1. Are Investigational New Drug
(IND) applications
required for clinical studies of botanical
products that are also lawfully marketed as
dietary supplements in the U.S.?
Yes. If a lawfully marketed botanical dietary
supplement is studied for its effects on
diseases in the proposed investigation (i.e.,
to cure, treat, mitigate, prevent, or diagnose
disease including its associated symptoms),
then it is an investigational new drug and
will be subject to IND requirements. This applies
to studies in INDs sponsored for both
commercial and academic research purposes.
2. Are INDs
required for studies evaluating the uses of
botanical dietary supplement as dietary
supplements?
No. When a lawfully marketed botanical dietary
supplement is studied for its dietary
supplement use (i.e., structure and/or
function claims), an IND is not required.
Structure and function claims are statements
that describe the effect a dietary supplement
may have on the structure or function of the
human body. Refer to
FDA/CFSAN: Structure/Function Claims, Small
Entity Compliance Guide for further
information.
3. What is a Dietary
Supplement?
There are numerous botanical preparations that
are marketed in the U.S. as dietary
supplements.
-
A dietary supplement is a
product taken by mouth that contains a dietary
ingredient intended to supplement the diet.
-
The dietary ingredients in these products may
include: vitamins, minerals, herbs or other
botanicals, amino acids, and substances such
as enzymes, organ tissues, glandulars, and
metabolites.
-
Dietary supplements can also be
extracts or concentrates, and may be found in
many forms such as tablets, capsules, softgels,
gelcaps, liquids or powders.
-
Dietary supplements can also take
other forms, such as a bar. If they do,
information on their label must not represent
the product as a conventional food or a sole
item of a meal or diet.
Whatever their form may be, the Dietary
Supplement Health and Education Act (DSHEA) of
1994, places dietary supplements in a special
category under the general umbrella of foods,
not drugs and requires that every supplement
be labeled a dietary supplement. Dietary
supplements are labeled to describe how a
nutrient or dietary ingredient affects the
structure or function in humans or to describe
the documented mechanism by which a nutrient
or dietary ingredient acts to maintain the
structure or function. The labeling on a
dietary supplement can not make a disease
claim to diagnose, cure, mitigate, treat or
prevent disease.
For information on the regulation of dietary
supplements and the reporting of safety
problems for dietary supplements currently on
the market, please see the FDA Center for Food
Safety and Applied Nutrition (CFSAN) website
FDA/CFSAN Dietary Supplements: Overview
4. Can an IND with a phase 3 study be
submitted when the non-U.S. phase 1 and 2 studies were not
conducted under an IND?
Yes.
Clinical data collected from non-U.S. phase 1
and phase 2 studies may be used to support a
phase 3 study in a new IND. The botanical
product (drug substance and formulation/dosage
form) used in the proposed phase 3 study
should be the same as the product in phase 1
and phase 2 clinical studies and also in the
preclinical studies. If different
formulations were used, the bioequivalence of
all tested products will need to be
determined.
5. It appears
that the changes in regulatory approaches
described in the Botanical Guidance concern
only IND applications. How will the
regulatory approaches be applied to the final
New Drug Application (NDA) requirements for botanical drugs?
To
facilitate the clinical development of
botanical drugs, CDER focuses discussions in
the Guidance on INDs first, especially the
initial phases of clinical development. For NDA approval, the standards for the safety and
efficacy of a botanical drug are the same as
those for a conventional chemical drug with
the same indication. However, the quality
standards for a botanical drug may be
different from that for a purified chemical
drug. The Guidance contains recommendations
for establishing appropriate quality standards
for botanical drugs.
6. Protecting
intellectual property rights is a significant
concern for sponsors developing new drugs from
well-known botanical preparations. How does
CDER protect the confidentiality of the
sponsor’s submission? What kind of IND and
NDA data may be released without prior
permission from the sponsor?
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).
7. One of the
major premises of the new Botanical Guidance
is that many botanical products have been used
by a large population for long period of time;
therefore, for many botanicals it is presumed
that it is safe to proceed with clinical
trials without conventional preclinical
studies. What kinds of data are sponsors
required to submit to document previous human
experience?
CDER
recognizes that prior human experiences with
the botanical products may be documented in
many different forms and sources, some of
which may not meet the quality standards of
modern scientific testing. Sponsors are
encouraged to provide as much data as
available. The quality of the submitted data
will have to be assessed case-by-case. CDER
maintains the same standards for safety and
efficacy for marketing approval whether it is
a botanical-sourced product or a purified
chemical. The Botanical Guidance simply
recommends the use of different types of data
for preliminary safety consideration (e.g.,
large quantities of mostly anecdotal human
data in place of well-controlled animal
studies) of human trials in an IND.
8. In many cases,
botanical therapies are highly individualized
with variations in the relative contents of
multiple plant ingredients tailored for each
patient. Is a sponsor required to submit a
separate IND for every change in the
composition of individual constituents if
similar patients are being treated for the
same indication?
Multiple formulations
may be included in one IND as long as they are
being studied in a single clinical trial. It
is important to provide in the IND application
the rationale for using multiple formulations
and the criteria used to assign patients to
different treatment regimens. The final
determination regarding formulation variations
of this type is made by the review division.
9. Many medicinal
plants with therapeutic potentials have
toxicity. Is it
possible to study known toxic botanicals?
Yes,
in some cases this can be done. The CDER review division will
evaluate the known risk and the potential
benefit of an investigational new drug in the
proposed study. When the potential benefit of
an investigational drug outweighs its risk in
the studied patient population, an IND is
often allowed. For example, a relatively
higher level of toxicity of an investigational
drug used in a study of terminally-ill cancer
patients may be acceptable.
10. Botanical
preparations may be intravenous, topical, or
inhalation formulations. Are these non-oral
formulations evaluated any differently than
oral formulations under the Botanical
Guidance?
The
Botanical Guidance applies to all dosage forms
of botanical products. As with conventional
chemical drugs, the type of quality testing
for botanical products varies from dosage form
to dosage form. For example, injectable
products are required to be sterile and
pyrogen-free whereas oral tablets may not. In
addition, the human experience of an orally
administered dietary supplement may not be
applicable to an identical botanical product
with the same ingredient(s) when given by a
non-oral route of administration.
11. Once a
botanical is studied under an IND or approved
as a new drug in an NDA, is its status as a
dietary supplement jeopardized?
No, dietary supplements lawfully marketed
before the IND and subsequent NDA approval
are not at risk. Please refer to the CFSAN
website,
http://www.cfsan.fda.gov/~dms/ds-ingrd.html
for further information.
12. Will CDER give
the same administrative considerations for
botanical drug products as for other drugs?
Yes. Administratively, CDER treats botanical products the
same as any other drug products.
13.
How does a sponsor request a meeting?
Information on the meeting process is
available in the
Guidance for Industry - Formal Meetings for Sponsors and Applicants
for PDUFA Products .
14. How does a sponsor prepare and submit an IND?
All information on the investigational new
drug application process is available at the
CDER Web site
Investigational New Drug Application (IND)
Process and the
Small Business Assistance Web site.
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Botanical Review Team