MODELS FOR HIV DISEASE AND AIDS-RELATED MALIGNANCIES
Release Date: May 16, 2001
PA NUMBER: PA-01-094 (see replacement PA-04-157)
National Cancer Institute
THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.
This Program Announcement (PA) replaces PA-99-042, which was published in NIH
Guide Volume 25, Number 1, January 29, 1999.
PURPOSE
The purpose of the this Program Announcement (PA) is to encourage
investigator-initiated grant applications for the development of useful and
predictive biochemical, cellular, in vivo and mathematical models for the
preclinical evaluation of new therapies against HIV and AIDS-related
malignancies. The availability of well-characterized in vitro and in vivo
models would accelerate the pace of evaluation of different paradigms of
disease progression and would facilitate the discovery of successful
treatments, including drugs, vaccines, gene therapy, and immune modulators.
This PA will expire on September 3, 2003 unless reissued. NIH Grants policies
apply to these awards.
RESEARCH OBJECTIVES
Background
Despite many recent advances in our knowledge of the molecular biology of HIV-
1 (human immunodeficiency virus) and HIV-2 and our increased understanding of
HIV pathogenesis in the development of acquired immune deficiency syndrome
(AIDS), no cure is available for HIV associated disease or AIDS-related
malignancies, including Kaposi"s sarcoma, high-grade B cell non-Hodgkin"s
lymphoma, Hodgkin"s disease, Castleman=s Disease and anogenital dysplasia and
cancer. As of December 2000, the World Health Organization (WHO) estimated
that more than 5.3 million new cases of AIDS occurred and 3.0 million people
died of AIDS worldwide in the last year. More than 21.8 million people
worldwide have died of AIDS since the beginning of the epidemic and more than
36 million people are infected and living with HIV/AIDS as the pandemic
continues unabated.
The goal of this PA is to foster the development of useful and predictive
biochemical, cellular, in vivo and mathematical models for the evaluation of
new therapies against HIV disease and AIDS-related malignancies. New relevant
and cost-effective models are needed for various stages of preclinical therapy
development, including lead discovery, lead optimization, and final evaluation
of the most promising candidates for clinical trial. While progress has been
made with cell-based and mechanism-based screens, such as those for reverse
transcriptase and proteases, many other suitable targets exist but need to be
employed in assays. There is an urgent need for simpler, safer, more
relevant, and less expensive in vivo models to assess the in vivo efficacy of
potential therapeutic candidates. However, exploratory basic research studies
on the mechanism of action of HIV genes, cellular genes involved in HIV gene
replication, and gene products are excluded from this PA.
The research scope encourages applications in the following areas, which are
illustrated by but not in any way limited to the examples provided:
o Biochemical Assays. Rapid, resource efficient, and cost-effective assays
to block steps in HIV virus replication are encouraged. Models for well-
studied targets such as HIV reverse transcriptase and proteases are not
advocated, whereas models for promising new targets such as the nef or other
HIV proteins are encouraged. Applicants should consider high volume screens
that would accommodate the needs of combinatorial chemistry programs. For
those AIDS-related cancers in which a putative cofactor may be involved, such
as the Kaposi"s Sarcoma-Associated Herpesvirus (KSHV/HHV-8), Epstein Barr
Virus (EBV), or Human Papilloma viruses (HPV), approaches are sought to
identify and define the precise role of the cofactor in the specific
malignancy and to exploit this information for therapeutic advantage.
o Cell Culture Assays. It is desirable that new cell culture models be
developed for HIV replication and AIDS-related malignancies that more closely
simulate the in vivo state. For example, models that mimic the three
dimensional, multicellular environment or those based on single cycle
replication kinetics would be of utility. For AIDS-related cancers, cell
culture systems predictive of in vivo events that allow for studies of the
mechanism(s) of action of specific viral factors of cofactors and that would
be useful for evaluating potential therapies are highly encouraged.
o In Vivo Models. Models that reflect the current state of knowledge of HIV
pathogenesis and are simpler, safer, more relevant and less expensive than
currently available models are urgently needed for the evaluation of therapies
for HIV disease and viral associated AIDS-related malignancies. Novel
approaches using transgenic and gene knockout animals are especially
encouraged. Although the use of small animals such as mice is most practical
because of their availability and low cost, other animal models may be
proposed. However, non-lentivirus, retroviral animal models are not
encouraged. For the models of both HIV disease and AIDS-related malignancies,
the development of valid surrogate endpoints for survival is favored in the
interest of conserving resources and reducing assay time and animal
discomfort.
o Mathematical Models. Refinement of mathematical models for viral levels,
CD4+T cell counts, etc. that can be used as predictors of therapeutic efficacy
and/or viral resistance and in conjunction with clinical studies will be
considered. New paradigms of HIV pathogenesis that can provide alternative
treatment strategies are encouraged.
Applicants are reminded to provide a rationale for their model, to justify and
demonstrate its potential utility over existing models, if applicable, to
provide a research plan involving a testable hypothesis, and to use the model
to demonstrate its utility. Relevance to the in vivo disease state,
reproducibility using appropriate statistical analysis, and other important
parameters of the assay should be documented.
MECHANISM OF SUPPORT
Support of this program will be through the National Institutes of Health
(NIH) research project grant (R01) mechanism and the exploratory/developmental
grant (R21) mechanisms. Applicants will be responsible for the planning,
direction, and execution of the proposed project. All PHS and NIH grants
policies will apply to applications received and awards made in response to
this PA.. The R21 mechanism supports pilot projects or feasibility studies.
Accordingly, a sound rationale and a well designed research plan but not
preliminary data are required. The R01 supports more advanced projects.
Responsibility for the planning, direction, and execution of the proposed
research for all applicable mechanisms of support will be solely that of the
applicant. Applicants for the R21 grant mechanism may request up to $100,000
direct costs (four budget modules) per year unless the application includes
consortium costs, in which case the limit is $125,000 direct costs (five
budget modules) per year. For R21 grants, support may not exceed two years.
Though the size of award may vary with the scope of research proposed, it is
expected that R21 applications will stay within the budgetary guidelines for
an exploratory/developmental project. The R21 grants are non-renewable, and
competitive continuation of projects developed under this program will be
through the R01 research grant mechanism. Applications for the R01 grant
mechanism may not exceed five years.
This PA is one-time solicitation. Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and be
reviewed according to the customary
peer review procedures.
Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and eligible
agencies of the Federal government. Foreign institutions may participate in
laboratory programs through subcontract or consortium arrangements.
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.
INQUIRIES
Inquiries concerning this PA are encouraged. The opportunity to clarify any
issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Dr. Kenneth Cremer
Biological Carcinogenesis Branch
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 5016
Bethesda, MD 20892-7398
Telephone: 301 496-6085
FAX: 301-496-2025
Email: cremerk@mail.nih.gov or kc47i@nih.gov
Dr. Mary Wolpert
Developmental Therapeutics Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
Executive Plaza North, Room 8153
Bethesda, MD 20892-7456
Telephone: 301 496-8783
FAX: 301-402-5200
Email: wolpertm@mail.nih.gov or mw8u@nih.gov
Direct inquiries regarding fiscal matters to:
Ms. Eileen Natoli
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd, Suite 243, MSC 7150
Bethesda, MD 20892-7150
Telephone: (301) 496-8791
FAX: 301-496-8601
Email: natoliea@gab.nci.nih.gov
Mr. Bill Wells
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd, Suite, 243 MSC 7150
Bethesda, MD 20892-7150
Telephone: (301) 496-8796
FAX: 301-496-8601
Email: ww14j@nih.gov or wellsw@gab.nci.nih.gov
APPLICATION PROCEDURES
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there
is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers and Institute
staff. The research grant application form PHS 398 (rev. 4/98) is to be used
in applying for these grants, with the modifications noted below. Applications
will be accepted at the standard application deadlines as indicated in the
application kit. Receipt dates for applications for AIDS-related research are
January 2, May 1, and September 1. Applications kits are available at most
institutional offices of sponsored research and may be obtained 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: grantsinfo@nih.gov. The title and number of the PA must be
typed on line 2 of the face page of the application form and the YES box must
be marked. For those applicants with Internet access, the 398 kit may be found
at: http://grants.nih.gov/grants/forms.htm.
Applicants are strongly encouraged to call the program contacts listed in
INQUIRIES above with any questions regarding the adherence to the guidelines
of their proposed project to the goals of this PA.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT
BUDGET INSTRUCTIONS
Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year for R01 and, up to a total
direct cost request of $100,000 per year ($125,000 if there are
consortium/contractual Cost) for R21. Applications that request more than
$250,000 direct costs for an R01 in any year must follow the traditional PHS
398 application instructions. The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities
and Administrative (F&A) costs] for the initial budget period. Items 8a and
8b should be completed indicating the Direct and Total Costs for the entire
proposed period of support.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required
and will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages). At the top of the page, enter the total direct costs requested for
each year. This is not a form page.
o Under Personnel, list all project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.
For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of all personnel, and the role
on the project. Indicate whether the collaborating institution is domestic or
foreign. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount. Include the Letter of
Intent to establish a consortium.
Provide an additional narrative budget justification for any variation in the
number of modules requested.
o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual"s qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all key personnel, following the instructions below. No more than three pages
may be used for each person. A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm.
- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years,
- List selected peer-reviewed publications, with full citations.
o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the type
of agreement and the date. All appropriate exclusions must be applied in the
calculation of the F&A costs for the initial budget period and all future
budget years.
The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.
Submit a signed, typewritten original of the application, including the
checklist, and five 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/courier service)
REVIEW CONSIDERATIONS
Applications will be assigned on the basis of established PHS referral
guidelines. Applications will be evaluated for scientific and technical merit
by an appropriate scientific review group convened in accordance with the
standard NIH peer review procedures. As part of the initial merit review, all
applications will receive a written critique and undergo a process in which
only those applications deemed to have the highest scientific merit, generally
the top half of applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate national
advisory council or board.
Review Criteria
The five criteria to be used in the evaluation of grant applications are
listed below.
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.
Significance: Does this study address an important problem? 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?
Approach: Are the conceptual framework, design, methods, and analyzes
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
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?
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)?
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?
The initial review group will also examine: the adequacy of plans to include
both genders and minorities and their subgroups, and children as appropriate
for the scientific goals of the research and plans for the recruitment and
retention of subjects, the provisions for the protection of human and animal
subjects, and the safety of the research environment.
AWARD CRITERIA
This section must describe the factors, including the scientific and technical
merit reflected in the priority score or percentile, that will be used to make
award decisions. PAs can apply other criteria such as the geographical
location of the applicant organization. The most common award criteria are:
scientific merit as determined by peer review, availability of funds, and
programmatic priorities.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups and
their sub- populations must be included in all NIH-supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are provided indicating that inclusion
is inappropriate with respect to the health of the subjects or the purpose of
the research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should read the
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-
048.html), a complete copy of the updated Guidelines is available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable, and b) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are clear and compelling reasons not to include them. This
policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS
All investigators proposing research involving human subjects should read the
NIH policy on education in the protection of human research participants now
required for all investigators, which is published in the NIH Guide for Grants
and Contracts, June 5, 2000 (Revised August 25, 2000), available at the
following URL address: http://grants.nih.gov/grants/guide/notice-files/NOT-
OD-00-039.html. A continuing education program in the protection of human
participants in research is now available online at http://cme.nci.nih.gov/.
URLS IN NIH GRANT APPLICATIONS OR APPENDICES
All applications and proposals for NIH funding must be self-contained within
specified page limitations. Unless otherwise specified in an NIH
solicitation, Internet addresses (URLs) should not be used to provide
information necessary to the review because reviewers are under no obligation
to view the Internet sites. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2010," a PHS led national
activity for setting priority areas. This PA, Models for HIV Disease and AIDS-
Related Malignancies, is related to priority area of human immunodeficiency
virus/AIDS and cancer Potential applicants may obtain a copy of "Healthy
People 2010" at http://www.health.gov/healthypeople/.
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.399 Cancer Cause and Prevention Research and 93.395 Cancer Treatment
Research. Awards are made under authorization of Sections 301 and 405 of the
Public Health Service Act as amended (42 USC 241 and 284) 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.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
|
|
|
|
Department of Health and Human Services (HHS)
|
|
|
|
NIH... Turning Discovery Into Health®
|