Guidance for Industry and Reviewers
Exploratory IND
Studies
This
draft guidance, when finalized, will represent the Food and Drug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.
I.
INTRODUCTION
This guidance clarifies what preclinical and
clinical approaches (including chemistry, manufacturing, and
controls) should be considered when planning exploratory IND
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 terms of the amount of data that need
to be submitted with an IND application, depending on the goals of
an investigation, the specific human testing being 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 their INDs than is required by
regulations. This guidance is intended to clarify what approaches
(preclinical and clinical) 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 occurs very early in phase 1, involves very limited
human exposure, and has no therapeutic 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 involving
investigational new drug and biological products that assess
feasibility for further development of a 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 during early drug development on candidates that are
unlikely to succeed,
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, but that will enable
sponsors to move ahead more efficiently with the development of
promising candidate products while maintaining needed human
subject protections.
Typically, during pharmaceutical development,
large numbers of molecules are generated in very small quantities
with the goal of identifying the most promising candidates for
further development. These molecules are generally related in
some way, either as a single active ingredient with multiple salts
or esters, or closely related active moieties. 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 pharmacological parameters. 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, often healthy
volunteers.
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
pharmacological 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, drug candidates
that subsequently are found to have unacceptable profiles when
evaluated in humans. Fewer than 10 percent of INDs for new
molecular entities (NME) progress beyond the investigational
stage. 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 an
investigation, the specific human testing being 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 regulations. This guidance is intended to clarify
what preclinical and clinical approaches (including chemistry,
manufacturing, and controls) should be considered when planning
exploratory IND studies in humans, including studies of closely
related drugs or therapeutic biological products, under an
investigational new drug (IND) application (21 CFR 312).
Exploratory IND studies, which usually
involve very limited human exposure and have no therapeutic
intent, can serve a number of useful goals. For example, an
exploratory IND study can help sponsors
- Gain an
understanding of the relationship between a specific mechanism
of action and the treatment of a disease
- Provide
important information on pharmacokinetics, including, for
example, biodistribution of a candidate drug
- Select the most
promising lead product from a group of candidates
designed to interact with a particular therapeutic target in
humans
- 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 select promising drugs.
The studies discussed in this guidance
involve dosing a limited number of subjects with a limited dose
range for a limited period of time. Under an exploratory IND,
depending on the study, the preclinical testing programs for
exploratory IND studies can be more flexible 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. They often provide more supporting information
in their INDs than is required by the regulations. Because
exploratory IND studies involve administering either
sub-therapeutic doses of a product, or doses expected to produce a
pharmacological, 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.
Therefore, limited exploratory IND investigations in humans can be
initiated with less, or different, preclinical support than is
required for traditional IND studies because exploratory IND
studies present fewer potential risks than do traditional phase 1
studies that look for dose-limiting toxicities.
The Agency expects that this early phase 1,
exploratory IND approach will apply to a number of different study
paradigms. This guidance explores several potential applications;
however, 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 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 information 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, we recommend
that an exploratory IND application articulate the rationale for
selecting a compound (or compounds) and for studying them in a
single trial or related trials as this represents what is known
about the overall development plan at this stage. This section
should also describe the plan to withdraw the exploratory IND
application
after completing the outlined study or studies, or the intent to
supplement the exploratory IND with the appropriate complement of
preclinical data to permit expanded clinical testing.
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. 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 otherwise 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 of the candidate
product presents any signals of potential human risk (e.g.,
specific findings in preclinical studies associated with known
risks of related compounds) (§ 312.23). If so, these signals
should be discussed, and the steps proposed to monitor for such
risks should be described, or the reasons why the signals are not
relevant to safety should be discussed.
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 the 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).
- For oral
administration, sponsors can consider using suspensions or
solutions in addition to pills, powders, and capsules. For
products intended for ophthalmic, inhalational, or parenteral
administration, sterility must be ensured. Any formulation or
routes of administration intended to be used in the human trial
should be described in the submission. All excipients should be
generally recognized as safe
or approved in another product by the same route of
administration and amount.
·
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 packaging including 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 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 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, 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. We recommend
establishing the impurity profile to the extent possible for
future reference and/or comparison. However, all impurities of
the candidate product may not 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 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)
Pharmacology and toxicology information is
derived from preclinical safety testing performed in animals and
in vitro. 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 lies in the reduced
scope of an exploratory IND study. Although exploratory IND
studies in some cases are expected to induce pharmacological
effects, they are not designed specifically 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 mechanism of action;
evaluating binding affinity or metabolites across species;
establishing the novelty of a potential therapeutic target in
comparison to other therapies; and validating a clinical model in
healthy volunteers. Three examples are discussed in detail in the
following paragraphs.
A
microdose is defined as less than 1/100th of the dose
calculated to yield a pharmacological effect of a test substance
and a maximum dose of <100 micrograms.
Microdose studies are designed to evaluate pharmacokinetics or
imaging of specific targets and are designed not to induce
pharmacological effects. Because of this, the potential 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.
FDA’s
current policy 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 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 the intended clinical route. In these studies,
animals should be observed for 14 days postdosing with an interim
sacrifice, typically on day 2, and endpoints evaluated should
include body weights, clinical signs, clinical chemistries,
hematology, and histopathology. 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.
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.
A second
example involves clinical trials designed to study pharmacological
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. If a rodent species
is used, additional studies in nonrodents, most often dogs, can be
used to confirm that the rodent is an appropriately sensitive
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 meaningfully identify a toxic
response. 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.
If an
exploratory IND study is designed to elicit pharmacological
effects, 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.
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 to be studied. The genetic
toxicology tests should include a bacterial mutation assay using
all strains and exposure conditions
as well as a test for chromosomal aberrations either in vitro or
in vivo. The in vivo test can be performed in conjunction with
the repeated dose toxicity study in the rodent species. The high
dose in this case should be a maximally tolerated dose.
The
results from the preclinical program may 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 an mg/m2
basis. The maximum clinical dose would be the lowest of the
following: (1) ¼ of the 2-week NOAEL; (2) 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; or (3) the dose that produces a
pharmacological response or at which target modulation is observed
in the clinical trial. Escalation from the proposed stopping dose
should only be performed after consultation with and concurrence
of the FDA.
A third example involves clinical studies intended to evaluate
mechanisms of action (MOAs). To support this approach, the FDA
will accept alternative, or modified, pharmacological 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 is 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, many
informative endpoints (e.g., hematology and histopathology)
typically incorporated into toxicity studies should be
investigated at all doses.
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. Nonetheless, the Agency realizes that
not all GLP provisions apply to all studies and, indeed, for some
special studies, certain of the GLP provisions may compromise
proper science. For this reason, sponsors should provide a
factual basis for exemptions from conformity with GLP provisions
(21 CFR 312.23(a)(8)(iii)). Sponsors are encouraged to discuss
the necessity of exemptions from GLP provisions with the FDA prior
to conducting safety related studies.
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 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 detailed and more flexible
than for traditional IND studies. This is because for the
approaches discussed in this guidance, which involve administering
sub-therapeutic 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.