Download General Requirements for the Submission of IND Application

General Requirements for the Submission of IND
Applications for Clinical Research Studies1
I. Drugs (including biologics) Not Currently Approved for Commercial
Marketing by the U.S. Food and Drug Administration (FDA) 2
A. General requirements.
In general, the submission of an Investigational New Drug (IND)
application is required for any clinical research study that proposes the
use (e.g., as a research tool to explore a physiological or
pathophysiological process) or evaluation (i.e., for safety and/or
effectiveness) of an unapproved drug3.
B. Exceptions to the general requirements for the submission of an IND
application.
1. Dietary supplements:
Under the Dietary Supplement Health and Education Act (DSHEA) of
1994, a dietary supplement is defined, in part, as a product taken by
mouth that is intended to supplement the diet and that contains a
dietary ingredient. Dietary supplements are not regulated by the FDA
as “drugs” provided that they are intended for oral administration and
for use in affecting the structure or a function of the body (i.e., a
“structure or function” claim). Thus, research studies directed at using
or evaluating a marketed dietary supplement (administered orally) for a
structure or function claim are exempt from the requirement for
submission of an IND application. However, research studies directed
at using or evaluating a marketed dietary supplement administered by
other than an oral route; or for the diagnosis, cure, mitigation,
prevention, or treatment of a specific disease or condition (i.e., a “drug”
claim), or symptoms characteristic of a specific disease or condition,
must be conducted under a FDA-accepted IND application.
Refer also to the FDA’s Guidance for Industry: Investigational New Drug Applications (INDs) –
Determining Whether Human Research Studies Can Be Conducted Without an IND
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M229175.pdf)
2 I.e., drugs for which the FDA has not accepted a New Drug Application (NDA) or Abbreviated
New Drug Application (ANDA).
3 The Federal Food Drug and Cosmetic (FD&C) Act defines a “drug” as “any article intended for
the diagnosis, cure, mitigation, prevention, or treatment of disease in man or animals. Articles
(other than food) intended to affect the structure or function of the body or man or animals.”
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For additional discussion of structure and functional claims for dietary
supplements, refer to the FDA’s Guidance for Industry:
Structure/Function Claims – Small Entity Compliance Guide
(http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/
GuidanceDocuments/DietarySupplements/ucm103340.htm) and the
FDA document, Claims That Can be Made for Conventional Foods and
Dietary Supplements (http://www.cfsan.fda.gov/~dms/hclaims.html).
2. Human cells, tissues, and cellular and tissue based products
(HCT/Ps):
Certain HCT/Ps are regulated solely under section 361 of the Public
Health Services (PHS) Act and, as such, are exempt from the FDA’s
regulation as a drug, device, or biological product under section 351 of
the PHS Act. Hence, the submission of an IND application is not
required for clinical research studies involving the use or evaluation of
HCT/Ps that meet the criteria for regulation under section 361 of the
PHS Act. It must be emphasized, however, that the manufacture of
such HCT/Ps remains subject to the facility registration and other
requirements addressed under the FDA regulations at 21 CFR Part
1271.
In order to qualify for regulation under section 361 of the PHS Act (and
be exempt from the requirement for submission of an IND application),
the HCT/P being used or evaluated under the clinical research study
must meet each of the following criteria:

the HCT/P is minimally manipulated;
o Minimal manipulation means (1) for structural tissue, processing
that does not alter the original relevant characteristics of the
tissue relating to the tissue’s utility for reconstruction, repair, or
replacement; and (2) for cells or nonstructural tissues,
processing that does not alter the relevant biological
characteristics of the cells or tissues.

The HCT/P is intended for homologous use only;
o Homologous use means the repair, reconstruction, replacement,
or supplementation of a recipient’s cells or tissues with an
HCT/P that performs the same basic function or functions in the
recipient as in the donor.

The manufacture of the HCT/P does not involve the combination of
the cells or tissues with another article, except for water,
crystalloids, or a sterilizing, storage or preserving agent; provided
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that the addition of water, crystalloids, or the sterilizing, preserving,
or storage agent does not raise new clinical safety concerns with
respect to the HCT/P; and
o Manufacture means, but is not limited to, any or all steps in the
recovery, processing, storage, labeling, packaging, or
distribution of any HCT/P, and the screening or testing of the
cell or tissue donor.
o Crystalloid means an isotonic salt and/or glucose solution used
for electrolyte replacement or to increase intravascular volume,
such as saline solution, Ringer’s lactate solution, or 5%
dextrose in water.

Either the HCT/P (1) does not have a systemic effect and is not
dependent upon the metabolic activity of living cells for its primary
function; or (2) the HCT/P has a systemic effect or is dependent
upon the metabolic activity of living cells for its primary function,
and is (a) for autologous use, (b) for allogeneic use in a first-degree
or second-degree blood relative, or (c) for reproductive use.
3. Radioactive drugs for basic research uses:
Clinical investigations involving the use of certain unapproved
radioactive drugs for basic research applications do not require the
submission of an IND application provided that:

The research study is intended to obtain basic information
regarding the metabolism or kinetics of the radioactive drug or
regarding human physiology, pathophysiology, or biochemistry; but
not intended for immediate therapeutic, diagnostic or similar
purposes or to determine the safety and/or effectiveness of the
radioactive drug for such purposes; and

The radioactive drug and its use in the clinical investigation are
approved by a Radioactive Drug Research Committee (RDRC) in
accordance with the provisions of the FDA regulations at 21 CFR
Part 361.1. In order for the RDRC to approve a clinical
investigation under these regulations:
o The mass of the radioactive drug to be administered must be
known not to cause any clinically detectable pharmacological
effect in human beings based on data available from published
literature or other valid human studies; and
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o The total radiation dose resulting from the administration of the
radioactive drug and from any other procedures that emit
ionizing radiation which are performed specifically for the
purpose of the clinical investigation must be less than (1) 3 rems
(Adult - Single Study) or 5 rems (Adult – Total Annual) to the
gonads, lens of the eye, blood-forming organs, and effective
dose equivalent; and (2) 5 rems (Adult-Single Study) or 15 rems
(Adult – Total Annual) to all other organs. The radiation dose
limits for child-subjects are 10% of these adult limits.
4. Unapproved drug substances labeled with stable isotopes.
Based on FDA guidance4, the submission of an IND application is not
required for clinical investigations involving the use of certain
unapproved drug substances labeled with stable isotopes provided that
each of the following criteria are met:

The research is intended to obtain basic information regarding the
metabolism (including kinetics, distribution, and localization) of the
drug labeled with the stable isotope or regarding human physiology,
pathophysiology, or biochemistry;

The research is not intended for immediate therapeutic, diagnostic,
or preventative benefit to the study subject;

The dose of the labeled drug to be administered is known not to
cause any clinically detectable pharmacologic effect in humans
based on clinical data from published literature or other valid
human studies;

The quality of the labeled drug meets relevant quality standards;
and
o The research protocol should address how the appropriate
identity, strength, and purity of the labeled drug will be
ascertained (e.g., review of Certificate of Analysis provided with
the order of the labeled drug, on-site testing) prior to use.
o If the labeled drug is intended for parenteral administration,
there must be verification that the formulation of labeled drug is
sterile and apyrogenic.
Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether
Human Research Studies Can Be Conducted Without an IND, U.S. Food and Drug
Administration, 2010
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M229175.pdf)
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
The research is reviewed and approved by an IRB that functions in
compliance with 21 CFR Part 56 and informed consent is obtained
from the research subjects in accordance with 21 CFR Part 50.
C. Clinical investigations involving of the use or evaluation of special
classes of drug – IND application required5
1. Endogenous compounds
Provocation or challenge studies in which an endogenous compound
(e.g., bradykinin, histamine, angiotensin) is administered to research
subjects to evoke a physiological response, characterize a disease, or
establish the mechanism of action require the submission of an IND
application; unless the study falls into one of the categories for
exemption as discussed under I.B., above. Although the endogenous
compound is not being used for a diagnostic or therapeutic purpose,
there is intent to affect the structure or function of the body. Thus, the
compound would be considered a drug and regulated as such by the
FDA.
2. Live Organisms
An IND is required for challenge studies in which a live organism (e.g.,
virus, bacteria, or fungi that is modified or wild-type) is administered to
human subjects to study the pathogenesis of disease or the host
response to the organism. Although the challenge organism is not
being administered for a diagnostic or therapeutic purpose, there is
intent to affect the structure or function of the body. Thus the organism
would be considered a drug (i.e. biological product) and regulated as
such by the FDA. Similarly, an IND would be required for a clinical
investigation designed to evaluate whether a product colonized with a
strain of bacteria and administered to subjects can treat or prevent
disease in patients with a chronic immune disorder.
II. Drugs (including biologics) Currently Approved for Commercial
Marketing by the FDA
A. Clinical investigations involving the use or evaluation of a FDAapproved drug for the clinical indication(s) specified in the FDAapproved product labeling
Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether
Human Research Studies Can Be Conducted Without an IND, U.S. Food and Drug
Administration, 2010
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The submission of an IND application is not required for clinical
investigations of an FDA-approved drug being used or evaluated in
accordance with its current FDA-approved product labeling.
B. Clinical investigations involving the use or evaluation of a FDAapproved drug for a clinical indication that is not currently specified
in the FDA-approved product labeling (i.e., an “off-label” indication)
In accordance with the FDA regulations at 21 CFR Part 312.(b), the
clinical investigation of a FDA-approved drug being used or evaluated for
an “off-label” indication is exempt from the requirement for the submission
of an IND application provided that each of the following criteria are met:
1. The drug product is lawfully marketed in the United States;
2. There is no intent to report the investigation to the FDA as a wellcontrolled study in support of new labeling indication and no intent to
use the investigation to support any other significant change in the
labeling of the drug;
3. The investigation is not intended to support a significant change in the
advertising for the drug;
4. The investigation does not involve a route of administration, dose,
patient population, or other factor that significantly increases the risks
(or decreases the acceptability of risks) associated with the use of the
drug product;

Route of administration: A change in the route of administration
can introduce a significant new risk. E.g., there could be a
significant increase in risk if a marketed drug for oral administration
is converted to a dosage form that is to be administered by a
parenteral or inhalation route. These other routes of administration
introduce concerns regarding sterility, pyrogenicity, hypersensitivity
(e.g., airway reactivity), variations in absorption and metabolism,
and other issues not present with oral administration.6

Dose: Increases in dose, frequency, or duration of administration,
compared to labeled dosing regimens, can significantly increase
the risk of the marketed drug. It is possible that a decrease in dose
could also significantly increase risk. For example, administering a
low dose of a pure polysaccharide vaccine to study subjects can
induce hypo-immunologic or non-immunologic responses in the
Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether
Human Research Studies Can Be Conducted Without an IND, U.S. Food and Drug
Administration, 2010
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subjects and can also induce tolerance to the vaccine; thus
rendering the study subjects at increased risk for the infectious
disease that the vaccine is intended to prevent. The significance of
changes in dose (in particular increases in dose) can vary across
therapeutic areas. For example, the cancer treatment guidance7
provides some latitude for conducting investigations of high-dose
cancer treatments without the requirement for an IND submission,
because of the oncologists’ familiarity with the implications of highdose regimens, in general.8

Patient population: The acceptability of known and unknown risks
can vary considerably across different treatment populations. For
example, a drug with significant toxicity can be approved for use in
a population with a life-threatening or severely debilitating disease
because the risk of toxicity is acceptable in that population. Use of
that drug in a clinical investigation of a population that is not so ill
(e.g., to evaluate the drug for prevention of the disease or
symptomatic relief), however, would present a different risk-benefit
situation in which the risks would likely not be acceptable. When
the acceptability of the risk is significantly decreased, the study
would have to be conducted under an IND application.9
5. The investigation is conducted in compliance with the requirements for
review by an IRB that operates in accordance with 21 CFR Part 56 and
with the requirements for informed consent at 21 CFR Part 50; and
6. The investigation is conducted in compliance with the requirements of
21 CFR Section 312.7; i.e., the investigation is not intended to promote
or commercialize the drug product by charging the research participant
(or his/her insurance provider) for the drug under evaluation.
7Refer
to the FDA’s Guidance for Industry: IND Exemptions for Studies of Lawfully Marketed
Drug or Biological Products for the Treatment of Cancer
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/uc
m071717.pdf)
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Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether
Human Research Studies Can Be Conducted Without an IND, U.S. Food and Drug
Administration, 2010
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Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether
Human Research Studies Can Be Conducted Without an IND, U.S. Food and Drug
Administration, 2010
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