ANTI-ORTHOPOXVIRUS DRUG DISCOVERY AND DEVELOPMENT
Release Date: October 20, 1999
RFA: AI-00-002
National Institute of Allergy and Infectious Diseases
Letter of Intent Receipt Date: December 15, 1999
Application Receipt Date: January 19, 2000
PURPOSE
As part of DHHS-wide efforts for civilian defense from
possible bioterrorism, the Division of Microbiology and
Infectious Diseases (DMID), National Institute of Allergy
and Infectious Diseases (NIAID), National Institutes of
Health (NIH), invites research applications to (1) discover
and design drugs against orthopoxvirus and (2) provide
sufficient quantities of promising compounds for evaluation
in animals.
HEALTHY PEOPLE 2000
The Public Health Service (PHS) is committed to achieving
the health promotion and disease prevention objectives of
"Healthy People 2000," a PHS-led national activity for
setting priority areas. This Request for Applications
(RFA), ANTI-ORTHOPOXVIRUS DRUG DISCOVERY AND DEVELOPMENT, is
related to one or more of the priority areas. Potential
applicants may obtain a copy of "Healthy People 2000" at
http://odphp.osophs.dhhs.gov/pubs/hp2000.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic for-profit and
non-profit organizations; public and private institutions,
such as universities, colleges, hospitals, laboratories,
units of State and local governments; and eligible agencies
of the Federal government. Foreign institutions are not
eligible to apply however foreign investigators may
participate as collaborators, consultants or subcontractors.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal
Investigators.
MECHANISM OF SUPPORT
The administrative and funding mechanism to be used to
undertake this program will be the Cooperative Agreement
(U01), an "assistance" mechanism, rather than an
"acquisition" mechanism, in which substantial NIH scientific
and/or programmatic involvement with the awardee is
anticipated during the performance of the activity. Under
the cooperative agreement, the NIH purpose is to support
and/or stimulate the recipient's activity by involvement in
and otherwise working jointly with the award recipient in a
partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity. Details
of the responsibilities, relationships, and governance of a
study funded under cooperative agreement(s) are discussed
later in this document under the section Terms and
Conditions of Award.
The total project period for applications submitted in
response to this RFA may not exceed five years. At present,
the NIAID is administratively limiting the duration of U01
cooperative agreements to four years; this administrative
limitation may change in the future. At this time, the
NIAID has not determined whether or how this solicitation
will be continued beyond the present RFA.
FUNDS AVAILABLE
The estimated total funds (direct and facilities and
Administrative (F&A) costs) available for the first year
of support for all awards made under this RFA will be $1.5
million. However, depending on Fiscal Year 2000 budget
appropriations, this amount may increase. In Fiscal Year
2000 the NIAID plans to fund 1 to 4 awards. In Fiscal Year
2001, with the addition of the scale-up synthesis, the
estimated total funds will be $1.75 million. The usual NIH
policies governing grants administration and management will
apply. Although this program is provided for in the financial
plans of the NIAID, awards pursuant to this RFA are contingent
upon the availability of funds for this purpose and the receipt of a
sufficient number of applications of high scientific merit.
Funding beyond the first and subsequent years of the grant
will be contingent upon satisfactory progress during the
preceding years and availability of funds.
RESEARCH OBJECTIVES
Background
In recent years, there has been a significant change in both
the nature and degree of the threat posed by the use of
weapons of biological warfare. The risk of using such
weapons once appeared to be restricted to international
conflicts involving small numbers of industrialized nations.
However, an increasing number of developing countries, as
well as terrorist groups, and rogue individuals now view the
use of biological weapons as agents of terror, rather than
as instruments of warfare. Recent events, such as
disclosures of international biological weapons programs,
the bacterial contamination of restaurant food by cultists,
and the delivery of a putative anthrax bacterial culture to
a DC office, have dramatized both the possibility of
bioterrorist attack and the vulnerability of the U.S.
population to such an event. Although the DoD has developed
some defenses for biological warfare to protect military
personnel, comparable and additional defenses need to be
developed to protect the civilian population. One is that
the populations to be protected are different as civilians
include people of all ages and physical conditions. Thus,
the important research goals for biological agents with the
potential terrorist use include; 1) rapid, accurate
diagnosis; 2) effective therapy for those infected; 3)
protective vaccination for those at risk of exposure; and 4)
basic research, which provides the essential underpinning of
the other areas.
Of the organisms that might be used in bioterrorism,
smallpox would likely have the most horrific impact on the
health of the U.S. population. As the result of a
successful immunization program, smallpox disease was
eliminated in the U.S. by the 1960s. Routine immunization
against smallpox was terminated. Americans today either have
never been immunized or were vaccinated more that 30 years
ago and those have little, if any, remaining protection.
Smallpox is highly contagious and mortality is in the range
of 30%. There is no available antiviral therapy. As a
result of the eradication of the disease, antiviral research
on smallpox and related orthopoxviruses has largely been
abandoned. This Request for Applications (RFA) will support
broad, innovative, multidisciplinary approaches to the
design and discovery of drugs for prophylactic and/or
therapeutic use in the event of an outbreak of smallpox.
The NIAID has already initiated some activities in this
area. Current contractors engaging in antiviral screening
and animal models of viral infections have been supplemented
to establish cell-based in vitro anti-vaccinia virus screens
and murine animal models of vaccinia and cowpox. Any
investigators who have novel compounds can request services
of our contractors to evaluate their compounds with the
approval of NIAID’s project officer.
Further, an orthopoxvirus genomics facility will be
established under a separate RFA to assist with the
identification of gene targets for intervention. Some
genomic information will be available through this research
facility.
In addition, the NIAID has entered into an agreement with
the U.S. Army Medical Research Institute of Infectious
Diseases (USAMRIID) to perform in-depth preclinical
evaluation of candidate drugs in animal models, primarily
the infection of non-human primates with monkeypoxvirus.
Although compounds with activity against vaccinia virus in
cultured cells have repeatedly been reported in the
literature, a drug that meets the requirements of efficacy,
safety and ease of delivery, qualities essential for
response to a potential terrorist event, has not been
identified. This RFA will support the design and discovery
of such new agents. Through studies of antivirals developed
for other infections, scientists at USAMRIID have recently
identified a potential anti-orthopoxvirus drug: cidofovir,
an FDA-approved drug for retinitis caused by human
cytomegalovirus (HCMV) in AIDS patients. Cidofovir
demonstrated significant efficacy for the treatments of
cowpox infection in mice and monkeypox in cynomolgus
monkeys. However, this drug has several disadvantages -
including the need to be given intravenously and serious
potential toxicity problems that make it impractical for
emergency use.
Viruses are intracellular pathogens sharing many of the
nutritional requirements and synthetic pathways with the
host cells they infect. Therefore, an ideal antiviral agent
will be one that effectively interdicts viral infection as a
consequence of interaction with a target that is unique to
the virus, and hence has little or no impact on uninfected
host tissues. In principle, such selective antiviral
activity is best achieved by directing drugs toward virus-
specific genes, enzymes, or cellular receptors, or other
cellular gene that contributes to pathogenesis. Recent
developments in chemistry and biology suggest that one can
logically apply such information for rational design and
discover selective antiviral drugs. A recent dramatic
example is the design of clinically effective inhibitors
based on the crystal structures of the HIV protease and
influenza neuraminidase. Recent preliminary clinical trials
have also shown encouraging results with inhibitors of the
picornavirus receptor-binding interaction. Antisense
oligonucleotides targeting specific viral mRNA sequences of
HIV, HCMV, or human papillomavirus (HPV) are also now in
clinical trials.
Advances in the science of molecular diversity generated
from combinatorial libraries, natural products, and chemical
databases present a series of rich sources of novel
diversified chemical entities ready for drug discovery.
Knowledge-based searches of such sources could lead to the
discovery of active compounds with unanticipated structures.
These advanced knowledge and technologies have provided
unprecedented opportunities for identifying novel
therapeutics, and for hastening the drug discovery process.
Research Objectives and Scope
This Request for Applications (RFA) will support research to
design and discover pharmaceuticals suitable for the mass
treatment of smallpox virus infection. The objective is to
stimulate preclinical research in the design, synthesis,
discovery, and in vitro evaluation of novel compounds aimed
at the effective prophylaxis and/or therapy of smallpox
virus infection for the purpose of civilian defense against
bioterrorism.
Viral-specific or virus-induced events in viral replication,
pathogenesis, and host interaction pathways might provide
appropriate targets for selective antiviral agents.
Important or new targets would then be utilized for new lead
generation and optimization.
Possible strategies may include, but are not limited to:
o Structural determination of viral gene targets, molecular
modeling and de novo design, quantitative structure-activity
relationships, computer-assisted structural searching,
mechanism-based design, and/or transport and receptor-based
design;
o Exploitation of molecular diversity generated from
structure-based combinatorial libraries (chemical or
biological) and natural products coupled with
functional/target-based high-throughput screening
strategies;
o Optimization of lead compounds by the principles of
medicinal chemistry.
Investigators should have the capability of scale-up
synthesis of up to five compounds per year to supply
sufficient amounts for animal model evaluations. Funds
will be added to this initiative in the second year for this
purpose. It is assumed that there will not be any compounds
ready for animal evaluation in the first year.
The areas outlined above are not intended to be all-
inclusive.
Collaborations between different scientific disciplines,
such as chemistry and virology, as well as collaborations
between industrial and academic investigators are
encouraged.
The following areas of investigation, some of which are
supported by different initiatives, will be considered not
responsive to this RFA:
o Pharmacological agents such as therapeutic vaccines,
cytokines, antibodies, and biological response modifiers.
o Large-scale random screening of compounds.
o Development of alternative synthetic methods for cost
effective re-synthesis of currently existing compounds.
o Development of prodrugs for currently existing compounds.
o Development of animal models.
o Extensive studies required for the clinical development
of identified potential drugs, such as toxicological testing
and formulation development.
NIAID-supported contractors who engage in preclinical
evaluation of potential antiviral compounds can be available
to further evaluate the antiviral agents designed and
discovered by investigators supported by this RFA. The
contractors provide NIAID-supported animal models, which
examine compounds' in vivo efficacy and toxicity and limited
pharmacokinetics. The models currently available are murine
models of vaccinia and cowpox. Highly promising candidate
drugs can be further studied in monkeypox model by the
investigators of USAMRIID.
It is anticipated that this RFA will lead to the
identification and optimization of lead structures.
TERMS AND CONDITIONS OF AWARD
The administrative and funding instrument used for this
program is the cooperative agreement (U01), an "assistance"
mechanism (rather than an "acquisition" mechanism), in which
substantial NIH scientific and/or programmatic involvement
with the awardee is anticipated during the performance of
the activity. Under the cooperative agreement, the NIH
purpose is to support and/or stimulate the recipient's
activity by involvement in and otherwise working jointly
with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role
in the activity.
Consistent with this concept, the dominant role and prime
responsibility for the activity resides with the awardees
for the project as a whole, although specific tasks and
activities in carrying out the research will be shared among
the awardees and the NIAID Scientific Coordinator.
Cooperative agreements are subject to the administrative
requirements outlined in OMB circulars A-102 and A-110. All
pertinent HHS, PHS, and NIH grant regulations, policies and
procedures, with particular emphasis on PHS regulations at
42 CFR part 52 and HHS regulations at CFR 45 Part74, are
applicable. These special terms and conditions pertaining to
the scope and nature of the interaction between the NIAID
and the investigators will be incorporated in the Notice of
Grant Award. However, these terms will be in addition to,
not in lieu of,the customary programmatic and financial
negotiations that occur in the administration of cooperative
agreements.
1. AWARDEE RIGHTS AND RESPONSIBILITIES
Awardees will have primary responsibility for defining the
research objectives, approaches and details of the projects
within the guidelines of the RFA and for performing the
scientific activity. Specifically, awardees have primary
responsibility as described below.
a. The Principal Investigator defines the details for the
project within the guidelines of the RFA, retains primary
responsibility for the performance of the scientific
activity, and agrees to accept close assistance of NIAID
staff in aspects of scientific and technical management of
the project in accordance with the terms mutually agreed
upon prior to the award.
b. The awardee is to plan and conduct the research
stipulated in the application and to ensure that the results
obtained are analyzed and published in a timely manner.
Awardees will retain custody of and have primary rights to
the data developed under these awards, subject to Government
rights of access consistent with current HHS, PHS, and NIH
policies.
c. The awardee is to participate in an annual meeting of
investigators funded under this and related RFAs to discuss
progress and strategies for future research.
2. NIAID STAFF RESPONSIBILITIES
Assistance via Cooperative Agreement differs from the
traditional research grant in that, in addition to the
normal programmatic and administrative stewardship
responsibilities, the component awarding the Cooperative
Agreement anticipates substantial programmatic involvement
during performance of the project. NIAID staff assistance
is to participate in, but not direct, the research to ensure
that important disease targets are addressed. The Antiviral
Research and Antimicrobial Chemistry Program Officer,
Virology Branch, DMID will serve as Scientific Coordinator
and will participate as a member of the research team. The
Scientific Coordinator will interact with the Principal
Investigators and Co-investigators in the overall research
planning and in data analysis. During performance of the
award, the NIAID Scientific Coordinator may provide
appropriate assistance by participating in the design of
research group activities; advising in the selection of
sources or resources; coordinating or participating in
collection and/or analysis of data; and, advising in
management and technical performance. The Scientific
Coordinator may assist with arrangements for the further
evaluation, both in vitro and in animal models, of agents
resulting from this research. However, the role of NIAID
will be to facilitate and not to direct the activities.
Specifically, it is presently envisioned that the NIAID will
be actively engaged in the facilitation of components
including assisting the awardees in:
a. Collaborative participation in overall research planning
and data analysis. Specifically, the NIAID Scientific
Coordinator may suggest studies within the scope of the
award's objectives and research activities; may present to
the investigators experimental findings from published
sources or from contract projects in support of these
suggestions; may participate in the design of experiments;
and may participate in the analysis of results.
b. Provision of needed resources and information that may
not be otherwise available to the investigator. This may
include the provision of data from testing conducted in
resource contract laboratories subject to the terms of
confidentiality agreements with drug sponsors. NIAID staff
will coordinate collaboration between this activity and
other components of the orthopoxvirus research program, such
as the genomics facility and animal model evaluation.
c. In the event that an awardee's research results in a
procedure or a product that requires testing of a nature
beyond the awardee's capabilities, the NIAID Scientific
Coordinator may provide resources available to the Institute
for comprehensive preclinical efficacy evaluations.
d. The NIAID Scientific Coordinator will organize an annual
symposium in Bethesda, Maryland at which the principal
investigators will discuss their progress. This will
facilitate overall program planning and development, the
evaluation of the feasibility of the attempted approaches,
and will promote productive interactions among the
successful applicants. The NIAID Scientific Coordinator
will also ensure the participation in this symposium of
investigators from other NIAID preclinical and clinical
programs to provide the most relevant antiviral expertise
possible to facilitate planning for future research and
expedite the design and development of novel antiviral
agents.
3. Arbitration
Any disagreement that may arise on scientific or
programmatic matters (within the scope of the award) between
award recipients and the NIAID may be brought to
arbitration. An arbitration panel will be composed of three
members -- one selected by the individual awardee in the
event of an individual disagreement, a second member
selected by the NIAID, and the third member with expertise
in the relevant area and selected by the two prior members
will be formed to review any scientific or programmatic
issue that is significantly restricting progress. While the
decisions of the Arbitration Panel are binding, these
special arbitration procedures will in no way affect the
awardee's right to appeal an adverse action in accordance
with PHS regulations at 42 CFR Part 50, subpart D, and HHS
regulations at 45 CFR Part 16.
LETTER OF INTENT
Prospective applicants are asked to submit, by December 15,
1999, a letter of intent that includes a descriptive title
of the overall proposed research; the name, address and
telephone number of the Principal Investigator; and the
number and title of this RFA. Although the letter of intent
is not required, is not binding, does not commit the sender
to submit an application, and does not enter into the review
of subsequent applications, the information that it contains
allows NIAID staff to estimate the potential review workload
and to avoid conflict of interest in the review. The letter
of intent is to be sent to Dr. Madelon Halula at the address
listed under INQUIRIES.
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is
to be used in applying for these grants. These forms are
available: (1) at most institutional offices of sponsored
research; (2) from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910,
telephone 301/710-0267, email: [email protected]; and (3)
on the internet at
http://grants.nih.gov/grants/funding/phs398/phs398.html.
The RFA label available in the PHS 398 (rev. 4/98)
application form must be affixed to the bottom of the face
page of the application. Failure to use this label could
result in delayed processing of the application such that it
may not reach the review committee in time for review. In
addition, the RFA title and number must be typed on line 2
of the face page of the application form and on the RFA
label and the YES box must be marked. The sample RFA label
at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has
been modified to allow for this change. Please note this
is in pdf format.
Applications must be received by the application receipt
date of January 19, 2000. If an application is received
after that date, it will be returned to the applicant
without review.
The Center for Scientific Review (CSR) will not accept any
application in response to this RFA that is essentially the
same as one currently pending initial review, unless the
applicant withdraws the pending application. The CSR will
not accept any application that is essentially the same as
one already reviewed. This does not preclude the submission
of substantial revisions of applications already reviewed,
but such applications must include an introduction
addressing the previous critique.
Applicants are strongly encouraged to call NIAID program
staff with any questions regarding the responsiveness of
their proposed project to the goals of this RFA.
Submit a signed, typewritten original of the application,
including the checklist, and three signed, exact, single-
sided photocopies, in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express mail or courier service)
At the time of submission, two additional exact copies of
the grant application and all five sets of any appendix
material must be sent to Dr. Halula at the address listed
under INQUIRIES.
Applicants from institutions that have a General Clinical
Research Center (GCRC) funded by the NIH National Center for
Research Resources may wish to identify the GCRC as a
resource for conducting the proposed research. If so, a
letter of agreement from either the GCRC Program Director or
Principal Investigator should be included with the
application.
REVIEW CONSIDERATIONS
Review Considerations
Upon receipt, applications will be reviewed for completeness
and adherence to the Special Instructions above by the NIH
Center for Scientific Review and for responsiveness by NIAID
staff; those judged to be incomplete will be returned to the
applicant without review. Those considered to be non-
responsive will be returned without review.
Applications that are complete and responsive to the RFA
will be evaluated for scientific and technical merit by an
appropriate peer review group convened by the NIAID. As
part of the initial merit review, a process will be used by
the initial review group in which all applications receive a
written critique and undergo a process in which only those
applications deemed to have the highest scientific merit
will be discussed, assigned a priority score, and receive a
second level review by the National Advisory Allergy and
Infectious Diseases Advisory Council.
Review Criteria
The criteria to be used in the evaluation of grant
applications are listed below. To put those criteria in
context, the following information is contained in
instructions to the peer reviewers.
The goals of NIH-supported research are to advance our
understanding of biological systems, improve the control of
disease, and enhance health. The reviewers will comment on
the following aspects of the application in their written
critiques in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of
these goals. Each of these criteria will be addressed and
considered by the reviewers in assigning the overall score
weighting them as appropriate for each application. Note
that the application does not need to be strong in all
categories to be judged likely to have a major scientific
impact and thus deserve a high priority score. For example,
an investigator may propose to carry out important work that
by its nature is not innovative but is essential to move a
field forward.
1. Significance. Does this study address the goal of the
RFA? If the aims of the application are achieved, how will
scientific knowledge be advanced? What will be the effect
of these studies on the concepts or methods that drive this
field?
2. Approach. Are the conceptual framework, design,
methods, and analyses adequately developed, well-integrated,
and appropriate to the aims of the project? Does the
applicant acknowledge potential problem areas and consider
alternative tactics?
3. Innovation. Does the project employ novel concepts,
approaches or method? Are the aims original and innovative?
Does the project challenge existing paradigms or develop new
methodologies or technologies?
4. Investigator. Is the investigator appropriately trained
and well suited to carry out this work? Is the work
proposed appropriate to the experience level of the
principal investigator and other researchers (if any)?
5. Environment. Does the scientific environment in which
the work will be done contribute to the probability of
success? Do the proposed experiments take advantage of
unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of
institutional support?
In addition to the above criteria, in accordance with NIH
policy, all applications will also be reviewed with respect
to the following:
o The adequacy of plans to include both genders, minorities
and their subgroups, and children as appropriate for the
scientific goals of the research. Plans for the recruitment
and retention of subjects will also be evaluated.
o The reasonableness of the proposed budget and duration in
relation to the proposed research
o The adequacy of the proposed protection for humans,
animals or the environment, to the extent they may be
adversely affected by the project proposed in the
application.
AWARD CRITERIA
Funding decisions will be made on the basis of scientific
and technical merit as determined by peer review, program
balance, and the availability of funds. The earliest
anticipated date of award is September 2000.
INQUIRIES
Written and telephone inquiries concerning this RFA are
encouraged. The opportunity to clarify any issues or
questions from potential applicants is welcome.
Direct inquiries regarding programmatic (research scope and
eligibility) issues to:
Dr. Christopher Tseng
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room 3134
6700-B Rockledge Dr. MSC 7630
Bethesda, MD 20892-7630
Telephone: (301) 496-7453
FAX: (301) 496-8030
E-Mail: [email protected]
Direct inquiries regarding review issues; address the letter
of intent to; and mail two copies of the application and all
five sets of appendices to:
Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr. MSC 7616, Room 2150
Bethesda, MD 20892-7616
Telephone: (301) 496-2550
FAX: (301) 496-2638
E-Mail: [email protected]
Direct inquiries regarding fiscal matters to:
Annette Hanopole
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive MSC 7614, Room 2122
Bethesda, MD 20892-7614
(zip for express mail is 20817)
Telephone: (301) 496-7075
Fax: (301) 480-3780
E-mail: [email protected]
Schedule
Letter of intent receipt date: December 15, 1999
Application receipt date: January 19, 2000
Scientific review date: June 2000
Advisory Council date: September 2000
Earliest award date: September 2000
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic
Assistance No. 93.856, Microbiology and Infectious Diseases
Research, and No. 93.855 - Immunology, Allergy, and
Transplantation Research. Awards are made under
authorization of the Public Health Service Act, Title IV,
Part A (Public Law 78-410, as amended by Public Law 99-158,
42 USC 241 and 285) and administered under NIH grants
policies and Federal Regulations 42 CFR 52 and 45 CFR Parts
74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review.
The PHS strongly encourages all grant recipients to provide
a smoke-free workplace and promote the non-use of all
tobacco products. In addition, Public Law 103-227, the Pro-
Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in
which regular or routine education, library, day care,
health care, or early childhood development services are
provided to children. This is consistent with the PHS
mission to protect and advance the physical and mental
health of the American people.
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