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Seeds of Confusion:
Understanding FDA’s Regulation of Botanical
Drugs Versus Dietary Supplements
Ivan Wasserman
Partner
Manatt, Phelps & Phillips, LLP
Botanicals
 The term “botanicals” includes plant materials,
algae, macroscopic fungi, and their
combinations.
 It does not include:
 Materials derived from genetically modified botanical
species (i.e., cloning);
 Fermentation products; or
 Highly purified or chemically modified substances
derived from botanical sources.
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Botanical Products
 Botanical products may be:

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
Foods (including dietary supplements);
Drugs (including biological drugs);
Medical devices; or
Cosmetics
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Botanical
Product
Applied to body for
cleansing, beautifying, or
altering appearance
Cosmetic
To prevent
disease
Conventional
Food or
Dietary
Supplement
Yes
No
Is the proposed
indication appropriate
for nonprescription
use?
Yes
Has it been marketed for
a specific OTC indication
for a material time and to
a material extent?
Drug
Meets dietary
supplement
definition in 21
U.S.C. 321 (ff)?
No
No
Yes
Structure/function
claims comply
with all
requirements of
21 U.S.C.
343(r)(6)?
No
No
Yes
Yes
Yes
Food
To affect structure or function
of body
To diagnose, cure, mitigate,
or treat disease
Authorized
health claim?
Does available evidence
of safety and
effectiveness warrant
inclusion in an OTC
monograph?
Consumed for its
taste, aroma, or
nutritive value
What is the
intended
use?
No
Dietary
Supplement
Is there sufficient evidence
of safety and effectiveness
and adequate CMC
information to support an
NDA?
Yes
No
Is marketing
exclusivity
desired?
No
OTC
monograph
Yes
NDA application
IND
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Go to
Attachment B
Dietary Supplements
 Dietary supplements are products intended to
supplement the diet that bear or contain one or
more of the following dietary ingredients:
A vitamin;
A mineral;
An herb or other botanical;
An amino acid;
A dietary substance for use by man to supplement the
diet by increasing the total dietary intake; or
 A concentrate, metabolite, constituent, extract, or a
combination of any ingredient mentioned above.

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


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Dietary Supplements
 Must be intended for ingestion;
 Cannot be represented for use as a conventional
food or as a sole item of a meal or the diet;
 Has not been approved as a new drug, certified
as an antibiotic, or licensed as a biologic;
 Has not been authorized for investigation as a
new drug.
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Dietary Supplement Claims
 Dietary supplements may bear the following
claims:
 Benefit related to a classical nutrient deficiency
disease;
 How the product is intended to affect the structure or
function of the human body;
 The documented mechanism by which the product
acts to maintain such structure or function; or
 Describes general well-being from consumption of the
product.
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Claims: Disease vs.
Structure/Function
 Dietary supplements may not claim to
diagnose, mitigate, treat, cure, or prevent a
specific disease or class of diseases.
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Definition of “Disease”
Section 101.93(g) defines disease as:
...damage to an organ, part, structure, or system
of the body such that it does not function
properly (e.g., cardiovascular disease), or a state
of health leading to such dysfunctioning (e.g.,
hypertension); except that diseases resulting
from essential nutrient deficiencies (e.g., scurvy,
pellagra) are not included in this definition.
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What is a Disease Claim?
 A claim to diagnose, mitigate, treat, cure or
prevent disease:
 Has an effect on a specific disease or class of disease;
 Has an effect on the characteristic signs or symptoms
of a specific disease or class of diseases, using
scientific or lay terminology.
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What is a Disease Claim?
 Has an effect on abnormal condition associated with
a natural state or process, if the abnormal condition is
uncommon or can cause significant or permanent
harm.
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What is a Disease Claim?
 Factors that can contribute to the decision that a
disease claim is being made:
 Name of the product (“CancerCure”);
 Use of pictures or symbols (“Rx” or EKG);
 Belongs to a class of products that is intended to
diagnose, mitigate, treat, cure or prevent a disease
(antibiotic, analgesic);
 Is a substitute for a product that is a therapy for a
disease (“Herbal Viagra”).
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Structure Function Claim vs.
Disease Claim?
 Examples – Structure Function:
 “supports weight loss”
 “supports cartilage and joint function”
 “improves absentmindedness”
 Examples – Disease:
 “treats obesity”
 “reduces joint pain”
 “cures Alzheimer's”
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New Dietary Ingredients
 A “new dietary ingredient” is one that was not
sold in the U.S. in a dietary supplement before
October 15, 1994.
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New Dietary Ingredient
Notification
 75 days prior to marketing an NDI, you must
submit information to FDA showing the basis on
which you have concluded that a dietary
supplement containing such dietary ingredient is
reasonably expected to be safe.
 Not needed if present in the food supply as an article
used for food in a form in which the food has not
been chemically altered.
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NDI Notifications
 The FDA sends an acknowledgement of receipt
after submission of the NDI notification;
 FDA will not disclose the existence of, or the
information contained in, the new dietary
ingredient notification for 90 days after the filing
date of the notification;
 After the 90th day, all information in the
notification will be placed on public display
(except for trade secret or confidential
commercial information);
 Failure of the agency to respond to a notification
does not constitute a finding that the new
dietary ingredient is safe or is not adulterated.
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Botanical Drug Products
 A botanical drug product may be marketed
under:
 (1) an OTC drug monograph; or
 (2) a New Drug Application (“NDA”) or an
Abbreviated New Drug Application (“ANDA”).
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Marketing Botanical Drugs Under
an OTC Drug Monograph
 For a botanical drug to be included in an OTC
drug monograph, there must be data
establishing general recognition of safety and
effectiveness, usually including results of
adequate and well-controlled clinical trials.
 Cascara, psyllium, and senna are botanical drugs
currently included in an OTC drug monograph.
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Marketing Botanical Drugs Under
an OTC Drug Monograph
 A request to amend an OTC drug monograph
can be submitted by a citizen petition.
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Time and Extent Application
(“TEA”)
 21 C.F.R. § 330.14
 No fee, no time frame, and no patent
exclusivity;
 Can be used to amend the OTC drug
monograph;
 U.S. marketing experience after OTC drug review
began.
 OTC drugs with marketing experience outside of the
U.S.
 Meets “material extent” and “material time”
requirements of § 201(p).
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Time and Extent Application
(“TEA”)
 Can be used for:
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
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Active ingredient or botanical substance;
Dosage form;
Dosage strength;
Route of administration.
 Marketed for ≥ 5 continuous years in the same
country and in sufficient quantity.
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Time and Extent Application
(“TEA”)
 Step 1: Submission of TEA and publication of
Federal Register notice of eligibility
 Step 2: FDA reviews safety and efficacy data to
determine GRASE
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Marketing Botanical Drugs under a
New Drug Application (“NDA”)
 A botanical drug product that is not generally
recognized as safe and effective for its
therapeutic claims is considered a new drug.
 Any person wishing to market a botanical drug
as a new drug must obtain FDA approval of an
NDA or ANDA of that product.
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Applicability of Combination
Drug Regulations
 Botanical drug products that are derived from a
single plant or from a single species of alga or
macroscopic fungus are not considered to be
fixed-combination drugs within the meaning of
21 C.F.R. § 300.50 and 330.10(a)(4)(iv).
 These single plant drug products do not need to
demonstrate that each component or active ingredient
makes a contribution to the claimed effects.
 They also do not need to meet other requirements for
combination drugs.
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Applicability of Combination
Drug Regulations
 Botanical drugs that are derived from multiple
parts of a single species of plant, alga, or
macroscopic fungus (of from different species),
are subject to the combination drug
requirements.
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Investigational New Drug Application:
Requirements for Botanical Drugs
 An Investigational New Drug Application
(“IND”) is required when a botanical drug is
studied in the U.S. for drug use, even if such
study is intended solely for research purposes.
 Note: if the intent is to study the effect of a product on
the structure or function of the body, no IND is
needed.
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IND Requirements
 The amount of information that needs to be
submitted in an IND depends on 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.
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General Phase I and II IND Requirements for
Botanical Products Without Safety Concerns
 IND submissions for botanical products without
safety concerns generally include:
 Description of product and documentation of human
use;
 Chemistry, Manufacturing, and Controls information;
 Pharmacology/Toxicology Information;
 Bioavailability; and
 Clinical considerations.
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Description of Product and
Documentation of Human Use
 Description of product:
 Common or usual names of the plant, alga, or
macroscopic fungus;
 Synonyms (e.g., Latin, Greek, English, etc.);
 Name of variety, species, genus, and family;
 Chemical class of active constituent.
 Documentation of Human Use:
 History of use (historical sources);
 Current marketed use.
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Chemistry, Manufacturing, and
Controls for Botanical Drug Products
 “CMC” documentation requirements for
botanical drug products are different from that of
synthetic or highly purified drugs.
 It is not essential for a manufacturer to identify
the active constituents of a botanical drug, if
such identification is not feasible.
 The nonclinical pharmacology and toxicology
information requirements for botanical drug
products are far lower than those for synthetic or
highly purified new drugs.
 In most cases, additional toxicology and CMC
data will not be required for initial clinical trials.
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Chemistry, Manufacturing, and
Controls
 The following information submission are
recommended:
 Botanical raw material – standard of identity;
 Botanical drug substance – general methods of
preparation;
 Botanical drug product – manufacturing standards:
 Qualitative description of finished product;
 The composition or quantitative description of the
finished product.
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IND Requirements for CMCs
 With regard to environmental analyses, plants
that are obtained from their native setting on
either public or private land are considered to
be taken from the wild, which is considered an
extraordinary circumstance under § 25.21.
 Additional details with respect to these requirements
are found in 21 C.F.R. § 312.23(a)(7)(iv)(a)-(e).
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Pharmacology/Toxicology
Information
 Information as 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;
 General toxicity;
 Target organs or systems of toxicity;
 Relationship of dosage and duration to toxic
responses;
 Pharmacological activity.
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Pharmacology/Toxicology
Information
 After the submission of initial clinical studies,
further pharmacology and toxicology studies of
a botanical drug generally would be needed
before later phases of clinical development and
before marketing approval.
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Bioavailability
 Botanical products often consist of more than
one chemical constituent, and the active
constituents are often unknown.
 Therefore, standard pharmacokinetic
measurements are often difficult to obtain.
 When feasible, sponsors are encouraged to
monitor blood levels of known active
constituents, representative markers, or major
chemical constituents in a botanical drug
product.
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Clinical Considerations
 The initial clinical trial for a product marketed
under DSHEA should be a well-controlled study
demonstrating effectiveness.
 Sponsors are 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 trials.
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Botanical Drug IND Statistics:
2006
 Active INDs: 2006
 Commercial: 5,445
 Non-commercial: 8,672
 INDs Received: 2006
 Commercial: 713
 Non-commercial: 1,150
Source: http://www.fda.gov/cder/rdmt/cyactind.htm
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Botanical Review Team
 The CDER Botanical Review Team (BRT)
provides scientific expertise on botanical issues
to the reviewing staff and ensures consistent
interpretation of the Guidance for Industry:
Botanical Drug Products.
 The BRT participates in all phases of review,
meetings and decision-making processes for all
botanical pre-Investigational New Drug (IND)
applications, INDs, and New Drug Applications
(NDAs).
 Headed by: Shaw T. Chen, M.D. Ph.D.,
Associate Director for Special Product Review
Botanical Drug Products.
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Contact Information
Ivan Wasserman
Partner
Manatt, Phelps & Phillips, LLP
Washington, DC
(202) 585-6529
[email protected]
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