NOTE:  A stay is in effect for parts of subsection VI.D of this guidance.  
Additional information about this stay can be found in the Notice of Stay that 
published in the Federal Register of October 30, 2015 (80 FR 66907). 
 
Guidance for Clinical 
Investigators, Sponsors, and 
IRBs 
 
Investigational New Drug 
Applications (INDs)
  
Determining Whether Human 
Research Studies Can Be 
Conducted Without an IND 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER)  
Center for Biologics Evaluation and Research (CBER) 
Center for Food Safety and Applied Nutrition (CFSAN) 
 
 
September 2013 
Clinical/Medical 
 
   
Guidance for Clinical Investigators, 
Sponsors, and IRBs 
 
Investigational New Drug Applications 
(INDs)  Determining Whether Human 
Research Studies Can Be Conducted  
Without an IND 
 
Additional copies are available from: 
 
Office of Communications, 
Division of Drug Information, WO 51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Avenue 
Rockville, MD  20993-0002 
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
Office of Communication, Outreach and 
Development, HFM-40 
Center for Biologics Evaluation and Research 
Food and Drug Administration 
1401 Rockville Pike, Rockville, MD 20852-1448 
Phone: 800-835-4709 or 301-827-1800 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
Outreach and Information Center 
Center for Food Safety and Applied Nutrition 
Food and Drug Administration 
5100 Paint Branch Parkway 
College Park, MD 20740 
Phone: 888-723-3366 
http://www.fda.gov/Food/GuidanceRegulation/default.htm 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Food Safety and Applied Nutrition (CFSAN) 
 
September 2013 
Clinical/Medical
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  RESEARCH STUDIES THAT REQUIRE AN IND ..................................................... 2 
A.  What Is a Drug? ........................................................................................................................... 3 
B.  What Is a Clinical Investigation? ................................................................................................ 4 
IV.  CLINICAL INVESTIGATIONS THAT ARE EXEMPT FROM THE IND 
REQUIREMENTS BY REGULATION ..................................................................................... 4 
A.  Certain Research Involving Marketed Drug Products ............................................................. 4 
B.  Bioavailability or Bioequivalence Studies in Humans ............................................................... 8 
V.  HUMAN RESEARCH STUDIES INVOLVING RADIOACTIVE OR COLD 
ISOTOPES..................................................................................................................................... 8 
A.  Radioactive Isotopes .................................................................................................................... 8 
B.  Cold Isotopes ................................................................................................................................ 9 
VI.  SPECIFIC ISSUES CONCERNING THE APPLICATION OF THE IND 
REGULATIONS ........................................................................................................................... 9 
A.  Endogenous Compounds ........................................................................................................... 10 
B.  Live Organisms .......................................................................................................................... 10 
C.  Cosmetics .................................................................................................................................... 10 
D.  Foods .......................................................................................................................................... 11 
E.  Research With Noncommercial Intent ..................................................................................... 15 
VII.  FREQUENTLY ASKED QUESTIONS ........................................................................ 15 
VIII.  PROCESS FOR ADDRESSING INQUIRIES CONCERNING THE 
APPLICATION OF THE IND REQUIREMENTS ................................................................ 18 
APPENDIX .................................................................................................................................. 20 
 
 
 
 
 
 
 
 
 
 Part of this subsection is stayed. 
 
i 
  Contains Nonbinding Recommendations 
 
 
1
Guidance for Clinical Investigators, Sponsors, and IRBs  
 
Investigational New Drug Applications (INDs)   
Determining Whether Human Research Studies Can Be Conducted 
Without an IND 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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.  
You can use an alternative approach if the 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 is intended to assist clinical investigators, sponsors, sponsor-investigators,2 and 
institutional review boards (IRBs) in determining whether research studies involving human 
subjects must be conducted under an investigational new drug application (IND), as described in 
title 21 of the Code of Federal Regulations, part 312 (21 CFR part 312) (the IND regulations).  
This guidance describes when an IND is required, specific situations in which an IND is not 
required, and a range of issues that, in FDAs experience, have been the source of confusion or 
misperceptions about the application of the IND regulations.3  This guidance addresses only 
whether an IND is needed.  If your study also involves the use of a device, you should determine 
whether such use is subject to 21 CFR part 812 (the IDE regulations).   
 
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 
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER), the Center for 
Biologics Evaluation and Research (CBER), and the Center for Food Safety and Applied Nutrition (CFSAN) at the 
Food and Drug Administration (FDA or the Agency). 
2 The definitions in the IND regulations describe specific roles for the individual or individuals who conduct a 
clinical investigation (the investigators) and the individual or entity who has primary responsibility for and initiates 
the clinical investigation (the sponsor) ( 312.3(b)).  In the most common scenario, a commercial sponsor has 
primary responsibility for and initiates the clinical investigation, and multiple investigators are responsible for the 
actual conduct of the investigation at their respective study sites.  The term sponsor-investigator typically refers to 
an individual at an academic institution who takes responsibility for, initiates, and conducts a clinical investigation 
at a single site (sometimes referred to as an investigator-initiated study) and therefore meets the definition of both a 
sponsor and an investigator for purposes of the IND regulations.     
3 This guidance does not address expanded access to investigational drugs for treatment use under subpart I of 21 
CFR part 312. 
  1  Contains Nonbinding Recommendations 
 
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 
 
FDA has two primary objectives in reviewing an IND:  (1) to assure the safety and rights of 
subjects in all phases of an investigation and (2) in phases 2 and 3, to help assure that the quality 
of the scientific evaluation of the drug is adequate to permit an evaluation of the drugs 
effectiveness and safety (21 CFR 312.22).  
 
FDA receives frequent inquiries from the academic community (e.g., clinical investigators, 
IRBs) and the pharmaceutical industry about whether an IND should be submitted for various 
types of clinical research.  Inquiries have related to a range of issues concerning application of 
the IND requirements in part 312, including, for example: 
 
  Clinical investigations using marketed drugs 
  Bioequivalence/bioavailability studies 
  Studies using radiolabeled or cold isotopes 
  Studies using dietary supplements or foods 
  Studies using endogenous compounds 
  Pathogenesis studies using modified organisms 
  Studies using wild-type organisms in challenge models 
  Studies that do not have a commercial purpose 
 
Because of the large number of inquiries and wide range of issues, FDA determined that it would 
be helpful to provide to potential sponsors, clinical investigators, and sponsor-investigators an 
overview of the IND requirements and related issues.   
 
With certain exceptions, clinical investigations in which a drug is administered to human 
subjects must be conducted under an IND as required in part 312.  Sections III, IV, and V of this 
guidance elaborate on the criteria for when a study must be conducted under an IND; the types of 
studies that involve drugs, but that are exempt from the IND requirements; studies involving 
radioactive drugs that are generally recognized as safe and effective (and to which IND 
requirements therefore do not apply); and FDAs use of enforcement discretion with respect to 
certain studies using cold isotopes conducted without an IND.  Section VI discusses specific 
issues that frequently arise concerning application of the IND regulations; section VII contains 
frequently asked questions; and section VIII describes the process for seeking advice from FDA 
concerning the application of the IND regulations to a planned clinical investigation.   
   
III.  RESEARCH STUDIES THAT REQUIRE AN IND 
 
In general, the IND regulations in part 312 require that human research studies be conducted 
under an IND if all of the following conditions exist: 
 
  2  Contains Nonbinding Recommendations 
 
  The research involves a drug as that term is defined in section 201(g)(1) of the Federal 
Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 321(g)(1)). 
 
  The research is a clinical investigation as defined in the IND regulations (21 CFR 312.3).  
 
  The clinical investigation is not otherwise exempt from the IND requirements in part 312 
(see section IV of this guidance). 
 
A.  What Is a Drug? 
 
The definition of the term drug in section 201(g)(1) of the FD&C Act includes, among other 
things, articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of 
disease . . . and articles (other than food) intended to affect the structure or any function of the 
body of man or other animals.  Biological products subject to licensure under section 351 of the 
Public Health Service Act (42 U.S.C. 262) may also be considered drugs within the meaning of 
the FD&C Act.  A biological product is: 
  
. . . a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or 
derivative, allergenic product, protein (except any chemically synthesized polypeptide), 
or analogous product, or arsphenamine or derivative of arsphenamine (or any other 
trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a 
disease or condition of human beings.  
 
(42 U.S.C. 262(i))   
 
Biological products include, among other products, bacterial vaccines, allergenic extracts, gene 
therapy products, growth factors, cytokines, and monoclonal antibodies. 
 
It is important to note that the drug definition is not limited to compounds intended for a 
therapeutic purpose.4  The definition also includes compounds intended to affect the structure or 
function of the body, without regard to whether the compound is intended to influence a disease 
process.  For example, the definition includes compounds administered to healthy individuals to 
prevent pregnancy or treat male pattern baldness.  The definition also includes compounds used 
for research purposes in healthy subjects to blunt or provoke a physiologic response or study the 
mechanism of action or metabolism of a drug (see section VI.A).  Note, however, that (1) a 
dietary supplement intended only to affect the structure or function of the body and not intended 
for a therapeutic purpose is not a drug5 (see section VI.D.1) and (2) a food used as such (i.e., 
primarily for its taste, aroma, or nutritive value) and not for a therapeutic purpose or to affect the 
structure or function of the body, other than by providing nutrition, is not a drug (see section 
VI.D.2).6 
                                                 
4 In this guidance, the term therapeutic purpose is intended to encompass diagnosis, cure, mitigation, treatment, and 
prevention of disease. 
5 See 21 CFR 101.93(f) and (g); 65 FR 1000 (Jan. 6, 2000). 
6 See 21 U.S.C. 321(f) and (g)(1); Nutrilab v. Schweiker, 713 F.2d 335 (7th Cir. 1983)). 
  3  Contains Nonbinding Recommendations 
 
B.  What Is a Clinical Investigation? 
 
The IND regulations in  312.3(b) define clinical investigation7 as: 
 
 . . . [an] experiment in which a drug is administered or dispensed to, or used involving, 
one or more human subjects.  For the purposes of [the IND regulations], an experiment is 
any use of a drug [whether approved or unapproved] except for the use of a marketed 
drug in the course of medical practice. 
 
For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a 
clinical investigation and may require an IND.8  In contrast, use of a lawfully marketed drug for 
an unapproved use in the course of medical practice is not a clinical investigation and does not 
require an IND because it involves the use in an individual patient where the primary intent is to 
treat the patient.    
 
IV.  CLINICAL INVESTIGATIONS THAT ARE EXEMPT FROM THE IND 
REQUIREMENTS BY REGULATION 
 
FDA regulations describe two categories of clinical investigations that are exempt from the IND 
requirements in part 312, provided the criteria for exemption are met (see 21 CFR 312.2(b) and 
320.31(b)).  The two categories of clinical investigations and the applicable criteria are described 
in the following subsections. Ordinarily, clinical investigations of drugs that do not meet these 
criteria must be conducted under an IND as required in part 312.         
 
A.  Certain Research Involving Marketed Drug Products 
 
Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily 
depends on the intent of the investigation and the degree of risk associated with the use of the 
drug in the investigation.  A clinical investigation of a marketed drug is exempt from the IND 
requirements if all of the criteria for an exemption in  312.2(b) are met: 
 
  The drug product is lawfully marketed in the United States. 
  The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other significant 
change in the labeling of the drug. 
  In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for the drug. 
  The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreases the acceptability of the risk) 
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
                                                 
7 Additional information on clinical investigations is available on FDA's Web site at 
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.  
8 See section IV.A of this guidance. 
  4  Contains Nonbinding Recommendations 
 
  The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50). 
  The investigation is conducted in compliance with the requirements of  312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product). 
 
The potential sponsor or sponsor-investigator of a planned clinical investigation using a 
marketed drug is responsible for determining whether the investigation meets the criteria for an 
exemption.9  If there is uncertainty about whether the exemption criteria are met, the potential 
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND 
regulations ( 312.2(e)). 
 
Three of the criteria for exemption listed previously merit further discussion.  
 
  What is meant by a drug product that is lawfully marketed in the United States? 
 
The preamble to the final rule incorporating the IND exemption criteria into the IND 
regulations makes clear that the exemption provision was not intended to require use of only 
the marketed version of the drug product for a clinical investigation to be exempt from the 
IND requirements.  The intent was to provide some latitude to modify the marketed version 
of the drug product for use in a clinical investigation.  In responding to comments asking 
FDA to clarify to what extent a sponsor could change the marketed drug product or 
conditions of use and still be exempt from the IND regulations, FDA stated that: 
 
The exemption was not intended to require an investigator to use the drug in 
exactly the same dosage form, dosage levels, and patient populations described in 
the marketed labeling for the product, but rather to permit changes to the lawfully 
marketed drug product that do not increase the risks . . . over the risk presented by 
use of the product in conformance with its marketed labeling.10 
 
Therefore, sponsors or sponsor-investigators can make low-risk modifications to the lawfully 
marketed dosage form to, for example, blind a study.     
 
In making modifications to the marketed dosage form, sponsors and sponsor-investigators 
should consider the potential risk implications of the modifications based on the type and 
complexity of the dosage form.  For example, minor variations to solid oral dosage forms, 
                                                 
9 The preamble to the rule finalizing the IND regulations provides: 
FDA recognizes that a considerable amount of professional judgment must be exercised in determining 
whether the conditions of an investigation significantly increase the risk associated with use of the drug.  
Because the assessment of risks involved in a therapeutic procedure is an everyday part of the practice of 
medicine, the individual investigator should usually be able to determine the applicability of the exemption. 
(See the final rule on New Drug, Antibiotic, and Biologic Drug Product Regulations that published in the 
Federal Register of March 19, 1987 (52 FR 8798 at 8802)).  
10 Final rule, New Drug, Antibiotic, and Biologic Drug Product Regulations (52 FR 8798 at 8801, March 19, 
1987). 
 
  5  Contains Nonbinding Recommendations 
 
such as changing the color, scoring, or capsule size of the marketed dosage form for blinding 
purposes, would generally be low risk, provided the changes did not involve major 
manufacturing or formulation changes.  Similarly, using capsules to over-encapsulate the 
marketed dosage form would generally be low risk, provided the capsule met appropriate 
standards.  Changes to more complex oral dosage forms and injectable and other non-oral 
dosage forms might carry greater risk.  Products that are very sensitive to conditions in their 
environment (e.g., protein products) also carry greater risk because changes to the 
formulation, dosage form, manufacturing, or primary packaging might change the 
pharmacokinetics, immunogenicity, or other characteristics of such products.   
 
Given the range of possible modifications to a marketed dosage form, FDA cannot provide 
comprehensive guidance on the degree of risk presented by all such modifications.  If 
sponsors or sponsor-investigators have concerns about whether changes to a lawfully 
marketed dosage form increase risk to an extent that an IND would be required, they should 
consult FDA (see section VIII).  If a sponsor or sponsor-investigator consults FDA, they 
should provide FDA with a listing of chemistry, manufacturing, and controls (CMC) 
variations from the marketed version of the drug product, if CMC information for the 
marketed product is available to them, and any other pertinent information that would assist 
FDA in responding to an inquiry.    
 
  Is the risk associated with the product significantly increased (or the acceptability of the 
risk significantly decreased)? 
 
Historically, assessing whether a particular use of a drug in a clinical investigation 
significantly increases the risk or decreases the acceptability of the risk, compared to its 
approved use or uses, has been the most difficult issue in determining whether an IND is 
needed for a clinical investigation of a marketed drug (21 CFR 312.2(b)(1)(iii)).  This 
provision has been particularly difficult in the oncology setting where many of the therapies 
have significant toxicity; for that reason, FDA has issued guidance to help clinical 
investigators studying cancer treatments determine whether the risk associated with the use 
of the drug in a planned clinical investigation is significantly increased or the acceptability of 
the risk is significantly decreased.11  FDAs cancer treatment guidance is also a useful 
reference for clinical studies of marketed drugs in other therapeutic areas, particularly for 
studies in other serious and life-threatening conditions, as the risk-benefit scenarios are at 
least somewhat relevant to non-oncologic settings.  Investigators should carefully consider 
the risk implications of any conditions of use in the study that deviate from the conditions of 
use described in the drugs labeling, with particular attention to the following: 
 
                                                 
11 See the guidance for industry IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for 
the Treatment of Cancer (the cancer treatment guidance).  We update guidances periodically.  To make sure you 
have the most recent version of a guidance, check the Drugs guidance page at http://www.fda.gov/Drugs/ 
GuidanceComplianceRegulatoryInformation/Guidances/default.htm and the Biologics guidance page at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
  6  Contains Nonbinding Recommendations 
 
  Route of Administration:  A change in the route of administration can introduce a 
-
significant new risk.  For example, 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 injection or intravenous, intrathecal, or inhalation route.  These other 
routes of administration introduce concerns with increased local concentrations, 
sterility, pyrogenicity, hypersensitivity (e.g., airway reactivity), variations in 
metabolism, and other issues not present with oral administration that can 
significantly increase the risk, or decrease the acceptability of the risk, associated 
with use of the drug. 
 
  Dose:  Increases in dose, frequency, or duration of administration, compared to 
-
labeled dosing regimens, can significantly increase the risk in a study using a 
marketed drug.  It is also possible that a decrease in dose could significantly increase 
risk.   For example, administering a sub-therapeutic dose of an antiviral drug to study 
subjects could induce resistance in the subjects, thus rendering a subsequent 
therapeutic dose of the drug ineffective in treating the virus.  The significance of 
changes in dose (in particular, increases in dose) can vary across therapeutic areas.  
For example, the cancer treatment guidance provides some latitude for conducting 
studies of high-dose cancer treatments without an IND because oncologists are 
generally familiar with the implications of high-dose regimens.  In other clinical 
settings, use of higher doses than are recommended in labeling may be much more 
likely to significantly increase the risk or decrease the acceptability of the risk.   
 
  Patient Population:  The acceptability of known and unknown risks can vary across 
-
different treatment populations (see  312.2(b)(1)(iii)).  The population chosen for 
study could be at increased risk compared to the approved use population for a variety 
of reasons, such as increased age, different disease or stage of disease, concomitant 
illness, decreased renal or hepatic function, or concomitant therapy.  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 in a population that is 
not so ill (e.g., to evaluate the drug for prevention of disease or symptomatic relief), 
however, would present a different risk-benefit situation in which the known risks 
might not be acceptable.  When use of the drug in a specific patient population 
decreases the acceptability of the known risks, the study would have to be conducted 
under an IND as required under 21 CFR part 312. 
 
  Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study 
in support of a new indication, (2) use it to support any other significant change in the 
labeling of the drug, or (3) use it to support a significant change in the advertising (for 
prescription drugs only) for the drug? 
 
Generally, it seems reasonable to infer that any well-controlled trial of a marketed drug (e.g., a 
study of a new indication) sponsored by the manufacturer of the drug would be intended to be 
used to influence labeling or promotion in some significant way and would have to be conducted 
under an IND.  On the other hand, similar studies of marketed drugs conducted by an entity that 
  7  Contains Nonbinding Recommendations 
 
does not have an independent ability to change a drugs labeling  e.g., a study conducted by a 
sponsor-investigator in an academic setting or Government agency sponsor  would not 
generally be intended to be submitted to FDA to support a new indication or to otherwise 
influence the drugs labeling or promotion.  However, data from such studies may subsequently 
be submitted to FDA for that purpose and, therefore, FDA has an interest in helping to ensure 
that these studies are designed to yield data adequate to support a labeling change.  A sponsor 
who would like to obtain FDA advice on study design can submit an IND for FDA review. 
 
B.  Bioavailability or Bioequivalence Studies in Humans 
 
FDA regulations describe criteria under which bioavailability or bioequivalence (BA/BE) studies 
using unapproved versions of approved drug products can be conducted without submission of 
an IND (21 CFR 320.31(b) and (d)).  Although these regulations are intended to facilitate 
development of generic drugs, a planned BA/BE study need not be intended for that purpose to 
be exempt from the IND regulations.  A BA/BE study in humans does not require an IND if all 
of the following conditions are met: 
 
  The drug product does not contain a new chemical entity (21 CFR 314.108), is not 
radioactively labeled, and is not cytotoxic. 
  The dose (single dose or total daily dose) does not exceed the dose specified in the 
labeling of the approved version of the drug product. 
  The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50). 
  The sponsor meets the requirements for retention of test article samples (21 CFR 
320.31(d)(1)) and safety reporting (21 CFR 320.31(d)(3)). 
 
V.  HUMAN RESEARCH STUDIES INVOLVING RADIOACTIVE OR COLD 
ISOTOPES 
 
A.  Radioactive Isotopes 
 
FDA regulations (21 CFR 361.1) describe conditions under which radioactive drugs (drugs 
containing unstable isotopes) can be used for certain research without an IND because they are 
generally recognized as safe and effective for those uses.  These regulations apply to radioactive 
versions of both approved and unapproved drugs.12     
 
Under 21 CFR part 361, human research using a radioactive drug or biological product may be 
conducted without an IND if (1) it involves basic research not intended for immediate 
therapeutic, diagnostic, or similar purposes, or otherwise to determine the safety and efficacy of 
                                                 
12 For information on determining whether human research with a radioactive drug can be conducted under a 
Radioactive Drug Research Committee (RDRC), see FDAs guidance for industry and researchers The Radioactive 
Drug Research Committee:  Human Research Without an Investigational New Drug Application (the RDRC 
guidance).  
  8  Contains Nonbinding Recommendations 
 
the product, (2) the use in humans is approved by a Radioactive Drug Research Committee 
(RDRC) that is composed and approved by FDA, (3) the dose to be administered is known not to 
cause any clinically detectable pharmacological effect in humans, and (4) the total amount of 
radiation to be administered as part of the study is the smallest radiation dose practical to 
perform the study without jeopardizing the benefits of the study and is within specified limits. 
 
B.  Cold Isotopes 
 
Cold isotopes (isotopes that lack radioactivity) have been increasingly used for the same research 
purposes as radioactive isotopesto obtain basic information about drug metabolism or about 
human physiology, pathophysiology, or biochemistry.  When used for these basic research 
purposes, cold (or stable) isotopes ordinarily present fewer safety concerns than radioactive 
isotopes.  Unlike radioactive isotopes, however, there is no specific regulation analogous to 21 
CFR 361.1 that addresses cold isotopes of approved drugs and unapproved drugs when used for 
these basic research purposes.  However, FDA believes there is no need to have more stringent 
requirements for studies that use cold isotopes than for those that use radioactive isotopes, and 
historically, FDA has not objected to studies using cold isotopes being conducted without an 
IND.  In exercising its enforcement discretion, FDA does not intend to object to clinical 
investigations using cold isotopes of unapproved drugs being conducted without an IND, 
provided the following conditions are met (the conditions are based on the criteria for studies 
using radiolabeled drugs (see 21 CFR  361.1)):13 
 
  The research is intended to obtain basic information regarding the metabolism (including 
kinetics, distribution, and localization) of a drug labeled with a cold isotope or regarding 
human physiology, pathophysiology, or biochemistry. 
  The research is not intended for immediate therapeutic, diagnostic, or preventive benefit 
to the study subject. 
  The dose 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 cold isotope meets relevant quality standards. 
  The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and the requirements for informed consent (21 CFR part 50). 
 
VI.  SPECIFIC ISSUES CONCERNING THE APPLICATION OF THE IND 
REGULATIONS 
 
                                                 
13 Note that studies using cold isotopes of approved drugs frequently meet the criteria for exemption from the IND 
requirements in part 312 for studies of marketed drugs (see section IV.A) because the studies involve low doses and 
present low risk.  In such cases, enforcement discretion would not be needed for these studies to be conducted 
without an IND. 
  9  Contains Nonbinding Recommendations 
 
This section addresses specific issues that frequently arise in discussions with outside parties 
concerning the application of the IND requirements in 21 CFR part 312. 
 
A.  Endogenous Compounds 
 
FDA has received numerous questions concerning the application of the IND requirements to 
studies in which endogenous compounds are administered to human subjects.  A common 
question is whether provocation or challenge studies in which an endogenous compound (e.g., 
bradykinin, histamine, angiotensin) is administered to subjects to evoke a physiologic response, 
characterize a disease, or establish the mechanism of action are subject to IND requirements.  In 
these cases, the endogenous compound is plainly not being used for a therapeutic purpose.  There 
is, however, intent to affect the structure or function of the body, so the compound would be 
considered a drug under these circumstances.  Therefore, these types of studies are clinical 
investigations and require an IND under part 312, unless the study meets the criteria for an 
exemption in  312.2(b) or  320.31(b) (see section IV) or the criteria in  361.1, or the 
compound is labeled with a cold isotope and used in the manner described in section V, is a 
dietary supplement (see section VI.D.1), or is an article used for food or drink (i.e., primarily for 
taste, aroma, or nutritive value, rather than for some other effect on the structure or function of 
the body) in the study (see section VI.D.2). 
 
B.  Live Organisms 
 
An IND is required for challenge studies in which a live organism (e.g., virus, bacteria, or fungi, 
whether modified or wild-type) is administered to subjects to study the pathogenesis of disease 
or the host response to the organism (see part 312).  Although the challenge organism is not 
intended to have a therapeutic purpose, there is intent to affect the structure or function of the 
body.  Thus, the organism is both a biological product (see 21 CFR 600.3(h)(1)) and a drug, and 
an IND is required for the clinical investigation, unless the criteria for exemption in 21 CFR 
312.2 are met or the product meets the definition of a dietary supplement14 or is an article used 
for food or drink (i.e., primarily for taste, aroma, or nutritive value, rather than for some other 
effect on the structure or function of the body) in the study.  Similarly, an IND is required for a 
clinical investigation designed to evaluate whether colonization with a strain of bacteria can treat 
or prevent disease in patients with a chronic immune disorder. 
 
C.  Cosmetics 
 
                                                 
14 Section 201(ff) of the FD&C Act does not specifically mention live organisms in the definition of a dietary 
supplement (21 U.S.C. 321(ff)), but does include more general language that results in some products containing 
live organisms falling within the dietary supplement definition, depending on the specific facts related to the 
product.  The relevant language is found in section 201(ff)(1), which lists the substances that may be used as 
dietary ingredients in dietary supplements.  Section 201(ff)(1)(E) provides that dietary substance[s] for use by 
man to supplement the diet by increasing the total dietary intake are dietary ingredients; section 201(ff)(1)(F) 
further defines dietary ingredient to include a concentrate, metabolite, constituent, extract, or combination of any 
other dietary ingredient.  Taken together, these two provisions indicate that a live organism that is a constituent of an 
article that is commonly used as human food or drink (e.g., a probiotic in yogurt) may be used as a dietary ingredient 
in a dietary supplement.  
  10  Contains Nonbinding Recommendations 
 
Section 201(i) of the FD&C Act (21 U.S.C. 321(i)) defines a cosmetic as (1) articles 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, and (2) articles intended for use as a component of any such articles; except that 
such term shall not include soap.  With the exception of color additives and a few prohibited 
ingredients, a cosmetic manufacturer may use almost any raw material as a cosmetic ingredient 
and market the product without an approval from FDA. 
 
As a general matter, studies of ingredients or products marketed as cosmetics require an IND if 
the ingredient is being studied for use to affect the structure or function of the body or to prevent, 
treat, mitigate, cure, or diagnose a disease (see 21 U.S.C. 321(g)(1); 21 CFR 312.2).  This is true 
even if the study is intended to support a cosmetic claim about the ingredient or products ability 
to cleanse, beautify, promote attractiveness, or alter the appearance, rather than a 
structure/function claim.  For example, a study of the effect of a cosmetic product containing 
human or animal biological material (such as placenta) on skin repair mechanisms would require 
an IND, even if the study is intended only to support a claim of younger looking skin. 
 
D.  Foods 
 
Those who are evaluating published clinical literature or sponsoring new clinical studies while 
conducting safety assessments for dietary ingredients, food additives (including food contact 
substances), and GRAS substances, as well as those who conduct or sponsor research intended to 
support labeling claims for conventional foods or dietary supplements, should be aware of two 
provisions of the FD&C Act that, depending on the circumstances, may restrict the marketing of 
products containing substances that have been the subject of substantial clinical investigations 
whose existence has been made public.  Section 301(ll) of the FD&C Act (21 U.S.C. 331(ll)) 
prohibits the marketing of any food to which has been added a drug or biologic for which 
substantial clinical investigations have been instituted and for which the existence of such 
investigations has been made public, unless the drug or biologic was marketed in food before any 
substantial clinical investigations involving the drug or biologic were instituted or one of the 
other exceptions in section 301(ll) applies.  Section 201(ff)(3)(B)(ii) of the FD&C Act (21 
U.S.C. 321(ff)(3)(B)(ii)) excludes from the dietary supplement definition any article authorized 
for investigation as a new drug for which substantial clinical investigations have been instituted 
and for which the existence of such investigations has been made public, unless the article was 
marketed as a dietary supplement or as a conventional food before the IND became effective.15  
FDA interprets authorized for investigation to mean that the article is the subject of an IND 
that has gone into effect (see 21 CFR 312.40).  Marketing the substance of interest as a dietary 
supplement or as a food (under section 201(ff)) or in food (under section 301(ll)) before 
seeking an IND or beginning any clinical investigations preserves the option to continue to 
market the substance in those forms after substantial clinical investigations have been instituted 
and their existence has been made public.    
 
                                                 
15 FDA can create an exception to the exclusion by regulation, but only if the Agency finds that the use of the article 
in dietary supplements would be lawful.  To date, no such regulations have been issued.  The appropriate mechanism 
to request such a regulation is to file a citizen petition under 21 CFR 10.30. 
  11  Contains Nonbinding Recommendations 
 
1.  Dietary Supplements 
 
Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), a dietary 
supplement is defined, in part, as a product taken by mouth that is intended to supplement the 
diet and that contains one or more dietary ingredients.16  The dietary ingredients in these 
products can include vitamins, minerals, herbs and other botanicals, amino acids, other dietary 
substances intended to supplement the diet, and concentrates, metabolites, constituents, extracts, 
or combinations of the preceding types of ingredients.  Dietary supplements can be found in 
many forms such as tablets, capsules, softgels, liquids, or powders.   
 
Under DSHEA, a dietary supplement is not considered a drug and is not subject to the premarket 
approval requirements for drugs if the intended use for which it is marketed is only to affect the 
structure or any function of the body (i.e., not intended to be used for a therapeutic purpose).  
Similarly, whether an IND is needed for a clinical investigation evaluating a dietary supplement 
is determined by the intent of the clinical investigation.  If the clinical investigation is intended 
only to evaluate the dietary supplements effect on the structure or function of the body, an IND 
is not required.   
 
However, if the clinical investigation is intended to evaluate the dietary supplements ability to 
diagnose, cure, mitigate, treat, or prevent a disease,17 an IND is required under part 312.  For 
example, a clinical investigation designed to study the relationship between a dietary 
supplements effect on normal structure or function in humans (e.g., guarana and maximal 
oxygen uptake) or to characterize the mechanism by which a dietary supplement acts to maintain 
such structure or function (e.g., fiber and bowel regularity) would not need to be conducted 
under an IND.  However, a clinical investigation designed to evaluate a dietary supplements 
ability to prevent osteoporosis or to treat chronic diarrhea or constipation would need to be 
conducted under an IND.    
 
2.  Conventional Food 
 
Section 201(f) of the FD&C Act (21 U.S.C. 321(f)) defines a food as (1) articles used for food 
or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any 
such article.  For studies intended to evaluate the effects of a food, the analysis for whether an 
IND is needed turns on the intent of the clinical investigation.   
 
As is the case for a dietary supplement, a food is considered to be a drug if it is intended for use 
in the diagnosis, cure, mitigation, treatment, or prevention of disease,18 except that a food may 
bear an authorized health claim about reducing the risk of a disease without becoming a drug 
(see section VI.D.3).  Therefore, a clinical investigation intended to evaluate the effect of a food 
                                                 
16 See section 201(ff) of the FD&C Act (21 U.S.C. 321(ff)). 
17 For purposes of the dietary supplement labeling requirements, a disease is 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 (21 CFR 101.93(g)(1)).  
18 21 U.S.C. 321(g)(1)(B). 
  12  Contains Nonbinding Recommendations 
 
on a disease would require an IND under part 312.  For example, a clinical investigation intended 
to evaluate the effect of a food on the signs and symptoms of Crohns disease would require an 
IND. 
 
The following paragraph in brackets [ ] is STAYED.  
[The FD&C Act also defines drug to include articles (other than food) intended to affect the 
structure or any function of the body.19  This provision contains a parenthetical exception for 
foods that affect the structure and function of the body by virtue of providing nutrition to sustain 
life and health.  Consistent with case law interpreting the other than food exception as applying 
to articles consumed primarily for taste, aroma, or nutritive value, FDA regulates conventional 
foods (including infant formula) that are intended to affect the structure or function of the body 
as foods, not drugs, as long as the intended structure or function effect derives from the products 
character as a food  its taste, aroma, or nutritive value.20  However, if an edible product that 
might otherwise be a conventional food is intended for a use other than providing taste, aroma, or 
nutritive value, such as blocking the absorption of carbohydrates in the gut, the product becomes 
a drug because the primary purpose of consuming it has changed.  In other words, the product is 
no longer being consumed as a food  primarily for taste, aroma, or nutritive value  but used 
as a drug for some other physiological effect.  Accordingly, a clinical investigation intended only 
to evaluate the nutritional effects of a food (including medical foods21) would not require an 
IND, but an investigation intended to evaluate other effects of a food on the structure or function 
of the body would.  For example, a study of the effect of iron on hemoglobin levels in which 
subjects were fed beef or lamb as a source of iron would not require an IND, but a study of the 
effect of soy isoflavones on bone metabolism would.  Similarly, a study of the ability of an infant 
formula to support growth of infants or of other nutritional properties of the formula would not 
require an IND.  However, a study of other effects of the formula on the structure or function of 
the body (e.g., an investigation of the effects of docosahexaenoic acid in infant formula on visual 
acuity of infants) would require an IND.] 
 
A clinical study intended to evaluate the safety of a food ingredient generally does not require an 
IND, even if the ingredient is known to have an effect on the structure and function of the body 
that is in addition to its taste, aroma, or nutritional effect.  For example, a study of the safety of a 
flavor ingredient that has been found to bind to a receptor outside of the target location in the 
mouth would not require an IND if the intent of the study was to evaluate the safety of the 
ingredient when ingested as food. The following sentence in brackets [ ] is STAYED. [In 
contrast, if the intent of the study was to evaluate the beneficial effects (beyond nutritional 
effects) of binding the newly found receptor, the study would require an IND.]  Similarly, a 
clinical study may be performed to evaluate the tolerability of a food in a specific susceptible 
population, including individuals with a disease. In such an evaluation, biological parameters 
affected by the disease may need to be assessed in order to establish tolerance. For example, the 
                                                 
19 21 U.S.C. 321(g)(1)(C). 
20 See Nutrilab v. Schweiker, 713 F.2d 335 (7th Cir. 1983). 
21 A medical food is a food which is formulated to be consumed or administered enterally under the supervision of 
a physician and which is intended for the specific dietary management of a disease or condition for which distinctive 
nutritional requirements, based on recognized scientific principles, are established by medical evaluation.  21 
U.S.C. 360ee(b)(3).   
  13  Contains Nonbinding Recommendations 
 
administration of high intensity sweeteners to diabetic patients to establish no adverse effect on 
HbA1c levels or the administration of a novel food protein ingredient to a potentially allergic 
population to establish lack of allergic reactivity in this population would not require an IND.  
However, if the intent of the study was to demonstrate an effect of the food in decreasing HbA1c 
levels in diabetic patients or an effect of the food to desensitize or raise threshold levels of 
allergic reactivity in sensitive individuals, the study would require an IND.   
  
Consistent with the considerations for conventional foods described in the previous paragraph, 
an investigation intended to evaluate the effects of a medical food on a disease would require an 
IND.  However, if the medical food is simply being fed to subjects for nutritional purposes 
during a study examining the effects of another intervention, the use of the medical food in the 
study would not trigger the need for an IND, although the study might require an IND or 
investigational device exemption (IDE) for the intervention being studied.   
 
3.  Studies Intended to Support a Health Claim 
 
NOTE:  The stay does not apply to clinical investigations intended to evaluate whether a 
food substance may reduce the risk of a disease in individuals less than 12 months of age, 
those with altered immune systems, and those with serious or life-threatening medical 
conditions.  This subsection is in effect for such clinical investigations.   
 
The following paragraph in brackets [ ] is STAYED, except as noted above. 
[Section 201(g) of the FD&C Act provides that a health claim in the label or labeling of a food 
(conventional food or dietary supplement) characterizing the relationship between a substance 
(food or food component) and a disease or health-related condition does not cause the food to be 
a drug on the basis of that claim, provided the claim is authorized under and made in accordance 
with the requirements of section 403(r)(1)(B) and (r)(3) of the FD&C Act22 (for conventional 
foods) or under section 403(r)(1)(B) and (r)(5)(D) (for dietary supplements).  Notwithstanding 
this provision, however, a clinical study designed to evaluate the relationship between a food 
substance and a disease and intended to provide support for such a claim is required to be 
conducted under an IND (21 CFR part 312), unless the substance-disease relationship being 
studied is already the subject of an authorized health claim.  Section 201(g) provides, in effect, 
an exemption from the normal operation of the drug definition  it permits the use of health 
claims that would, without the exemption, cause a conventional food or dietary supplement to be 
a drug.  However, the exemption does not apply until the health claim has been authorized by 
FDA.  Therefore, a study conducted to support a new or expanded health claim would require an 
IND.  For example, a study designed to evaluate whether vitamin D may reduce the risk of one 
or more site-specific cancers would require an IND, as there is currently no authorized health 
claim for this substance-disease relationship.  Similarly, a study conducted to support a petition 
to amend the health claim for soluble fiber from certain foods and reduced risk of coronary heart 
disease (21 CFR 101.81) to include a new type of fiber would require an IND.] 
 
                                                 
 
  14  Contains Nonbinding Recommendations 
 
E.  Research With Noncommercial Intent 
 
Some believe that the IND regulations do not apply to clinical investigations that are not 
intended to investigate a drugs potential for commercial sale.  Whether the IND regulations 
apply to a planned clinical investigation does not depend on whether the intent of the clinical 
investigation is commercial or noncommercial.  Therefore, these types of studies would require 
an IND under part 312, unless they meet the criteria for an exemption in  312.2(b) or 
320.31(b) (see section IV) or the criteria in  361.1, or the compound used is labeled with a cold 
isotope and used in the manner described in section V.   
 
VII.  FREQUENTLY ASKED QUESTIONS 
 
1.    Do I need an IND if I use a lawfully marketed drug for an unlabeled indication? 
 
If you are a health care provider and you prescribe a marketed drug to treat a patient for an 
unlabeled indication (also referred to as off-label use), an IND is not required because this use is 
considered to be within the scope of medical practice and not a clinical investigation.  However, 
if you use the marketed drug for the same purpose in a clinical investigation intended to evaluate 
the drugs ability to treat a disease or condition, an IND is required under part 312 unless the 
clinical investigation meets the criteria for an exemption for studies of lawfully marketed drugs 
(see 21 CFR 312.2(b) and section IV.A of this guidance).     
 
2.    If a drug marketed for use in adults is studied in an investigator-initiated, single-center 
study involving children, is an IND needed? 
 
An IND is required under part 312 unless the clinical investigation meets the criteria for an 
exemption in  312.2(b) (see section IV.A).  The criterion of most importance for the exemption 
in this situation is whether the change in study population from adult to pediatric, or any other 
condition of use in the study, would significantly increase the risks (or decrease the acceptability 
of the risks) associated with the use of the drug (21 CFR 312.2(b)(1)(iii)).  Whether risk would 
be significantly increased would depend on a variety of factors, including, for example, the age 
of the pediatric population being studied, the extent of prior pediatric experience with the drug in 
clinical studies or clinical practice, the amount of information available to support dosing in the 
study population, and the overall toxicity profile of the drug. 
 
3.    There are drugs on the market that have not been approved by FDA.  Do clinical 
investigations using those drugs need an IND? 
 
There are certain currently marketed drug ingredients that were first marketed before Congress 
passed the FD&C Act of 1938 (requiring demonstration of safety before marketing) or before it 
passed the 1962 amendments to the FD&C Act (requiring demonstration of effectiveness and 
safety before marketing).  Sponsors of clinical investigations that use products with these 
  15  Contains Nonbinding Recommendations 
 
ingredients should consult with FDA to determine whether the ingredient is lawfully marketed.23  
If the ingredient is not lawfully marketed, an IND is required under part 312. 
 
4.    Can I do research on radiolabeled endogenous peptides, such as neuropeptides, without an 
IND?  
 
If the research is intended to obtain basic information about the metabolism of the peptide or its 
role in physiology, pathophysiology, and biochemistry, and the criteria in 21 CFR 361.1 are met 
(i.e., among other things, the dose of endogenous peptide to be administered is known not to 
cause a clinically detectable pharmacologic effect in humans), an IND is not required (see the 
RDRC guidance).  However, if the study hypothesis concerns the diagnosis, cure, mitigation, 
treatment, or prevention of a disease in patients, or the criteria in  361.1 are otherwise not met, 
an IND is required under part 312. 
 
5.    Do clinical investigations of positron emission tomography (PET) drugs need INDs? 
 
An IND generally would be required for a PET drug investigation, unless the investigation meets 
the criteria in 21 CFR 361.1.  To meet these criteria, the research must be intended to obtain 
basic information regarding the metabolism (including kinetics, distribution, and localization) of 
a radioactively labeled drug or regarding human physiology, pathophysiology, or biochemistry, 
but not intended for immediate therapeutic, diagnostic, or similar purposes or to determine the 
safety and effectiveness of the drug in humans for such purposes (i.e., to carry out a clinical trial) 
(21 CFR 361.1(a)). 
 
6.    If a complementary or an alternative medicine that was derived from organic materials from 
a botanical source (e.g., broccoli, sprouts) is administered to subjects to study cancer 
prevention, is an IND required? 
 
A clinical investigation of a complementary or an alternative medicine derived from organic 
materials that is intended to evaluate the medicines ability to diagnose, cure, mitigate, treat, or 
prevent disease requires an IND under part 312.24   
 
7.    Is an IND required if a product containing attenuated microorganisms is evaluated for 
amelioration of symptoms of a disease or prevention of the disease? 
 
Even when a microorganism is attenuated with the intention to increase safety of a product, a 
clinical investigation that evaluates the potential for that microorganism to relieve symptoms of a 
disease or prevent the disease requires an IND under part 312, unless the study meets the criteria 
for an exemption under 21 CFR 312.2(b). 
 
                                                 
23 Ordinarily, such inquiries would be directed to CDER, Office of Compliance, Office of Unapproved Drugs & 
Labeling Compliance. 
24 See the guidance for industry on Botanical Drug Products.    
  16  Contains Nonbinding Recommendations 
 
8.    If a product containing substances generally recognized as safe (GRAS) for use in food is 
administered to subjects in a study intended to evaluate the effect of the substance on the 
pathogenesis of a human disease, is an IND required? 
 
Substances designated as GRAS for use in food are generally not approved as drug products.  A 
clinical investigation of a GRAS substance that is intended to evaluate the product's ability to 
diagnose, cure, mitigate, treat, or prevent disease requires an IND under part 312, unless the 
substance to be studied is also a lawfully marketed drug and the clinical investigation meets the 
criteria for exemption under 21 CFR 312.2(b).   
  
9.    For purposes of the exemption from the IND requirements for studies using radioisotopes 
and FDAs exercise of enforcement discretion for studies using cold isotopes, what support is 
needed to determine that the labeled drug does not have a clinically detectable 
pharmacological effect? 
 
There is no requirement for a formal dose-response study to define the lower threshold for a 
clinically detectable pharmacological effect, and, in some cases, a study may not be needed.  For 
example, if the labeled drug is an endogenous compound and the circulating blood levels or 
excretion rates of the endogenously produced substance are well known, there could be a basis to 
conclude that some small fraction of these levels or rates of administration (e.g., administration 
over a given interval of a very low percentage of the amount of a substance that is produced 
endogenously during the same interval) represents an amount without detectable 
pharmacological effect.  Similarly, if large amounts of a substance such as an amino acid or a 
sugar are regularly consumed as foodstuffs, it may be possible to conclude that consumption of a 
small amount of these substances (e.g., a small percentage of the amount usually consumed 
during a meal), at least by the oral route, would be without detectable pharmacological activity 
(also see footnote 11). 
 
10.    Do I need an IND if my study uses a home-made version of a lawfully marketed drug? 
 
Some investigators, or research pharmacies affiliated with the institution in which an investigator 
is conducting a study, compound their own versions of lawfully marketed drug products for use 
in clinical studies.  For example, FDA is aware of instances in which the methacholine used in 
respiratory studies for challenge purposes has been prepared locally from raw materials obtained 
from a chemical supply company.  Studies that use a drug product that is prepared from raw 
materials in place of the approved, finished product marketed by the manufacturer must be 
conducted under an IND (21 CFR part 312).  These studies cannot meet the criteria for an 
exemption from the IND requirements for marketed drugs ( 312.2(b)) because the drug product 
manufactured by the investigator or research pharmacy is not considered to be the lawfully 
marketed drug.   
 
11.    Do I need an IND if my study enrolls only a small number of subjects? 
 
The number of subjects enrolled has no bearing on whether the study is subject to the IND 
regulations.  The definition of clinical investigation specifically includes studies with as few as 
one subject (see section III.B). 
  17  Contains Nonbinding Recommendations 
 
 
12.    Do I need an IND if my study enrolls only healthy volunteers? 
 
The clinical condition of study subjects (e.g., the presence or absence of disease) has no bearing 
on whether the study is subject to the IND requirements in part 312.  The definition of clinical 
investigation refers only to subjects involved in an experiment.  It makes no distinction between 
healthy subjects or those with a disease (see section III.B).   
 
VIII.  PROCESS FOR ADDRESSING INQUIRIES CONCERNING THE 
APPLICATION OF THE IND REQUIREMENTS   
 
The sponsor (or sponsor-investigator of an individual investigator-initiated study) should, in 
most cases, be able to determine whether the IND regulations apply to a planned clinical 
investigation as required under 21 CFR 312.2(a).  If a sponsor is uncertain, however, we 
recommend that the sponsor contact the appropriate review division (i.e., for the therapeutic area 
being studied) in the appropriate FDA center for advice about whether the IND regulations apply 
(21 CFR 312.2(e)).  For products regulated by CDER, an inquiry concerning the application of 
the IND regulations should be directed to the Chief, Project Management Staff, in the 
appropriate CDER review division.  For products regulated by CBER, the inquiry should be 
directed to the applications division of the appropriate review Office.  
 
  Organizational charts listing the CDER review divisions and their telephone numbers are 
available on the Internet at 
http://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm135674.htm.  
  Organizational charts listing the CBER review divisions and their telephone numbers are 
available on the Internet at http://www.fda.gov/AboutFDA/CentersOffices/ 
OrganizationCharts/ucm135943.htm.  
  If the relevant review division is not known, we recommend the sponsor contact CDERs 
Division of Drug Information (druginfo@fda.hhs.gov) or CBERs Division of 
Manufacturers Assistance and Training (matt@cber.fda.gov), Office of Communication, 
Outreach and Development (both addresses and telephone numbers are provided on the 
second title page of this guidance).  
FDA will categorize inquiries concerning the application of the IND regulations as either 
informal or formal based on the following factors: 
 
  The medium in which the inquiry is received 
  The relative complexity of the inquiry 
  The type of response requested by the inquirer or given by FDA 
  
Informal inquiries have the following features: 
 
  They can be communicated either orally or in writing (written communication includes 
email, fax, or other written correspondence). 
  18  Contains Nonbinding Recommendations 
 
  They pose only relatively uncomplicated questions about a planned clinical investigation 
that FDA can answer based on somewhat limited information. 
  The inquirer is not seeking a formal written response. 
In response to an inquiry intended to be informal, FDA can (1) provide an informal (qualified, 
nonbinding) response, either orally or in writing, concerning the applicability of the IND 
regulations based on its understanding of the planned clinical investigation; (2) ask for additional 
information before providing an informal response; or (3) determine that the inquiry poses a 
complex question that should be submitted as a formal inquiry.  FDA will not retain and track 
informal responses to inquiries concerning the applicability of the IND regulations to planned 
clinical investigations.   
 
Formal inquiries have all of the following features: 
 
  They are in writing (can be paper or electronic). 
  They pose a question of any level of complexity. 
  The inquirer is seeking a formal written response or FDA determines that a formal 
written response should be given (i.e., that the inquiry cannot be answered informally).  
  The documentation contains enough detail to permit FDA to provide a formal response 
concerning the applicability of the IND regulations to a planned clinical investigation 
(e.g., a study protocol, information about the drug product). 
 
In response to a formal inquiry, FDA may provide a formal written response concerning the 
application of the IND requirements to a planned clinical investigation or may determine that it 
has insufficient information to provide a formal response and seek additional information before 
providing a response.  The scope of any formal response would be limited to the conduct of a 
clinical investigation consistent with the investigation described in documentation provided to 
FDA.  If there are significant changes to the protocol or other aspects of the planned 
investigation after FDA has provided a response, that response may no longer be valid.  FDA 
will archive formal inquiries and FDA responses to those inquiries. 
 
 
  19  Contains Nonbinding Recommendations 
 
APPENDIX 
 
Other Guidances that May Be Relevant to Questions Concerning  
the Application of the IND Requirements 
 
FDA has issued guidances in related areas.  Interested persons may wish to refer to the following 
documents, available on the Internet at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm:     
 
  Guidance for industry on Botanical Drug Products, which includes guidance on submitting 
INDs for botanical drug products, including those botanical products currently lawfully 
marketed as foods (including conventional foods and dietary supplements) in the United 
States. 
  Guidance for industry, investigators, and reviewers on Exploratory IND Studies, which is 
intended to clarify what preclinical and clinical approaches, as well as chemistry, 
manufacturing, and controls information, should be considered when planning exploratory 
studies in humans, including studies of closely related drugs or therapeutic biological 
products, under an IND.  
  Guidance for industry on CGMP for Phase 1 Investigational Drugs.   
  Guidance for industry and researchers on The Radioactive Drug Research Committee: 
Human Research Without an Investigational New Drug Application, which is intended to 
clarify whether research using a radioactive drug must be conducted under an IND (21 
CFR part 312), may be exempt from IND requirements (21 CFR 312.2(b)), or if certain 
conditions are met, can be conducted under the supervision and approval of an FDA-
approved Radioactive Drug Research Committee (21 CFR 361.1) without an IND.  In 
addition, FDA has established a Web site at 
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Oncology/default.htm for easy 
access to information by IRBs, clinical investigators, sponsors, and others. 
  Guidance for industry and FDA staff on FDA Acceptance of Foreign Clinical Studies Not 
Conducted Under an IND:  Frequently Asked Questions, which is intended to clarify for 
sponsors how they can demonstrate compliance with the requirements of 21 CFR 312.120, 
as well as provide recommendations for the submission of information, whether in an IND 
or application for marketing approval for a drug or biological drug product, to demonstrate 
that a non-IND foreign clinical study was conducted in accordance with GCP. 
  Guidance on Emergency Use Authorization of Medical Products, which is intended to 
inform industry, government agencies, and FDA staff of the Agencys general 
recommendations and procedures for issuance of Emergency Use Authorizations (EUAs). 
 
  20