
GLOSSARY
The following definitions are intended for use in this guidance
only and may not be appropriate in other contexts.
Active Constituent: The chemical constituent in a botanical
raw material, drug substance, or drug product that is responsible
for the intended pharmacological activity or therapeutic effect
Botanical; Botanical Product: A finished, labeled product
that contains vegetable matter, which may include plant materials
(see below), algae, macroscopic fungi, or combinations of these.
Depending in part on its intended use, a botanical product may be a
food, drug, medical device, or cosmetic.
Botanical Drug Product; Botanical Drug: A botanical product
that is intended for use as a drug; a drug product that is prepared
from a botanical drug substance. Botanical drug products are
available in a variety of dosage forms, such as solutions (e.g.,
teas), powders, tablets, capsules, elixirs, and topicals.
Botanical Drug Substance: A drug substance derived from one
or more plants, algae, or macroscopic fungi. It is prepared from
botanical raw materials by one or more of the following processes:
pulverization, decoction, expression, aqueous extraction, ethanolic
extraction, or other similar process. It may be available in a
variety of physical forms, such as powder, paste, concentrated
liquid, juice, gum, syrup, or oil. A botanical drug substance can be
made from one or more botanical raw materials (see Single-Herb and
Multi-Herb Botanical Drug Substance or Product). A botanical drug
substance does not include a highly purified or chemically modified
substance derived from natural sources.
Botanical Ingredient: A component of a botanical drug
substance or product that originates from a botanical raw material
Botanical Raw Material: Fresh or processed (e.g., cleaned,
frozen, dried, or sliced) part of a single species of plant or a
fresh or processed alga or macroscopic fungus
Cosmetic: An article intended to be rubbed, poured,
sprinkled, or sprayed on, introduced into, or otherwise applied to
the human body or any part thereof for cleansing, beautifying,
promoting attractiveness, or altering the appearance, or an article
intended for use as a component of any such article, except that
such term does not include soap (21 U.S.C. 321(i))
Dietary Supplement: The following definition is taken
directly from 21 U.S.C. 321(ff).
The term dietary supplement ¾
"(1) means a product (other than tobacco) intended to supplement
the diet that bears or contains one or more of the following dietary
ingredients: (A) a vitamin; (B) a mineral; (C) an herb or other
botanical; (D) an amino acid; (E) a dietary substance for use by man
to supplement the diet by increasing the total dietary intake; or
(F) a concentrate, metabolite, constituent, extract, or combination
of any ingredient described in clause (A), (B), (C), (D), or (E);
(2) means a product that (A)(i) is intended for ingestion in a
form described in section 411(c)(1)(B)(i) [of the Act]; or (ii)
complies with section 411(c)(1)(B)(ii); (B) is not represented for
use as a conventional food or as a sole item of a meal or the diet;
and (C) is labeled as a dietary supplement; and
(3) does (A) include an article that is approved as a new drug
under section 505 [of the Act] or licensed as a biologic under
section 351 of the Public Health Service Act (42 U.S.C. 262) and
was, prior to such approval, certification, or license, marketed as
a dietary supplement or as a food unless [FDA] has issued a
regulation, after notice and comment, finding that the article, when
used as or in a dietary supplement under the conditions of use and
dosages set forth in the labeling for such dietary supplement, is
unlawful under section 402(f) [of the Act]; and (B) not include (i)
an article that is approved as a new drug under section 505 [of the
Act], certified as an antibiotic under section 507 [of the Act], or
licensed as a biologic under section 351 of the Public Health
Service Act (42 U.S.C. 262), or (ii) an article authorized for
investigation as a new drug, antibiotic, or biological for which
substantial clinical investigations have been instituted and for
which the existence of such investigations has been made public,
which was not before such approval, certification, licensing, or
authorization marketed as a dietary supplement or as a food unless
[FDA], in [its] discretion, has issued a regulation, after notice
and comment, finding that the article would be lawful under this
Act. Except for purposes of section 201(g), a dietary supplement
shall be deemed to be a food within the meaning of this Act."
Dosage Form: A pharmaceutical product type, for example,
tablet, capsule, solution, or cream, that contains a drug ingredient
(substance) generally, but not necessarily, in association with
excipients
Drug: The following definition is taken directly from 21
U.S.C. 321(g)(1).
The term drug means "(A) articles recognized in the official
United States Pharmacopoeia, official Homeopathic Pharmacopeia of
the United States, or official National Formulary, or any supplement
to any of them; and (B) articles intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of disease in man or
other animals; and (C) articles (other than food) intended to affect
the structure or any function of the body of man or other animals;
and (D) articles intended for use as a component of any articles
specified in clause (A), (B), or (C). A food or dietary supplement
for which a claim, subject to sections 403(r)(1)(B) and 403(r)(3)
[of the Act] or sections 403(r)(1)(B) and (r)(5)(D), is made in
accordance with the requirements of section 403(r) is not a drug
solely because the label or the labeling contains such a claim. A
food, dietary ingredient, or dietary supplement for which a truthful
and not misleading statement is made in accordance with section
403(r)(6) is not a drug under clause (C) solely because the label or
the labeling contains such a statement."
Drug Product: A finished dosage form, for example, tablet,
capsule, solution, etc. (21 CFR 210.3 (b)(4))
Drug Substance: An active ingredient that is intended for use
to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease or
to affect the structure or any function of the human body (21 CFR
314.3(b))
Food: The term food means (1) articles used for food
or drink, (2) chewing gum, and (3) articles used for components of
such articles (21 U.S.C. 321(f)).
Formulation: A formula that lists the components (or
ingredients) and composition of the dosage form. The components and
composition of a multi-herb botanical drug substance should be part
of the total formulation.
Marker: A chemical constituent of a botanical raw material,
drug substance, or drug product that is used for identification
and/or quality control purposes, especially when the active
constituents are not known or identified.
Multi-Herb (Botanical Drug) Substance or Product: A botanical
drug substance or drug product that is derived from more than one
botanical raw material, each of which is considered a botanical
ingredient. A multi-herb botanical drug substance may be prepared by
processing together two or more botanical raw materials, or by
combining two or more single-herb botanical drug substances that
have been individually processed from their corresponding raw
materials. In the latter case, the individual single-herb botanical
drug substances may be introduced simultaneously or at different
stages during the manufacturing process of the dosage form.
Plant Material: A plant or plant part (e.g., bark, wood,
leaves, stems, roots, flowers, fruits, seeds, or parts thereof) as
well as exudates thereof.
Single-Herb (Botanical Drug) Substance or Product: A
botanical drug substance or drug product that is derived from one
botanical raw material. Therefore, a single-herb substance or
product generally contains only one botanical ingredient.
Spectroscopic and/or Chromatographic Fingerprint: A
spectroscopic and/or chromatographic profile of a botanical raw
material, drug substance, or drug product that is matched
qualitatively and quantitatively against that of a reference sample
or standard to ensure the identity and quality of a batch and
consistency from batch to batch.
QUESTIONS AND ANSWERS
Q1: Are INDs required for clinical studies of botanical products
that are lawfully marketed as dietary supplements in the United
States?
A1: It depends on what the botanical product is being studied
for. If a lawfully marketed botanical dietary supplement is
studied for a dietary supplement use, i.e., effect on the
structure and/or a function of the body, an IND is not
required (see final rule on "Structure and Function Claims for
Dietary Supplements," 65 FR 1000, January 6, 2000). Although an
IND is not legally required for such a study, CDER encourages
sponsors to submit one. If you have questions on how to design
such a study, FDA would be willing to review and provide advice
on protocols. You may contact CDER’s Botanical Review Team at
301-827-2250 or BOTANICALTEAM@cder.fda.gov.
If a botanical preparation is being studied for its
effects on a disease in the
proposed investigation (i.e., to cure, treat, mitigate, prevent,
or diagnose disease, including its associated symptoms), it is
considered a new drug and will need to be studied under an IND
(see § 312.2).
Q2: Are INDs required for clinical studies on marketed dietary
supplements for research purposes only?
A2: Again, it depends on the use. If the intent is to study
the effect of the product on the structure and/or a function of
the body, no IND is needed. If the study is to assess the
effects on disease, an IND is needed.
Q3: Is there any other setting in which an IND is not required
for the botanical study?
A3: When a nonmarketed botanical preparation is studied in
the United States for a dietary supplement use, an IND is not
required. In addition, clinical studies conducted in foreign
countries require no IND. However, FDA will accept an IND for
either kind of study. In the absence of an IND, an
investigational new drug intended for export for the purpose of
clinical investigation must comply with the requirements set
forth in § 312.110(b)(2) unless the new drug has been approved
or authorized for export under section 802 of the Act (21 U.S.C.
382).
Q4: May a sponsor submit an IND for a phase 3 study of a
botanical product not previously studied under an IND?
A4: Yes. Clinical data collected from phase 1 and phase 2
studies conducted without an IND can be used to support a phase
3 study involving the same drug substance if they are adequately
designed and conducted. The formulation/dosage form of the
botanical product used in the proposed phase 3 study ideally
would be the same as that of the product used in phase 1 and 2
studies as well as in the preclinical (nonclinical) studies. If
the product is different, additional studies may be appropriate.
Q5: For NDA approvals of botanical drug products, must all
studies be carried out under INDs?
A5: No. FDA does not require that all studies submitted in an
NDA be conducted under an IND. Clinical studies need not
necessarily be conducted under an IND (i.e., if they are carried
out abroad). The clinical data generated from these studies
conducted without an IND can be used to support an NDA if the
studies were adequately designed and conducted under good
clinical practices.
Although an IND is not required by law in all cases, the
sponsor is encouraged to go through the IND process. Compliance
with the IND requirements will help to ensure that an adequate
pharmaceutical product development program is in place so that
the material will meet the quality standards not only for
various phases of clinical trials but also for eventual
marketing. It will also help to ensure that the clinical trials
will be well designed so that data generated can be persuasive.
Q6: It appears that the changes in regulatory approaches
described in the guidance on Botanical Drug Products concern only
IND applications. How will these changes be applied to the NDA
requirements for botanical drugs?
A6: To facilitate the clinical development of botanical
drugs, FDA decided to focus initially on a guidance for INDs,
especially the early phases of clinical study. The standards for
the safety and efficacy required for marketing approval of a
botanical drug are the same as those required for a conventional
chemical drug for the same indication. However, the product
quality standards for a botanical drug can be different from
those for a purified chemical drug. The Botanical Drug Products
guidance contains recommendations for establishing appropriate
quality standards for botanical drugs.
Q7: Some botanical preparations are not administered orally,
e.g., intravenous, topical, and inhalation products. How are these
nonoral formulations considered in the guidance?
A7: The guidance applies to all dosage forms of botanical
products. All parenteral, topical, inhalation, or other
nonorally administered botanical products are considered to be
drugs, not dietary supplements, and must be studied under an IND
for any use (see section 201(ff) of the Act). Just as for
purified chemical drugs, the type of quality testing varies from
dosage form to dosage form. For example, all injectables are
required to be sterile and pyrogen-free (211.165(b) and 211.167
and 314.50(d)(1)(ii)(b); oral tablets are not. In addition,
dietary supplements are orally ingested and the human experience
of an orally administered botanical dietary supplement may not
be applicable to the same botanical product given through other
routes.
Q8: In terms of IND requirements and regulatory review by the
Agency, is there any difference between a commercial development
program and an academic research project?
A8: No. The Agency applies the same standards to both
commercial and academic sponsors when evaluating the safety and
quality of human studies proposed in INDs.
Q9: Intellectual property rights are a difficult issue for
developing new drugs from well-known botanical preparations. How
does FDA protect the confidentiality of a sponsor’s submission? What
kind of IND/NDA data may FDA release without prior permission from
the sponsor?
A9: IND information generally is not publicly available (see
§§ 312.130, 314.430). Once an NDA is approved, FDA may release
certain safety and efficacy information (§ 314.430(e)).
Manufacturing information (including information related to
growers and suppliers) provided in an NDA or a Drug Master File
(DMF) is considered proprietary and may not be released (21
U.S.C. 331(j); 21 CFR 20.61).
Q10: How does FDA ensure that the new Botanical Drug Products
guidance will be implemented consistently across the different new
drug review divisions?
A10: FDA will provide reviewers in all divisions with
training on how to implement the guidance.
Q11: One of the major premises of the new guidance is that
because many botanical products have been used by a large population
for a long period of time, they are presumed to be safe enough to be
studied in clinical trials without first undergoing conventional
nonclinical studies. What kind of documentation should a sponsor
submit to demonstrate prior human experience with the sponsor’s
product?
A:11 The Agency recognizes that prior human experience with a
botanical product can be documented in many different forms and
sources, some of which may not meet the quality standards of
modern scientific testing. The sponsor is encouraged to provide
as much data as possible, and the review team for the botanical
drug IND generally will accept all available information for
regulatory consideration. FDA will assess the quality of the
submitted data on a case-by-case basis. It should be emphasized
that, in reviewing botanical drugs, the Agency does not lower or
raise the safety and efficacy standards for marketing approval
that apply to purified chemical drugs. The guidance simply
recommends the use of different types of data for preliminary
safety consideration of human trials (for example, large
quantities of mostly anecdotal human data instead of animal
studies).
Q12: In many cases, botanical therapies are highly individualized
with variations in relative contents of multiple plant ingredients
tailored for each patient. Must a sponsor submit a separate IND for
every change in composition, if similar patients are being treated
for the same indication?
A12: Studies can be designed to take into account
individualized treatments. Multiple formulations can be included
in one IND if they are being studied under a single clinical
trial. It is important that the IND provide the rationale for
using multiple formulations and the criteria used to assign
patients to different treatment regimens.
Q13: Many medicinal plants with therapeutical potential are quite
toxic. Does the new guidance address the study of such botanicals?
A13: The guidance discusses this issue in the sections
addressing botanical drug products with known safety issues
(e.g., section VI.A). Well-known examples of safety issues
concerning botanicals include the nephrotoxicity associated with
herbal preparations containing aristolochic acid and the
hepatotoxicity associated with comfrey products containing
pyrrolizidine alkaloid. Other examples include the
cardiovascular and central nervous system effects associated
with yohimbe and the hepatotoxicity associated with germander
and chapparal. In such cases, FDA will evaluate the known risk
and the potential benefit of an investigational drug for its
intended use. When the potential benefit of an investigational
drug outweighs its risk in the intended patient population,
clinical trials may be allowed to proceed under an IND (see
§ 312.42). For example, FDA will accept a relatively higher
level of toxicity of an investigational drug when studied to
treat terminally ill cancer patients. However, additional
nonclinical studies may be appropriate to adequately
characterize the toxicity (e.g., can a dose be identified that
would not be expected to produce toxicity?) and/or additional
monitoring may be appropriate during the clinical trial. Also,
FDA may recommend against human studies (e.g., bioavailability,
clinical pharmacology) in healthy volunteers.
Q14: There is a concern that if a botanical is being studied
under an IND or is approved as a new drug in an NDA, its subsequent
status as a dietary supplement may be jeopardized. Is this true?
A14: No, it is generally not true for products already on the
market before approval of an NDA. It is also generally not true
for products marketed before authorization of an IND for which
substantial clinical investigations have been instituted and the
existence of such investigations has been made public (see
section 201(ff)(3) of the Act).
Q15: What is FDA’s advice on the initial approach for sponsors
not familiar with new drug development and regulatory processes?
A15: A sponsor should first consult the guidance. If there
are questions concerning the guidance document or other
questions about the submission of INDs for botanical drugs,
consult the appropriate CDER review division for the therapeutic
class of the sponsor’s product. CDER also grants pre-IND
meetings with sponsors.
Q16: The guidance states that the submission of an NDA for a drug
derived from plants taken from the wild is an extraordinary
circumstance requiring the submission of an environmental assessment
(EA) under § 25.21. Are plants maintained in their native setting on
private land considered wild?
A16: Yes. Plants that are obtained from their native setting
on either public or private land are considered to be taken from
the wild. Cultivated plants are considered those that are grown
collectively in controlled settings such as plantations, farms,
or greenhouses, i.e., purposely segregated from wildlife to the
extent practicable.
Q17: Is a drug made with a commercially available crude extract
viewed the same as a drug derived from plants taken from the wild
for purposes of determining the need for an EA?
A17: Yes. If an NDA is submitted for a drug made from a crude
extract or intermediate from a plant taken from the wild, an EA
is required under § 25.21. This is true whether or not the
extract or intermediate is commercially available. As for an IND
for a drug made from a crude extract or intermediate from a
plant taken from the wild, FDA will decide on a case-by-case
whether an EA is required.
Q18: What is the GMP status of botanical raw materials (starting
materials) in terms of compliance and inspection?
A18: Starting materials of botanical origin that are used to
produce a botanical drug substance should be evaluated for
quality. The use of appropriate starting materials and the drug
substance manufacturer’s ability to control the source depend on
appropriate specifications (tests, analytical procedures, and
acceptance criteria). In addition to establishing
specifications, manufacturers can achieve adequate quality
control of starting materials by applying the principles
outlined in FDA’s botanical guidance and by following good
agricultural and good collection practice for starting materials
of herbal origin (e.g., European Medicines Evaluation Agency
HMPWP/31/99). Upon receipt of the starting materials at a
processing facility, it is the responsibility of the drug
substance manufacturer to determine the suitability of these raw
materials before use. This can be accomplished by examining
and/or testing to ensure that the acceptance criteria are met
and by documenting the quality control for the processing of the
starting materials. FDA will review the inspection and
examination of starting materials upon receipt when conducting a
current good manufacturing practice (CGMP) inspection of a drug
substance manufacturer.
Q19: Will FDA assign the same level of priority to botanical drug
products as to other drugs with respect to meeting with IND sponsors
and NDA applicants?
A19: Yes, FDA treats botanical and purified chemical drugs
the same.
ATTACHMENT A: Regulatory Approaches FOR MARKETING BOTANICAL DRUG
PRODUCTS
ATTACHMENT B: INFORMATION TO
BE PROVIDED IN AN IND FOR A BOTANICAL DRUG
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Date created: June 15, 2004 |
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