Guidance for Industry,
Investigators, and Reviewers
Exploratory IND Studies

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2006
Pharmacology/Toxicology

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12/29/05

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Guidance for Industry,
Investigators, and Reviewers
Exploratory IND Studies
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2006
Pharmacology/Toxicology

Contains Nonbinding Recommendations

TABLE OF CONTENTSI.

INTRODUCTION............................................................................................................. 1II.

BACKGROUND ............................................................................................................... 2A.

Traditional Phase 1 Approach...................................................................................................... 2

B.

Exploratory IND Approach .......................................................................................................... 3

III.

CONTENT OF IND SUBMISSIONS ............................................................................. 5A.

Clinical Information ...................................................................................................................... 5

1. Introductory statement and general investigational plan ................................................................ 5
2. Types of studies ................................................................................................................................ 5
B. Chemistry, Manufacturing, and Controls Information ............................................................. 6
1. General information for the candidate product............................................................................... 6
2. Analytical characterization of candidate product ........................................................................... 8
C. Safety Program Designs — Examples.......................................................................................... 8
1. Clinical studies of pharmacokinetics or imaging ............................................................................ 9
2. Clinical trials to study pharmacologically relevant doses............................................................. 10
3. Clinical studies of MOAs related to efficacy ................................................................................. 11
D. GLP Compliance.......................................................................................................................... 12IV.

CONCLUSION ............................................................................................................... 12

ATTACHMENT ......................................................................................................................... 13

Contains Nonbinding Recommendations

Guidance for Industry and Reviewers1
Exploratory IND Studies

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
Alternative approaches can be used if the approach satisfies the requirements of the applicable statutes
and regulations. Discussions of an alternative approaches can be scheduled by contacting the FDA staff
responsible for implementing this guidance. If the appropriate FDA staff cannot be located, contact canbe made using the telephone number listed on the title page of this guidance.

I.

INTRODUCTION

This guidance 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 biologicalproducts, under an investigational new drug (IND) application (21 CFR 312). Existing
regulations allow a great deal of flexibility in the amount of data that needs to be submitted withan IND application, depending on the goals of the proposed investigation, the specific humantesting proposed, and the expected risks. The Agency believes that sponsors have not taken fulladvantage of that flexibility and often provide more supporting information in INDs than isrequired by regulations. This guidance is intended to clarify what manufacturing controls,
preclinical testing, and clinical approaches can be considered when planning limited, early
exploratory IND studies in humans.
For the purposes of this guidance the phrase exploratory IND study is intended to describe aclinical trial that- is conducted early in phase 1,- involves very limited human exposure, and- has no therapeutic or diagnostic intent (e.g., screening studies, microdose studies).

1

This guidance was developed by the Office of New Drugs in the Center for Drug Evaluation and Research(CDER).
This guidance contains information collection provisions that are subject to review by the Office of Management
and Budget under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The collection of information inthis guidance has been approved under OMB Control No. 0910-0014.

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Such exploratory IND studies are conducted prior to the traditional dose escalation, safety, andtolerance studies that ordinarily initiate a clinical drug development program. The duration of
dosing in an exploratory IND study is expected to be limited (e.g., 7 days). This guidance
applies to early phase 1 clinical studies of investigational new drug and biological products thatassess feasibility for further development of the drug or biological product.2
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements arecited. The use of the word should in Agency guidances means that something is suggested orrecommended, but not required.

II.

BACKGROUND

In its March 2004 Critical Path Report,3 the Agency explained that to reduce the time andresources expended on candidate products that are unlikely to succeed,4 new tools are needed to
distinguish earlier in the process those candidates that hold promise from those that do not. This
guidance describes some early phase 1 exploratory approaches that are consistent with regulatory
requirements while maintaining needed human subject protection, but that involve fewer
resources than is customary, enabling sponsors to move ahead more efficiently with thedevelopment of promising candidates.
A.

Traditional Phase 1 Approach

Typically, during pharmaceutical development, large numbers of molecules are generated withthe goal of identifying the most promising candidates for further development. These molecules
are generally structurally related, but can differ in important ways. Promising candidates areoften selected using in vitro testing models that examine binding to receptors, effects on enzyme
activities, toxic effects, or other in vitro pharmacologic parameters; these tests usually require
only small amounts of the drug. Candidates that are not rejected during these early tests areprepared in greater quantities for in vivo animal testing for efficacy and safety. Commonly, asingle candidate is selected for an IND application and introduction into human subjects, initiallyhealthy volunteers in most cases.
Before the human studies can begin, an IND must be submitted to the Agency containing, among
other things, information on any risks anticipated based on the results of pharmacologic and2Specifically, this guidance is limited to drug and certain well-characterized therapeutic biological products (e.g.,
recombinant therapeutic proteins and monoclonal antibodies) regulated by CDER. The guidance does not apply tohuman cell or tissue products, blood and blood proteins, vaccines, or to products regulated as devices.
3

Innovation or Stagnation, Challenge and Opportunity on the critical Path to New Medical Products (March 2004).

4"A new medical compound entering phase 1 testing, often representing the culmination of upwards of a decade ofpreclinical screening and evaluation, is estimated to have only an 8 percent chance of reaching the market," Critical
Path Report, March 2004.

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toxicological data collected during studies of the drug in animals (21 CFR 312.23(a)(8)). These
basic safety tests are most often performed in rats and dogs. The studies are designed to permit
the selection of a safe starting dose for humans, to gain an understanding of which organs may be
the targets of toxicity, to estimate the margin of safety between a clinical and a toxic dose, and to
predict pharmacokinetic and pharmacodynamic parameters. These early tests are usually
resource intensive, requiring significant investment in product synthesis, animal use, laboratory
analyses, and time. Many resources are invested in, and thus wasted on, candidate products that
subsequently are found to have unacceptable profiles when evaluated in humans — less than 10
percent of INDs for new molecular entities (NME) progress beyond the investigational stage tosubmission of a marketing application (NDA).3 In addition, animal testing does not always
predict performance in humans, and potentially effective candidates may not be developed
because of resource constraints.
Existing regulations allow a great deal of flexibility in terms of the amount of data that need tobe submitted with any IND application, depending on the goals of the proposed investigation, thespecific human testing proposed, and the expected risks. The Agency believes that sponsors
have not taken full advantage of that flexibility. As a result, limited, early phase 1 studies, suchas those described in this guidance, are often supported by a more extensive preclinical databasethan is required by the regulations.
This guidance describes preclinical and clinical approaches, and the chemistry, manufacturing,and controls information that should be considered when planning exploratory IND studies inhumans, including studies of closely related drugs or therapeutic biological products, under asingle IND application (21 CFR 312).
B.

Exploratory IND Approach

Exploratory IND studies usually involve very limited human exposure and have no therapeuticor diagnostic intent. Such studies can serve a number of useful goals. For example, an
exploratory IND study can help sponsors•

Determine whether a mechanism of action defined in experimental systems can also be
observed in humans (e.g., a binding property or inhibition of an enzyme)•

Provide important information on pharmacokinetics (PK)•

Select the most promising lead product from a group of candidates5 designed to interact
with a particular therapeutic target in humans, based on PK or pharmacodynamic (PD)properties

5

For the purposes of this guidance, the term candidate, or candidate product, is used to describe a drug or biologic
that is being tested in early exploratory studies under an IND. This guidance does not distinguish between a drug
product and a drug substance as some other Agency guidances do.
(Most guidances use the term drug product to refer to a finished dosage form (e.g., tablet, capsule, solution) that
contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients, or afinished dosage form that does not contain an active ingredient but is intended to be used as a placebo. Drug
substance usually refers to any component that is intended to furnish pharmacological activity or other direct effect3

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Explore a product’s biodistribution characteristics using various imaging technologies

Whatever the goal of the study, exploratory IND studies can help identify, early in the process,promising candidates for continued development and eliminate those lacking promise. As aresult, exploratory IND studies may help reduce the number of human subjects and resources,
including the amount of candidate product, needed to identify promising drugs. The studies
discussed in this guidance involve dosing a limited number of subjects with a limited range ofdoses for a limited period of time.
Existing regulations provide more flexibility with regard to the preclinical testing requirements
for exploratory IND studies than for traditional IND studies. However, sponsors submitting thekinds of studies described in this guidance have not always taken full advantage of thatflexibility. Sponsors often provide more supporting information in their INDs than is requiredby the regulations. Because exploratory IND studies involve administering either subpharmacologic doses of a product, or doses expected to produce a pharmacologic, but not a toxic,
effect, the potential risk to human subjects is less than for a traditional phase 1 study that, forexample, seeks to establish a maximally tolerated dose. Because exploratory IND studies
present fewer potential risks than do traditional phase 1 studies that look for dose-limiting
toxicities, such limited exploratory IND investigations in humans can be initiated with less, ordifferent, preclinical support than is required for traditional IND studies.6
The Agency expects that this early phase 1 exploratory IND approach will apply to a number ofdifferent study paradigms. Although his guidance explores several potential applications, manyothers can be proposed. The Agency believes that, consistent with its Critical Path Initiative,
clarifying Agency thinking about how much and what kind of testing is needed to support earlystudies in humans will facilitate the entry of new products into clinical testing and speed productdevelopment.
Although exploratory IND studies may be used during development of products intended for any
indication, it is particularly important for manufacturers to consider this approach whendeveloping products to treat serious diseases. Because the approach can help identify promising
candidates more quickly and precisely, exploratory IND studies could become an important partof the armamentarium when developing drug and biological products to treat a serious or lifethreatening illness. The Agency has previously articulated its commitment to ensuring thatappropriate flexibility is applied when patients with a serious disease and no satisfactory
alternative therapies are enrolled in a trial with therapeutic intent.7

in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the
body.)
6

Generally, these types of studies would not be carried out in pediatric patients or in pregnant or lactating women.

7

Subpart H Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses. See also FDA guidance
for industry Fast Track Drug Development Programs — Designation, Development, and Application Review.

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III.

CONTENT OF IND SUBMISSIONS

To begin any kind of testing in humans, applicants must submit an IND application to the
Agency with certain types of information (see 21 CFR 312.23 IND Content and Format). The
primary purpose of the IND submission is to ensure that subjects will not face undue risk ofharm. The major information that must be submitted includes:••••

Information on a clinical development plan
Chemistry, manufacturing, and controls information
Pharmacology and toxicology information
Previous human experience with the investigational candidate or related compounds,
if there is any

The following sections discuss the first three in more detail. Because the exploratory IND
studies addressed by this guidance will be first in human studies, previous human experience is
not pertinent and will not be discussed. The common theme throughout is that, depending on the
study, the informational requirements for exploratory IND studies are more flexible than fortraditional IND studies.
A.

Clinical Information

1.

Introductory statement and general investigational plan

A traditional IND application describes the rationale for the proposed clinical trial program anddiscusses the potential outcome of the clinical investigation. The exploratory IND studies
discussed here focus on a circumscribed study or group of studies, and plans for further
development cannot be formulated without the results of these studies. Therefore, an exploratory
IND application should articulate the rationale for selecting a compound (or compounds) and forstudying them in a single trial or related trials, as this represents all that is known about theoverall development plan at this stage. This section should also make it clear that the IND isintended to be withdrawn8 after completion of the outlined study or studies.
2.

Types of studies

Potentially useful study designs include both single- and multiple-dose studies. In single-dosestudies, a sub-pharmacologic9 or pharmacologic dose is administered to a limited number ofsubjects (healthy volunteers or patients). For example, microdose studies usually involve thesingle administration of a small dose with the goal of collecting pharmacokinetic information or
performing imaging studies, or both.
8

The withdrawn, or inactive, IND can be referenced in any subsequent traditional IND.

9

A radiolabeled candidate compound can be administered at doses that are known to have no pharmacologic effectin humans without an IND application in basic research studies when the compound has previously been studied inhumans and the results published in the literature. These basic research investigations are conducted under theoversight of an institutional review board (IRB) and a radioactive drug research committee (21 CFR 361.1).

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Repeat dose clinical studies can be designed with pharmacologic or pharmacodynamic
endpoints. In exploratory IND studies, the duration of dosing should be limited (e.g., 7 days).
For escalating dose studies done under an exploratory IND, dosing should be designed toinvestigate a pharmacodynamic endpoint, not to determine the limits of tolerability.
B.

Chemistry, Manufacturing, and Controls Information

The regulations at 21 CFR 312.23(a)(7)(i) emphasize the graded nature of chemistry,
manufacturing, and controls (CMC) information needed as development under an IND
application progresses. Although in each phase of a clinical investigational program sufficient
information should be submitted to ensure the proper identification, strength, quality, purity, andpotency of the investigational candidate, the amount of information that will provide thatassurance will vary with the phase of the investigation, the proposed duration of theinvestigation, the dosage form, and the amount of information already available. For the purposeof an exploratory IND application, the CMC information indicated below can be provided in asummary report to enable the Agency to make the necessary safety assessment.
The sponsor must state in the beginning of the exploratory IND application whether it believes
the chemistry or manufacturing of the candidate product presents any potential for human risk(e.g., specific findings in preclinical studies associated with known risks of related compounds)(§ 312.23). If so, these potential risks should be discussed, and the steps proposed to monitor forsuch risks should be described.
The Agency is in the process of developing guidance explaining the stepwise approach tomeeting current good manufacturing practice (CGMP) regulations. Once finalized, that guidance
will be useful to persons seeking to manufacture, or prepare, products intended for use in an
exploratory IND study.
1.

General information for the candidate product

Except as noted below, the extent and type of chemistry and manufacturing information to besubmitted in an exploratory IND application is similar to that described in current guidance foruse of investigational products.10 Information on each candidate product (i.e., the active
ingredient) can be submitted in a summary report containing the following items.
•

Description of the candidate product, including physical, chemical, and/or biologicalcharacteristics, as well as its source (e.g., synthetic, animal source, plant extract, or
biotechnology-derived) and therapeutic class (e.g., radiopharmaceutic,
immunosuppressant, agonist, antagonist) (see sections below for exceptions).

•

Description of the dosage form and information related to the dosage form

10

See guidance for industry Content and Format of Investigational New Drug Applications for Phase 1 Studies ofDrugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products.

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Description of the formulation or routes of administration intended to be used in thehuman trial. For oral administration, sponsors can consider using suspensions or
solutions in addition to the more usual tablets, powders, and capsules. For products
intended for ophthalmic, inhalational (aqueous base), or parenteral administration,sterility and apyrogenicity must be ensured. For biological candidate products, freedom
from contaminants associated with their manufacture, such as viruses, mycoplasma, andforeign DNA, also should be ensured. All excipients should be generally recognized assafe11 or part of a formulation that is approved or licensed in the United States for thesame route of administration and amount,12 or adequately qualified through appropriate
animal studies.

•

The grade and quality (e.g., USP, NF, ACS) of excipients used in the manufacture of theinvestigational candidate product, including both those components intended to appear in
the product and those that may not appear, but that are used in the manufacturing process•

Name and address of the manufacturer(s) (if different from the sponsor)•

The method of preparation of the candidate product lots used in preclinical studies andintended for the proposed human study, including a brief description of the method of
manufacture and the packaging procedure, as appropriate, with a description of thecontainer and closure system. For the active substance, include a list of the starting
materials, reagents, solvents, catalysts used, and purification steps employed to prepare
the candidate product. For sterile products, describe the sterilization process and controls
for ensuring sterility. For biological/biotechnology-derived products, also identify thesource material (e.g., Master Cell Bank), describe the expression system (e.g.,fermentation methods) and harvest methods, as well as methods for removal/inactivationof potential viral contaminants. We recommend the use of a detailed flow diagram that
includes all materials used as the usual, most effective, presentation of this information.

•

Quantitative composition of the product•A brief description of adequate test methods used to ensure the identity, strength, quality,
purity, and potency accompanied by the test results, or a certificate of analysis, of thecandidate product lots used in toxicological studies and intended for the proposed humanstudy. For biotechnology products produced in mammalian cells or animals, this will
include tests and studies to ensure the removal and/or inactivation of potential viralcontaminants.

•

Information that demonstrates the stability of the product during toxicology studies andan explanation of how stability will be evaluated during the clinical studies

11

Excipients considered to be generally recognized as safe (GRAS) are included in a list that is maintained on theInternet at http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. See also 21 CFR 330.1, which explains the
GRAS concept.

12

Novel excipients should be appropriately qualified for their intended use. FDA has issued guidance on
Nonclinical Studies for Development of Pharmaceutical Excipients.

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For ophthalmic, inhalational (aqueous base), or parenteral dosage forms, results fromsterility and pyrogenicity tests
2.

Analytical characterization of candidate productThere are two scenarios under which CMC information can be provided to an IND application.
In the first scenario, the same batch of candidate product is used in both the toxicology studies
and clinical trials. This material will be qualified for human use based on the CMC information(see III.B.1, above) and results of the toxicology studies described elsewhere in this guidance.
Although we recommend establishing the impurity profile to the extent possible for futurereference and/or comparison, not all impurities of the candidate product may needcharacterization at this stage of product development. If an issue arises during the toxicology
qualification of the product, the appropriate parameters can be studied further, on an as-neededbasis. Impurities (e.g., chemical and microbiological) should be characterized in accordancewith recommendations in Agency guidance,13 if, and when, the sponsor files a traditional IND
for further clinical investigation.
In the second scenario, the batch of candidate drug product to be used in the clinical studies may
not be the same as that used in the nonclinical toxicology studies. In such a case, the sponsor
should demonstrate by analytical testing that the batch to be used is representative of batches
used in the nonclinical toxicology studies. To achieve this, relevant analytical quality test results
should be sufficient to enable comparison of different batches of the product. Tests toaccomplish this include:
•
•
•
•
•
•
•
C.

Identity
Structure (e.g., optical rotation (for chiral compounds), reducing/non-reducing
electrophoresis (for proteins))
Assay for purity
Impurity profile (e.g., product- and process-related impurities, residual solvents,
heavy metals)
Assay for potency (biologic)
Physical characteristics (as appropriate)
Microbiological characteristics (as appropriate)
Safety Program Designs — Examples

Pharmacology and toxicology information is derived from preclinical safety testing performed inanimals and in vitro. Preclinical studies for small molecules are described in ICH M3 while
those for biologics follow guidance described in ICH S6. Some of the toxicology tests describedin this guidance may not be appropriate for biologics. The toxicology evaluation recommended
for an exploratory IND application is more limited than for a traditional IND application.14 The
13

See footnote 10 and guidance for industry, INDs for Phase 2 and Phase 3 Studies, Chemistry, Manufacturing,and Controls Information.

14

International Conference on Harmonisation (ICH) guidance for industry M3 Nonclinical Safety Studies for the
Conduct of Human Clinical Trials for Pharmaceuticals describes what is expected for a traditional IND.

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basis for the reduced preclinical package is the reduced scope of an exploratory IND clinicalstudy. Although exploratory IND studies in some cases are expected to induce pharmacologic
effects, they are not designed to establish maximally tolerated doses. Furthermore, the durationof drug exposure in exploratory IND studies is limited. The level of preclinical testing
performed to ensure safety will depend on the scope and intended goals of the clinical trials.
There are a number of study objectives for which the preclinical safety programs may be tailoredto the study design. Examples include: confirming that an expected mechanism of action can beobserved in humans; measuring binding affinity or localization of drug; assessing PK andmetabolism; comparing the effect on a potential therapeutic target with other therapies. Three
examples are discussed in detail in the following paragraphs.
1.

Clinical studies of pharmacokinetics or imaging

Microdose studies are designed to evaluate pharmacokinetics or imaging of specific targets andare designed not to induce pharmacologic effects. Because of this, the risk to human subjects isvery limited, and information adequate to support the initiation of such limited human studies
can be derived from limited nonclinical safety studies. A microdose is defined as less than
1/100th of the dose of a test substance calculated (based on animal data) to yield a pharmacologic
effect of the test substance with a maximum dose of <100 micrograms (for imaging agents, thelatter criterion applies).15 Due to differences in molecular weights as compared to synthetic
drugs, the maximum dose for protein products is ≤30 nanomoles.
FDA currently accepts the use of extended single-dose toxicity studies in animals to support
single-dose studies in humans. For microdose studies, a single mammalian species (both sexes)
can be used if justified by in vitro metabolism data and by comparative data on in vitro
pharmacodynamic effects. The route of exposure in animals should be by the intended clinicalroute. In these studies, animals should be observed for 14 days post-dosing with an interim
necropsy, typically on day 2, and endpoints evaluated should include body weights, clinicalsigns, clinical chemistries, hematology, and histopathology (high dose and control only if nopathology is seen at the high dose). The study should be designed to establish a dose inducing aminimal toxic effect, or alternatively, establishing a margin of safety. To establish a margin ofsafety, the sponsor should demonstrate that a large multiple (e.g., 100X) of the proposed humandose does not induce adverse effects in the experimental animals. Scaling from animals tohumans based on body surface area can be used to select the dose for use in the clinical trial.
Scaling based on pharmacokinetic/pharmacodynamic modeling would also be appropriate if suchdata are available.
Because microdose studies involve only single exposures to microgram quantities of test
materials and because such exposures are comparable to routine environmental exposures,
routine genetic toxicology testing is not needed. For similar reasons, safety pharmacology
studies are also not recommended.

15

See European Medicines Agency (EMEA), Evaluation of Medicines for Human Use, "Position Paper on NonClinical Safety Studies to Support Clinical Trials with a Single Microdose," CPMP/SWP/2599/02Rev 1, 23 June
2004.

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2.

Clinical trials to study pharmacologically relevant doses

A second example involves clinical trials designed to study pharmacologic effects of candidate
products. More extensive preclinical safety data would be needed to support the safety of suchstudies. However, since the goal would not include defining a maximally tolerated dose, theevaluation can still be less extensive than typically needed to support a traditional IND
application. See the flow chart in the Attachment to this document.
Repeat dose clinical trials lasting up to 7 days can be supported by a 2-week repeat dose
toxicology study in a sensitive species accompanied by toxicokinetic evaluations. The goal ofsuch a study would be to select safe starting and maximum doses for the clinical trial. The rat is
the usual species chosen for this purpose, but other species might be selected. In addition to
studies in a rodent species, additional studies in nonrodents, most often dogs, can be used toconfirm that the rodent is an appropriately sensitive species. If it is known that a particularspecies is most appropriate for a class of compounds, studies can be limited to that species. Thisconfirmation can be approached in a number of ways. A lack of gender difference in the rodent
study can serve as a basis for testing only a single sex in the second species if only a single sex
will be studied in the clinical trial.
The numbers of animals used in the confirmatory study can be fewer than normally used to attainstatistically meaningful comparisons, but of sufficient number to rule out any toxicologicallysignificant difference in sensitivity compared with rodent (e.g. four non-rodents per treatmentgroup). The confirmatory study could be a dedicated study involving repeat administrations of asingle dose level approximating the rat NOAEL16 calculated on the basis of body surface area.
Alternatively, the test in the second species could be incorporated as part of an exploratory, dose
escalating study culminating in repeated doses equivalent to the rat NOAEL. The number of
repeat administrations at the rat NOAEL should, at a minimum, be equal to the number ofadministrations, given with the same schedule, intended clinically. The route of administration
should be the same as the expected clinical route, and toxicokinetic measurements should be
used to assess exposure. The same endpoints assessed in the rodent study should be evaluated in
the second species. If the data from the confirmatory study suggest that the rodent is not themore sensitive species, a 2-week repeated dose toxicity study should be performed in the second
species to select doses for human trials. This study should include measurements of bodyweight, clinical signs, clinical chemistries, hematology, and histopathology.
In contrast to microdose studies, for clinical trials designed to evaluate higher or repeated doses,
each candidate product to be tested should be evaluated for safety pharmacology.17 Evaluationof the central nervous and respiratory systems can be performed as part the rodent toxicology
studies while safety pharmacology for the cardiovascular system can be assessed in the
nonrodent species, generally the dog, and can be conducted as part of the confirmatory or doseescalation study.

16

No-observed-adverse-effect level (NOAEL).

17

For details see the guidance for industry S7A Safety Pharmacology Studies for Human Pharmaceuticals.

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In general, each product in this type of exploratory IND should be tested for potential
genotoxicity unless such testing is not appropriate for the population (e.g. terminally ill patients)
or product to be studied. The genetic toxicology tests should include a bacterial mutation assay
using all five tester strains with and without metabolic activation18 as well as a test for
chromosomal damage either in vitro (cytogenetics assay or mouse lymphoma thymidine kinase
gene mutation assay) or in vivo. The in vivo test can be a micronucleus assay performed inconjunction with the repeated dose toxicity study in the rodent species. The high dose in thiscase should be a maximally tolerated or limit dose.
The results from the preclinical program can be used to select starting and maximum doses forthe clinical trials. The starting dose is anticipated to be no greater than 1/50 of the NOAEL fromthe 2-week toxicology study in the sensitive species on a mg/m2 basis. The maximum clinicaldose would be the lowest of the following:••••¼ of the 2-week rodent NOAEL on a mg/m2 basis
Up to ½ of the AUC at the NOAEL in the 2-week rodent study, or the AUC in the dog at
the rat NOAEL, whichever is lower
The dose that produces a pharmacologic and/or pharmacodynamic response or at whichtarget modulation is observed in the clinical trial
Observation of an adverse clinical response

Escalation from the proposed maximal clinical dose should only be performed after consultation
with and concurrence of the FDA.
It is recognized that the studies described above are most appropriate for chemical drugs. Other
animal models (e.g. nonhuman primates) may be more appropriate for biologics, and some tests
may be inappropriate (e.g. genetic toxicology testing) for proteins.
3.

Clinical studies of MOAs related to efficacy

A third example involves clinical studies intended to evaluate mechanisms of action (MOAs).
To support this approach, the FDA will accept alternative, or modified, pharmacologic andtoxicological studies to select clinical starting doses and dose escalation schemes. For example,
short-term, modified toxicity or safety studies in two animal species based on a dosing strategy
to achieve a clinical pharmacodynamic endpoint can in some instances serve as the basis forselecting the safe clinical starting dose for a new candidate drug. These animal studies would
incorporate endpoints that are mechanistically based on the pharmacology of the new chemical
entity and thought to be important to clinical effectiveness. For example, if the degree ofsaturation of a receptor or the inhibition of an enzyme were considered possibly related toeffectiveness, this parameter would be characterized and determined in the animal study and thenused as an endpoint in a subsequent clinical investigation. The dose and dosing regimen
determined in the animal study would be extrapolated for use in the clinical investigation. In
some cases, a single species could be used if it were established as the most relevant species
based on scientific evidence using the specific candidate intended for the clinical investigation.
18

For details see guidance for industry S2A: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for
Pharmaceuticals and S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing for Pharmaceuticals.

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Although the production of frank toxicity is not the primary intended goal of the nonclinicalstudy, relevant informative endpoints (e.g., hematology and histopathology) selected asimportant for clinical safety evaluation should be investigated. For example, an antibody thatbinds with a high degree of selectivity to a tumor-associated antigen could be studied inaccordance with this third category. The mechanism of action of antibody-based products isgenerally associated with their binding properties and the effect on functions associated withimmunoglobulins. Pharmacology and toxicology studies provide information about the selectionof doses used in clinical studies through evidence of both a safe upper and potentially efficacious
lower limit of exposure. These doses might be consistent with target plasma levels of the drug
based on animal models of disease. The upper safe levels could be established in animal studies
that show a lack of toxicity at these levels.
D.

GLP Compliance

It is expected that all preclinical safety studies supporting the safety of an exploratory IND
application will be performed in a manner consistent with good laboratory practices (GLP) (21
CFR Part 58). The GLP provisions apply to a broad variety of studies, test articles, and test
systems. Sponsors are encouraged to discuss any need for an exemption from GLP provisions
with the FDA prior to conducting safety related studies, for example, during a pre-IND meeting.
Sponsors must justify any nonconformance with GLP provisions (21 CFR 312.23(a)(8)(iii)).

IV.

CONCLUSION

Existing regulations allow a great deal of flexibility in the amount of data that needs to besubmitted with any IND application, depending on the goals of an investigation, the specifichuman testing being proposed, and the expected risks. Sponsors have not taken full advantage ofthat flexibility, and limited, early phase 1 studies, such as those described in this guidance, areoften supported by a more extensive preclinical database than is needed for those studies alone.
The common theme throughout this guidance is that, depending on the study, the preclinicaltesting programs for exploratory IND studies can be less extensive than for traditional IND
studies. This is because for the approaches discussed in this guidance, which involve
administering sub-pharmacologic doses of a candidate product or products, the potential risks tohuman subjects are less than for a traditional phase 1 study.
The Agency is undertaking a number of efforts to reduce the time spent in early drug
development on products that are unlikely to succeed. This guidance describes some exploratory
approaches that are consistent with regulatory requirements, but that will enable sponsors tomove ahead more efficiently with the development of promising candidate products while
maintaining needed human subject protections.

12Contains Nonbinding Recommendations
ATTACHMENT
A Preclinical Toxicology Testing Strategy for Exploratory INDs Designed To Administer
Pharmacologically Active Doses
SafetyPharmacology
CNS Pulmonary

2-week toxicology
study in rodent
species

In vivomicronucleus

Establishment of NOAEL

Repeat dose toxicology
study in nonrodent

SafetyPharmacology
CV

Nonrodent moresensitive
Nonrodent
equivalent or lesssensitive
Candidateexcluded fromexp IND

2-week tox
study innonrodent

Calculation of clinical start
dose, 1/50 of rat NOAEL

Calculation of clinicalstop dose (whichever islowest)Achievement ofpharmacologicaleffect or target
modulation

Clinical equivalent
to 1/4 rat NOAEL

13

Observation ofadverse clinicalresponse

Clinical equivalent of 1/2 of
AUC in rat or the nonrodent
AUC - whichever is lower