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Division of Anti-Viral
Products
Pre-IND Letter of Instruction
Thank you for your inquiry regarding
the Division of Antiviral Products (DAVP) Pre-IND Consultation
Program. This program allows communication between a sponsor or
investigator of a candidate drug and DAVP early in the development
of new therapeutics before sufficient data have been accumulated for
an IND submission. The list of products that DAVP reviews includes
drugs directed at:
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HIV and AIDS (including
antiretroviral therapy and Prevention of HIV transmission by
topical microbicides)
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Hepatitis (HBV and HCV)
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Herpesviruses
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Emerging viral infections (including
but not limited to respiratory viruses, zoonoses, and potential
biologic threat agents)
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Other non-life-threatening and
life-threatening viral infections
We believe early consultation with
DAVP can be valuable in the development of promising new drugs, by
allowing identification of optimal strategies for efficient data
collection. We encourage you to initiate discussions with us early
in the drug development process, so that you will have the
opportunity to consider our recommendations in planning your
nonclinical and clinical development programs.
So that we may give you the best assistance, we suggest that you
provide us with as much information as possible about your new drug
and your plans for its development. We recommend that you submit the
following information, together with a list of specific questions
related to the type and amount of data necessary to support
submission of an IND that you wish us to address. However, if
components of this information are not yet available but there are
development questions to be addressed, we recommend that you contact
DAVP to discuss a partial submission that may be the first in a
series of Pre-IND interactions.
DAVP Pre-IND interactions should be considered as preliminary
communications based on early development information, and will
generally take the form of written comments that may be supplemented
by teleconferences or meetings as needed and appropriate. Additions
or modifications to these communications may arise, as additional
information becomes available, during follow-up Pre-IND interactions
or when an IND is established.
Chemistry, Manufacturing and Controls
The chemistry, manufacturing and controls section of your Pre-IND
submission should provide enough information to assure us that the
identity, strength, quality, and purity of the new drug are
adequately characterized to assess its safety and to allow
interpretability of preclinical studies and clinical investigations.
Your submission should include descriptions of the identity of the
drug substance, components and composition of the finished dosage
form, name of the manufacturer(s), manufacturing processes, product
specifications, analytical methodology, and where available,
stability of the drug substance and the finished dosage form.
We recognize that many aspects of an investigational product may be
incompletely defined at an early stage and that refinement of
methods, formulations, and specifications usually requires
substantial research that will not be complete at the time of Pre-IND
consultation. We anticipate that, as drug development progresses and
the scale of clinical studies expands, the sponsor will update this
section with more definitive information.
Pharmacology/Toxicology
Toxicity and pharmacological testing are intended to determine the
quantitative and qualitative aspects of a drug's biological effects.
Toxicity testing is a stepwise process that allows progressive
refinement in the understanding of the interactions between a drug
and physiological systems. In support of regulatory submissions,
toxicity and pharmacological testing should include both general and
specialized studies addressing the drug's safety and range of
pharmacological activities. The initiation, completion and
submission of supporting nonclinical toxicity studies should be
integrated with the appropriate phases of clinical development.
Although most drugs under development for treatment of viral
infections are expected to undergo certain minimum toxicity and
pharmacological studies, it is understood that the number, sequence
and variety of such studies will vary in relation to the anticipated
toxicity, pharmacology, clinical application and pace of drug
development.
You may find it useful to consult the
Guidance for Industry –
Content and Format of
Investigational New Drug Applications (INDs) for Phase 1 Studies of
Drugs, Including Well-Characterized, Therapeutic,
Biotechnology-Derived Products,
Nov 1995.
Your Pre-IND submission should contain a description of your planned
program of toxicity and pharmacological testing. The results of any
studies completed to date should also be submitted, although it is
not necessary to provide comprehensive reports for each study.
Submission of a summary of each study completed, including
information addressing conformance to current Good Manufacturing
Practice (GMP) and Good Laboratory Practice (GLP) requirements, will
often allow us to make a preliminary assessment. We may then request
additional data as needed to assist in our review.
Microbiology (Virology)
The following two components should be included in the Pre-IND
submission of the preclinical microbiology development plan.
The first component should be a research plan describing all
specific microbiology studies proposed to support introduction of
the drug into clinical studies. These studies should provide
evidence of preclinical activity that will establish a rationale for
use of the drug in infected individuals, as well as provide
information about the potential risks of use in humans that will
complement the results of animal toxicity studies.
Specific areas that should be addressed include mechanism(s) of
action, antiviral activity in cell culture and/or animal models,
cytotoxicity (to assess the selectivity index in antiviral activity
assays, and also to assess potential drug toxicity relevant to human
tissues and cell-cycle phases), susceptibility of appropriate
clinical isolates (including recent specimens and varying subtypes,
quasispecies, or clades where applicable), potential for development
of drug resistance, cross-resistance with any approved drugs sharing
the target or mechanism of the candidate drug, and in vitro
combination activity relationships with approved drugs. In the case
of immunomodulatory drugs, the potential for unintended adverse
effects (including activation of viral replication) resulting from
the drug's actions on the immune system should be assessed. For some
immunomodulatory compounds, information on drug effects in
appropriate animal models may provide the only method for
pre-clinical evaluation of activity to support subsequent clinical
study design, but cell culture studies may still be important to
show whether viral replication is enhanced or whether the proposed
product alters the antiviral activity of approved drugs. It is
preferred that you select and use FDA approved assays in proposed
clinical studies. For investigational assays, you should include
information on the performance characteristics. Finally, a plan for
evaluation of resistance emergence in clinical studies should be
described.
The second component of the submission should be a summary of any
data already developed to support drug activity; complete raw data
should not be submitted for Pre-IND evaluation but will be required
to be included in all IND submissions. Sponsors typically have
characterized the mechanism of action at the time of Pre-IND
submission.
Proposed Animal Studies
For some rare or emerging infections, studies of activity in animal
models with varying levels of resemblance to human disease may
constitute a particularly important part of the development plan. In
addition to any animal data available at the time of Pre-IND
contact, sponsors are urged to submit plans and proposals for any
additional animal studies they may be considering together with the
rationale for use of the proposed models and study designs, so that
the selection, design, conduct, and utilization of animal studies
can be a topic of interdisciplinary discussion and advice during
Pre-IND interactions.
Such prospective discussion of animal studies is especially crucial
if the sponsor is considering possible use of the Animal Rule (21
CFR 314 Subpart I) for principal evidence of therapeutic antiviral
effects, but may also be important for other development situations
in which animal data may contribute significantly to evaluating the
product, and for the most efficient collection of supporting data
for safety as well as treatment effect.
Clinical Development Plan
Although most sponsors utilizing our Pre-IND consultation program
request advice regarding nonclinical development, we find that we
can offer better guidance to those sponsors who are also able to
provide us with information about their plans for initial clinical
development (i.e., phase 1 or 2 studies), as the latter will impact
on the selection and design of nonclinical studies. To allow us to
place your nonclinical program in perspective, we recommend that you
include the following information in your Pre-IND submission:
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The proposed rationale for use of
your new drug in infected patients or to prevent infection in
uninfected subjects
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The anticipated conditions of use,
including intended patient population(s) and plans for combination
therapy, if any
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Available information on any previous
human experience with your product or closely related products
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A summary of the proposed initial
clinical development program, including basic design and approximate
size and duration of any studies planned
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A synopsis of the proposed clinical
study protocol or protocols you plan to submit in an IND. This may
be a paragraph summarizing objectives, patient population, study
design, approximate sample size, treatment regimen (including route
of administration, dose level(s), if known, and frequency and
duration of dosing), and activity endpoints
Please submit your materials for our
Pre-IND review to the address listed on DAVP’s
Getting Started Page. Supply at least ten
(10) copies of your Pre-IND submission and clearly indicate in your
cover letter that the enclosed is a Pre-IND submission.
Contact Us
We will review your materials as quickly as possible, and will
contact you regarding our comments. At that time we can determine
how we can best assist you further.
Please direct any comments
to the appropriate
division referenced on the CDER
Pre-IND Consultation Contact
List.
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Date created: September 8, 2004, updated September 30, 2008 |
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