Guidance for
Industry and Reviewers
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 can be made using the telephone number
listed on the title page of this guidance.
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 biological products, 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 with an IND application, depending
on the goals of the proposed investigation, the specific human
testing proposed, and the expected risks. The Agency believes that
sponsors have not taken full advantage of that flexibility and
often provide more supporting information in INDs than is required
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 a clinical
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).
Such exploratory IND studies are conducted
prior to the traditional dose escalation, safety, and tolerance
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 that assess feasibility for further
development of the drug or biological product.
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 are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
In its March 2004 Critical Path Report,
the Agency explained that to reduce the time and resources
expended on candidate products that are unlikely to succeed,
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 the development of promising candidates.
Typically, during pharmaceutical development,
large numbers of molecules are generated with the goal of
identifying the most promising candidates for further
development. These molecules are generally structurally related,
but can differ in important ways. Promising candidates are often
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 are prepared in greater quantities for in
vivo animal testing for efficacy and safety. Commonly, a single
candidate is selected for an IND application and introduction into
human subjects, initially healthy 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 and 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
to submission 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 to be
submitted with any IND application, depending on the goals of the
proposed investigation, the specific 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, such as those described in this guidance,
are often supported by a more extensive preclinical database than
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 in humans, including studies
of closely related drugs or therapeutic biological products, under
a single IND application (21 CFR 312).
Exploratory IND studies usually involve very
limited human exposure and have no therapeutic or 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 candidates
designed to interact with a particular therapeutic target in
humans, based on PK or pharmacodynamic (PD) properties
- 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 a result, 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 of doses 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 the kinds of studies described in
this guidance have not always taken full advantage of that
flexibility. Sponsors often provide more supporting information
in their INDs than is required by the regulations. Because
exploratory IND studies involve administering either
sub-pharmacologic 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,
for example, 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, or different, preclinical support than
is required for traditional IND studies.
The Agency expects that this early phase 1
exploratory IND approach will apply to a number of different study
paradigms. Although his guidance explores several potential
applications, many others 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 early studies in humans will facilitate the entry of
new products into clinical testing and speed product development.
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
when developing products to treat serious diseases. Because the
approach can help identify promising candidates more quickly and
precisely, exploratory IND studies could become an important part
of the armamentarium when developing drug and biological products
to treat a serious or life-threatening illness. The Agency has
previously articulated its commitment to ensuring that appropriate
flexibility is applied when patients with a serious disease and no
satisfactory alternative therapies are enrolled in a trial with
therapeutic intent.
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
of harm. 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 for traditional IND studies.
A
traditional IND application describes the rationale for the
proposed clinical trial program and discusses 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 for studying them in a single trial or
related trials, as this represents all that is known about the
overall development plan at this stage. This section should also
make it clear that the IND is intended to be withdrawn
after completion of the outlined study or studies.
Potentially useful study designs include both
single- and multiple-dose studies. In single-dose studies, a
sub-pharmacologic
or pharmacologic dose is administered to a limited number of
subjects (healthy volunteers or patients). For example, microdose
studies usually involve the single administration of a small dose
with the goal of collecting pharmacokinetic information or
performing imaging studies, or both.
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, and potency of the investigational candidate, the
amount of information that will provide that assurance will vary
with the phase of the investigation, the proposed duration of the
investigation, the dosage form, and the amount of information
already available. For the purpose of an exploratory IND
application, the CMC information indicated below can be provided
in a summary 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 for
such risks should be described.
The Agency is in the process of developing
guidance explaining the stepwise approach to meeting 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.
Except as noted below, the extent and type of
chemistry and manufacturing information to be submitted in an
exploratory IND application is similar to that described in
current guidance for use of investigational products.
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
biological characteristics, 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
- Description
of the formulation or routes of administration intended to be
used in the human 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,
and foreign DNA, also should be ensured.
All excipients should be generally recognized as safe
or part of a formulation that is approved or licensed in the
United States for the same route of administration and amount,
or adequately qualified through appropriate animal studies.
- The grade and
quality (e.g., USP, NF, ACS) of excipients used in the
manufacture of the investigational 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 and intended for the proposed
human study, including a brief description of the method of
manufacture and the packaging procedure, as appropriate, with a
description of the container 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 the
source material (e.g., Master Cell Bank), describe the expression
system (e.g., fermentation methods) and harvest methods, as well
as methods for removal/inactivation of 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
the candidate product lots used in toxicological studies and
intended for the proposed human study. For biotechnology products
produced in mammalian cells or animals, this will include tests
and studies to ensure the removal and/or inactivation of potential
viral contaminants.
·
Information that demonstrates the stability of the
product during toxicology studies and an explanation of how
stability will be evaluated during the clinical studies
·
For ophthalmic, inhalational (aqueous base), or
parenteral dosage forms, results from sterility and pyrogenicity
tests
There 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 future reference and/or comparison, not all impurities of the
candidate product may need characterization 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-needed basis. Impurities (e.g.,
chemical and microbiological) should be characterized in
accordance with recommendations in Agency guidance,
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 to accomplish this include:
·
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)
Pharmacology and toxicology information is
derived from preclinical safety testing performed in animals 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 described in 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.
The basis for the reduced preclinical package is the reduced scope
of an exploratory IND clinical study. Although exploratory IND
studies in some cases are expected to induce pharmacologic
effects, they are not designed to establish maximally tolerated
doses. Furthermore, the duration of 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 tailored to the study
design. Examples include: confirming that an expected mechanism
of action can be observed in humans; measuring binding affinity or
localization of drug; assessing PK and metabolism; comparing the
effect on a potential therapeutic target with other therapies.
Three examples are discussed in detail in the following
paragraphs.
Microdose studies are designed to evaluate
pharmacokinetics or imaging of specific targets and are designed
not to induce pharmacologic effects. Because of this, the risk to
human subjects is very 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, the latter
criterion applies).
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 clinical route. 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, clinical signs, clinical chemistries,
hematology, and histopathology (high dose and control only if no
pathology is seen at the high dose). The study should be designed
to establish a dose inducing a minimal toxic effect, or
alternatively, establishing a margin of safety. To establish a
margin of safety, the sponsor should demonstrate that a large
multiple (e.g., 100X) of the proposed human dose does not induce
adverse effects in the experimental animals. Scaling from animals
to humans 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 such data 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.
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 such studies.
However, since the goal would not include defining a maximally
tolerated dose, the evaluation 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 of such 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 to confirm that the rodent is an
appropriately sensitive species. If it is known that a particular
species is most appropriate for a class of compounds, studies can
be limited to that species. This confirmation 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 attain statistically meaningful comparisons,
but of sufficient number to rule out any toxicologically
significant difference in sensitivity compared with rodent (e.g.
four non-rodents per treatment group). The confirmatory study
could be a dedicated study involving repeat administrations of a
single dose level approximating the rat NOAEL
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 of
administrations, 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
the more 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 body
weight, 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.
Evaluation of 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 dose-escalation study.
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 activation
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
in conjunction with the repeated dose toxicity study in the rodent
species. The high dose in this case should be a maximally
tolerated or limit dose.
The
results from the preclinical program can be used to select
starting and maximum doses for the clinical trials. The starting
dose is anticipated to be no greater than 1/50 of the NOAEL from
the 2-week toxicology study in the sensitive species on a mg/m2
basis. The maximum clinical dose 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
which target 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.
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 and toxicological 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 for selecting 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 of saturation of a
receptor or the inhibition of an enzyme were considered possibly
related to effectiveness, this parameter would be characterized
and determined in the animal study and then used 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. Although the production of frank
toxicity is not the primary intended goal of the nonclinical
study, relevant informative endpoints (e.g., hematology and
histopathology) selected as important for clinical safety
evaluation should be investigated.
For example, an antibody that binds with a high degree of
selectivity to a tumor-associated antigen could be studied in
accordance with this third category. The mechanism of action of
antibody-based products is generally associated with their binding
properties and the effect on functions associated with
immunoglobulins. Pharmacology and toxicology studies provide
information about the selection of 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.
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)).
Existing
regulations allow a great deal of flexibility in the amount of
data that needs to be submitted with any IND application,
depending on the goals of an investigation, the specific human
testing being proposed, and the expected risks. Sponsors have not
taken full advantage of that flexibility, and limited, early phase
1 studies, such as those described in this guidance, are often
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 preclinical testing 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 to human 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 to
move ahead more efficiently with the development of promising
candidate products while maintaining needed human subject
protections.
A
Preclinical Toxicology Testing Strategy for Exploratory INDs
Designed To Administer Pharmacologically Active Doses
