PHASED APPLICATION AWARDS IN CANCER PROGNOSIS AND PREDICTION
RELEASE DATE: May 5, 2004
PA NUMBER: PA-04-102
Updates:
March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date,
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using
the electronic SF424 (R&R) application. This announcement will stay active for
only the May 1, 2006 AIDS and AIDS-related application submission date. The
non-AIDS portion of this funding opportunity expires on the date indicated below.
Replacement R21/R33 (PA-06-434) and R33 (PA-06-435) funding opportunity announcements
have been issued for the submission date of June 1, 2006 and submission dates
for AIDS and non-AIDS applications thereafter.
August 12, 2005 - Expiration date extended, see NOT-CA-05-026
This Program Announcement (PA) replaces PAR-03-098, which was published in
the NIH Guide on April 8, 2003.
EXPIRATION DATE for Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for AIDS and AIDS-Related Applications: May 2, 2006
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov)
COMPONENT OF PARTICIPATING ORGANIZATION:
National Cancer Institute (NCI)
(http://www.nci.nih.gov)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.394
THIS PA CONTAINS THE FOLLOWING INFORMATION
o Purpose of the PA
o Research Objectives
o Mechanisms of Support
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Receipt and Review Schedule
o Required Federal Citations
PURPOSE OF THIS PA
The Cancer Diagnosis Program of the National Cancer Institute invites
applications for research projects to evaluate the utility and pilot the
application of new strategies for determining prognosis or predicting
response to therapy. This will provide tools to improve clinical decision-
making in the care of cancer patients. This PA provides support for a first
phase (R21) for technical development and a second phase (R33) for
application and evaluation of clinical utility. The first phase should
produce data to demonstrate the technical feasibility of the study design
proposed for the second phase, including the analytic performance of the
assay or test system on samples comparable to those that will be used in the
second phase. The second phase should be designed to test whether
application of the strategy will provide clinical benefit to a defined set of
cancer patients.
RESEARCH OBJECTIVES
Background
The number of clinical laboratory assays currently in routine use in oncology
is very small. For example, estrogen and progesterone receptor status of
breast cancers is used to predict response to hormonal therapy. Blood levels
of prostate specific antigen and human chorionic gonadotropin in prostate
cancer and germ cell cancer, respectively, are used to assess the
effectiveness of treatment and to detect recurrence. Patients whose tumor
cells exhibit over-expression or amplification of the Her2/neu gene may be
offered trastuzumab, forerunner of a new class of therapeutic agents directed
against specific molecular targets. These markers are the exception, not the
rule. During the past six years the College of American Pathologists,
American Society of Clinical Oncology (ASCO) Expert Panels, and the American
Joint Committee on Cancer have carefully considered many new markers proposed
for use in managing breast, colon, and prostate cancer, but have found none
with proven clinical utility sufficient to justify their adoption for routine
practice.
Recently, the NCI has sought to encourage the rapid appraisal of new
candidate prognostic and predictive markers through a series of program
announcements soliciting exploratory (R21) studies. An increasing number of
publications have described new molecules, new patterns of gene expression,
and new aspects of tumor cell growth that appear to be correlated with known
prognostic factors. However, very few markers progress beyond the stage of
an initial promising result. Studies to move the development of a new
diagnostic test beyond the exploratory stage require large numbers of patient
samples with associated clinical data; a robust, efficient assay technique;
and substantial statistical input.
The transition from an exploratory marker study to initial confirmatory
testing in a clinical setting may involve additional developmental work. For
example, the study design may change from a retrospective to a prospective
analysis or from a single institution to a multi-institutional setting.
Frequently, an assay format must be modified, which may require the
generation and characterization of additional reagents. Procedures for
standardization between collaborating laboratories may be needed. These
tasks will usually fall outside the scope of an initial R21 grant, but
without this preliminary work it may be difficult for the investigator to
establish the feasibility of a larger project.
The phased innovation award, introduced by the NCI initially to support
technology development, provides an appropriate mechanism to support the
development of new prognostic and predictive markers. The R21/R33 phased
innovation award permits an investigator to perform initial developmental
work in the R21 phase, to demonstrate feasibility by meeting a set of
quantitative, peer-reviewed milestones, and then to move directly into the
clinical study in the R33 phase. Investigators with sufficient preliminary
data to demonstrate feasibility can apply directly for an R33 award.
Research Goals and Scope
This program is intended to accelerate the translation of new discoveries
into clinical practice by enabling investigators to apply new diagnostic
strategies to clinical problems. The desired outcome will be studies with
sufficient statistical power using efficient assay techniques that are
conclusive enough to support the initiation of larger clinical trials
designed to influence practice recommendations or to pursue FDA approval of a
new device or analytic reagent.
Applicants should justify their proposals on the strength of the study
proposed in the R33 component. Applicants who can provide sufficient
preliminary data are encouraged to apply for R33 grants.
The R21 component of an R21/R33 application will be considered exploratory,
so that extensive preliminary data from the applicant’s own laboratory are
not required. However, the project must be based on a strong rationale, and
the applicant should provide evidence that the initial clinical evaluation of
the proposed diagnostic strategy is promising. The R21 phase provides time
for necessary preliminary work such as, for example, the substantial
modification of an assay format. An application that includes an R21
component may use results obtained during a previous R21 award to support a
proposal in response to this PA.
Applicants for R21/R33 projects need to provide information in the
application or to propose milestones that will demonstrate the feasibility of
the R33 phase. Milestones must be designed to permit a straightforward
decision as to whether or not the applicant is ready to initiate the R33
phase of the project. Milestones should also be provided to show that the
assay format to be used in the R33 phase meets necessary performance
standards for sensitivity, specificity, and reproducibility.
For example, milestones could be used to demonstrate the feasibility of the
R33 project in the following ways:
o Establish assay conditions: types of specimens, fixation processes,
antigen retrieval methods, reagents and other components of the assay system,
detection system, positive and negative controls, etc;
o Define procedures for scoring and for reporting data;
o Demonstrate that the assay or test system proposed for use in the R33
phase has the required sensitivity, specificity and reproducibility;
o Establish procedures for standardization and demonstrate that comparable
results can be obtained from assays performed at multiple sites;
o Estimate the prevalence of the marker on a pilot set of specimens of the
same type (fixed, frozen, etc.) and the same patient characteristics as the
set proposed for the R33 study; and
o Provide evidence that the number of participants or specimens required by
the study design in the R33 phase can be accrued.
This list is intended for illustration, and is not meant to prescribe or to
limit the milestones an application may include. See below (SPECIFIC
INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD
APPLICATION) for examples.
The R33 phase of the study must be described in sufficient detail to permit
reviewers to assess the significance and innovation of the proposed work and
the strength of the experimental design. Applicants are expected to provide
promising evidence of clinical utility for their proposed diagnostic strategy
and to show how their new test or procedure will aid the process of clinical
decision-making for a specific group of patients. Applicants should plan to
report correlations between the new diagnostic test and other measures used
in the same clinical setting.
Investigators who propose prospective studies must clearly describe the
arrangements for collection and analysis of patient outcome data, especially
if follow-up will be required beyond the end of the award period. Proposals
will be evaluated on the strength of the scientific rationale, the
significance of the problem to be addressed, the adequacy of the proposed
statistical design, the feasibility of accrual of study participants or human
tissue specimens and the choice of assay format and analytic performance
criteria.
Investigators may apply for either an R21/R33 or an R33 award, but not for an
R21 alone under this PA. Applicants who are interested in R21 projects
without an R33 phase should consider NCI Program Announcements such as PA-03-
003 (Exploratory Studies in Cancer Detection, Diagnosis and Prognosis) or PA-
03-064 (Correlative Studies Using Specimens from Multi-Institutional
Prevention and Treatment Trials). Exploratory studies focused on cancer
imaging, including new imaging modalities, agents and analysis methods, are
more appropriate for PA-04-045 (In Vivo Cancer Imaging
Exploratory/Developmental Grants) or PAR-03-124 (Novel Technologies for In
Vivo Imaging [R21/R33], both sponsored by the NCI Cancer Imaging Program.
Summary
Applicants should clearly describe the clinical question that their new test
or procedure is intended to address: for example, diagnosis, prognosis,
prediction of response to therapy, disease monitoring, etc., in a specific
group of patients. Applicants should describe what additional information
beyond standard clinical parameters that the new test is expected to provide.
They should also demonstrate that the proposed assay has the sensitivity or
accuracy adequate to answer the clinical question and that the proposed R33
study has the necessary statistical power. The R21 phase is available, if
necessary, to accomplish the development or refinement of an assay.
MECHANISMS OF SUPPORT
This PA will use the Exploratory/Developmental Research Grant Phase 2 (R33)
and the combined R21/R33 Phased-Innovation Award mechanisms. The R33 is a
NIH grant mechanism to provide a second phase for the support of innovative
exploratory and development research initiated under the R21 mechanism.
Transition of the R21 to the R33 phase will be expedited and is dependent on
completion of negotiated milestones. Applicants will be solely responsible
for planning, directing, and executing the proposed project.
Under this PA, applicants can submit either a combined R21/R33 application
(Phased Innovation Award application) or the R33 application alone, if
feasibility can be documented, as described in the SPECIFIC INSTRUCTIONS
section of this program announcement. Applications for R21 support alone
will not be accepted. The total project period for an application submitted
in response to this PA may not exceed the following duration: R33, 4 years;
combined R21/R33 application, 5 years. In the combined application the R21
phase cannot extend beyond 2 years.
For combined R21/R33 applications, the R21 phase may not exceed $275,000
direct costs (excluding sub-contractual party Facilities and Administrative
costs) for the two-year period. For example, the applicant may request
$100,000 direct costs in the first year and $175,000 direct costs in the
second year. The request should be tailored to the needs of the project.
Normally, no more than $200,000 direct costs may be requested in any single
year. Although the R33 application has no official budgetary limit,
applications requesting $500,000 or more dollars direct costs in any single
year of the grant period require prior approval before submission. It is
strongly recommended that applicants contact NCI staff at an early stage of
application development to convey critical information, such as potentially
large budget requests or to discuss programmatic adherence to the guidelines
of the proposed project. Early contact with NCI staff is particularly
critical relative to this PA because it uses the R33 grant mechanism as well
as an expedited review procedure. Refer to the INQUIRIES sections of this
program announcement for NCI staff contacts.
The combined R21/R33 application offers the following advantages over the
regular application process:
1. Single submission and evaluation of both the R21 and the R33 as one
application; and
2. Minimal or no funding gap between R21 and R33.
The award of R33 funds will be based on program priorities, on the
availability of funds, and on successful completion of negotiated scientific
milestones as determined by NCI staff in the context of peer review
recommendations.
To be eligible for the Phased Innovation Award, the R21 phase must include
well defined quantifiable milestones that will be used to judge the success
of the proposed research, as well as a credible plan for the clinical study
for the R33 phase. The Phased Innovation Award must have a section labeled
Milestones at the end of the Research Plan of the R21 application. This
section must include milestones for completion of the R21 part of the
application, a discussion of the suitability of the proposed milestones for
assessing the success in the R21 phase, and a discussion of the implications
of successful completion of these milestones for the proposed R33 study.
This PA uses just-in-time concepts. It also uses the modular budgeting as
well as the non-modular budgeting formats (see
http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if
you are submitting an application with direct costs in each year of $250,000
or less, use the modular budget format. Otherwise follow the instructions
for non-modular budget research grant applications. (See additional SPECIFIC
INSTRUCTIONS below.) This program does not require cost sharing as defined
in the current NIH Grants Policy Statement at
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm#_Toc54600040 .
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations;
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories;
o Units of State and local governments;
o Eligible agencies of the Federal government; and
o Domestic or foreign institutions/organizations.
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
Prior to funding an application, the NCI Program Director will contact the
applicant to discuss the proposed milestones and any changes suggested by the
review panel as indicated in the Summary Statement. The Program Director and
the applicant will negotiate and agree on a final set of milestones. These
will be the basis for judging the success of the R21 work. At least one
interim progress report will be required during the R21 phase.
For funded applications, completion of the R21 milestones will elicit an
expedited review by the NCI that will determine whether or not the R33 grant
should be awarded. The release of R33 funds will be based on successful
completion of negotiated scientific milestones, program priorities, and on
the availability of funds. The expedited transitional review may result in
additional negotiations of award.
An annual meeting of all investigators funded through this program will be
held to share results and research insights that may accelerate progress.
Applicants should request travel funds in their budgets for the principal
investigator and one additional senior investigator to attend this annual
meeting.
WHERE TO SEND INQUIRIES
We encourage your inquiries concerning this PA and welcome the opportunity to
answer questions from potential applicants. Inquiries may fall into two
areas: scientific/research and financial or grants management issues:
o Direct your questions about scientific/research issues to:
Tracy G. Lugo, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Blvd., EPN Room 6035A
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-1591
FAX: (301) 402-7819
Email: lugot@mail.nih.gov
(for general inquiries and for projects specifically related to breast
cancer, lung cancer, gynecologic cancers, or brain tumors)
Magdalena Thurin, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Blvd., Room EPN 6035A
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-1591
FAX: (301) 402-7819
Email: thurinm@mail.nih.gov
(for projects related to colon cancer, gastric cancer, pancreatic cancer,
skin cancers including melanoma, sarcomas, or acute leukemias)
James V. Tricoli, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Blvd., Room EPN 6035A
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-1591
FAX: (301) 402-7819
Email: tricolij@mail.nih.gov
(for projects related to prostate cancer, renal or bladder cancer, head and
neck cancer, esophageal cancer, liver cancer, lymphomas, or chronic
leukemias)
o Direct your questions about financial or grants management matters to:
Amy Connolly
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd, Room 243
Bethesda, MD 20892-7150
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-8786
Fax: (301) 496-8601
Email: amyconnolly@nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). Applications must have a Dun and
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the
Universal Identifier when applying for Federal grants or cooperative
agreements. The DUNS number can be obtained by calling (866) 705-5711 or
through the web site at http://www.dunandbradstreet.com/. The DUNS number
should be entered on line 11 of the face page of the PHS 398 form. The PHS
398 document is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance, contact GrantsInfo; Telephone: (301) 710-0267; Email: GrantsInfo@nih.gov.
The title and number of this program announcement must be typed on line 2 of
the face page of the application form and the YES box must be checked.
SUPPLEMENTARY INSTRUCTIONS
SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION
AWARD APPLICATION:
(See below for instructions for preparing an R33 application without the R21
phase.)
R21/R33 applications must include specific aims that are relevant to each
phase as well as feasibility milestones that would justify transition to the
R33 phase. Applications must include a specific section labeled Milestones
following the Research Plan of the R21 phase. Milestones should be well
described, quantifiable and scientifically justified and should not be simply
a restatement of the R21 specific aims. A discussion of the implications of
successful completion of the milestones for the R33 phase should be included.
This section should be indicated in the Table of Contents. Applications
lacking this information, as determined by CSR or NCI staff, will be returned
to the applicant without review.
The R21/R33 application must be submitted as one application with one Face
Page. Although it is submitted as a single application, it should be clearly
organized into two phases. To accomplish a clear distinction between the two
phases, applicants are directed to complete Sections a-d of the Research Plan
twice: one write-up of Sections a-d and milestones for the R21 phase and
Sections a-d again for the R33 phase. The Form 398 Table of Contents should
be modified to show Sections a-d for each phase as well as the milestones.
There is a page limit of 25 pages for the combined text (i.e., Section a-d
and milestones for the R21 and Section a-d for the R33 phase must be
contained within the 25 page limit.) Background material or preliminary data
presented in the R21 research plan need not be repeated in the plan for the
R33. Sections e (Human Subjects) and f (Vertebrate Animals, if applicable)
should be included for each phase; the page limits do not apply to these
sections, but be concise.
In preparing the R21/R33 application, investigators should consider the fact
that applications will be assigned a single priority score. For these
reasons, the clarity and completeness of the R21/R33 application with regard
to feasibility milestones and specific goals for each phase are critical. The
presentation of milestones that are not sufficiently scientifically rigorous
to be valid for assessing progress in the R21 phase will reflect upon the
scientific judgment of the applicant.
1. FACE PAGE OF THE APPLICATION:
Item 2. Check the box marked YES and type the NUMBER AND TITLE of this PA.
Also, indicate that the application is submitted as an R21/R33.
Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT:
For the R21 phase of the combined R21/R33 application, direct costs
(excluding subcontractual party Facilities and Administrative costs) are
limited to a maximum of $275,000 for the 2-year period, and the award may not
be used to supplement an ongoing project. Insert the total costs requested
for the first year of R21 support in item 7a.
Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:
The R21 phase may be either 1 or 2 years in duration. For the R21 phase,
direct costs requested for the proposed period may not exceed $275,000 for 2
years of support. Insert the sum of all years of requested support (R21 plus
R33) in item 8a.
2. PAGE 2 - DESCRIPTION:
As part of the description, identify concisely the diagnostic strategy to be
developed, the specific clinical question to be addressed, the relationship
to presently available capabilities for cancer prognosis or prediction and
the expected impact on patient care.
3. BUDGET:
The application should contain a modular budget for the R21 phase (see below,
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS.) For R33 applications
requesting up to $250,000 direct costs per year, submit a separate modular
budget for the R33 phase. For applications requesting more than $250,000
direct costs in any year of the R33 phase, the modular format is not to be
used for the R33 phase. In this case the application should provide a
DETAILED BUDGET for Initial Budget Period (form page 4) for the initial year
of the R33 phase as well as a budget for the entire proposed period of R33
support (form page 5). Form pages should indicate which years are R21 and
R33.
4. RESEARCH PLAN:
Item a: Specific Aims:
The applicant must present specific aims that the applicant considers to be
scientifically appropriate for each of the two phases of the project. The
instructions in the PHS 398 booklet for this section of research grant
applications suggest that the applicant state the hypotheses to be tested.
Since the goal of this PA is to develop new methods for cancer prognosis and
prediction, clearly state the clinical questions to be addressed. Identify
the patient population(s) to be studied and the assay(s) or test system(s) to
be employed.
Item b: Background and Significance:
Clarify how the prognostic or predictive strategy proposed for evaluation in
this project is a significant addition to existing approaches. Explain the
potential of the proposed technology for a broad impact on patient care and
improvement in patient outcomes. Clearly identify how the project, if
successful, would result in new capabilities for cancer prognosis or
prediction. If preliminary data from the applicant’s own laboratory are not
available, this section must provide current evidence from the literature or
from other investigators to substantiate the potential clinical utility of
the proposed strategy.
Item c: Preliminary studies/Progress report:
While preliminary data are not required for the R21 phase, easily
understandable data that provide relevant information to aid review should be
included when available. An applicant may use preliminary data obtained with
the support of a previous R21 award. The R33 section of the application need
not repeat information already provided in the R21.
Applicants are encouraged to include all information required for adequate
evaluation by reviewers. However, in the event that assays and technology
are not yet patent protected and the applicant does not wish to include
complete details, the application should at a minimum provide a demonstration
(results) of the capabilities of the proposed approach.
Item d: Research Design and Methods:
Instructions for PHS 398 should be followed. In addition, for the R21 phase
only, the following information must be included as a final section of Item
d:
Applications must include a specific section labeled Milestones following the
Research Design and Methods of the R21 phase. Milestones should be well
described, quantifiable, and scientifically justified and not be simply a
restatement of the specific aims. A discussion of the milestones relative to
the success of the R21 phase, as well as implications of successful
completion of the milestones for the R33 phase should be provided. The page
number of the Milestones section should be listed in the Table of Contents.
Applications lacking this information, as determined by NIH staff, will be
returned to the applicant without review.
The following examples are provided to illustrate the recommended level of
detail for milestones, but should not be considered an exhaustive list of
potentially appropriate milestones. Nor is this list intended to recommend
the use of specific statistical tests. You should apply those methods that
are most appropriate for your data.
o Assay conditions will be optimized to achieve conditions where the
analytic sensitivity is at least X and the specificity is at least Y when Z
samples, half of which are truly positive for the analyte, are studied.
o The assay to be used in the R33 phase will perform reproducibly as defined
by a coefficient of variation less than Y in a series of X test specimens.
o Show that the marker, as defined by a cut-off value of X, is correlated
with the outcome of interest in the patient population for the R33 phase by
demonstrating that there is a difference of at least Y percent in the
prevalence of the marker when comparing N1 patients with outcome type 1 to N2
patients with outcome type 2.
o The prognostic significance of molecular profiles defined in the training
set will be demonstrated in an independent set of X specimens. This milestone
will be met if values of Y percent or higher are achieved for both
sensitivity and specificity in predicting the clinical outcome of interest
for the R33 phase.
For the R33 phase, Item d of the Research Plan should include a statistical
section that discusses the choice of the study design and laboratory methods.
Sample sizes must be clearly stated and justified with power calculations.
The statistician involved with the project should be identified and a letter
of support included if no effort is requested in the budget. Plans for data
management and verification of clinical research data should also be
described. Collaborative arrangements should be clearly documented, and where
collaborations involve NCI-sponsored clinical trials the protocol numbers
should be provided. Letters of support should be included in the application
to substantiate plans for collection of follow-up information beyond the
period of award. Where appropriate, applicants are strongly encouraged to
include a copy of the complete clinical protocol in the Appendix.
Item e, Human Subjects: Refer to the instructions for the PHS 398. For each
phase of the project provide a separate description of the participation of
human subjects in research, and place it following item d of the Research
Plan. The description for each phase must include sections that respond to
the instructions in the PHS 398 for Human Subjects Research, Women and
Minority Inclusion in Clinical Research" and the "Inclusion of Children" and
Data and Safety Monitoring if the research involves a clinical trial.
Although no specific page limits apply to these sections of the application,
be succinct.
Item f, Vertebrate Animals: Refer to the instructions for the PHS 398. If
applicable, for each phase of the project provide a separate description of
the use of vertebrate animals in the proposed research that responds to the
instructions in the PHS 398. Place it following item e of the Research Plan.
Although no specific page limits apply to these sections of the application,
be succinct.
5. CONSULTANTS/COLLABORATORS:
Include letters of support from collaborators in this section of the
application. Do not place them in the Appendix.
SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED
WITHOUT THE R21 PHASE:
1. FACE PAGE OF THE APPLICATION:
Item 2. Check the box marked "YES" and type the TITLE AND NUMBER of this PA.
Also, indicate that the application is for an R33.
2. DESCRIPTION:
As part of the description, identify concisely the diagnostic strategy to be
developed, the specific clinical question to be addressed, the relationship
to presently available capabilities for cancer prognosis or prediction and
the expected impact on patient care.
3. BUDGET:
For R33 applications requesting up to $250,000 direct costs per year, submit
a modular budget (see below, SPECIFIC INSTRUCTIONS FOR MODULAR GRANT
APPLICATIONS). For R33 applications requesting more than $250,000 direct
costs in any year, the modular format is not to be used. In this case the
application should provide a DETAILED BUDGET for Initial Budget Period (form
page 4) for the initial year of the R33 as well as a budget for the entire
proposed period of support (form page 5).
4. RESEARCH PLAN:
Item a: Specific Aims:
The instructions in the PHS 398 booklet for this section of research grant
applications suggest that the applicant state the hypotheses to be tested.
Since the goal of this PA is to develop new methods for cancer prognosis and
prediction, clearly state the clinical questions to be addressed. Identify
the patient population(s) to be studied and the assay(s) or test system(s) to
be employed.
Item b: Background and Significance:
Clarify how the prognostic or predictive strategy proposed for evaluation in
this project is a significant addition to existing approaches. Explain the
potential of the proposed technology for a broad impact on patient care and
improvement in patient outcomes. Clearly identify how the project, if
successful, would result in new capabilities for cancer prognosis or
prediction. If preliminary data from the applicant’s own laboratory are not
available, this section must provide current evidence from the literature or
from other investigators to substantiate the potential clinical utility of
the proposed strategy.
Item c: Preliminary studies/Progress Report:
R33 applications should clearly state how feasibility for the project has
already been demonstrated. Preliminary data relevant to both the laboratory
assay(s) or test system(s) and the clinical outcome measurements should be
presented. This section must document that progress has been achieved which
is essentially equivalent to that expected from an R21 grant. An applicant
may use preliminary data obtained with the support of a previous R21 award.
Item d: Research Design and Methods:
Instructions for PHS 398 should be followed. Item d of the Research Plan
should include a statistical section that discusses the choice of the study
design and laboratory methods. Sample sizes must be clearly stated and
justified with power calculations. The statistician involved with the project
should be identified and a letter of support included if no effort is
requested in the budget. Plans for data management and verification of
clinical research data should also be described. Collaborative arrangements
should be clearly documented, and where collaborations involve NCI-sponsored
clinical trials, the protocol numbers should be provided. Letters of support
should be included in the application to substantiate plans for collection of
follow-up information beyond the period of award. Where appropriate,
applicants are strongly encouraged to include a copy of the complete clinical
protocol in the Appendix.
Item e: Human Subjects
Follow all instructions in the PHS 398.
Item f: Vertebrate Animals
Follow all instructions in the PHS 398 if applicable.
5. CONSULTANTS/COLLABORATORS:
Include letters of support from collaborators in this section of the
application. Do not place them in the Appendix.
APPLICATION RECEIPT DATES: Applications submitted in response to this program
announcement will be accepted at the standard application deadlines, which
are available at http://grants.nih.gov/grants/dates.htm. Application
deadlines are also indicated in the PHS 398 application kit.
SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications
requesting up to $250,000 per year in direct costs must be submitted in a
modular grant format. The modular grant format simplifies the preparation of
the budget in these applications by limiting the level of budgetary detail.
Applicants request direct costs in $25,000 modules. Section C of the
research grant application instructions for the PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step
guidance for preparing modular grants. Additional information on modular
grants is available at
http://grants.nih.gov/grants/funding/modular/modular.htm. See also SPECIFIC
INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD
APPLICATION above.
SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:
Applications requesting $500,000 or more in direct costs for any year must
include a cover letter identifying the NIH staff member within one of NIH
institutes or centers who has agreed to accept assignment of the application.
Applicants requesting more than $500,000 must carry out the following steps:
1)Contact the IC program staff at least 6 weeks before submitting the
application, i.e., as you are developing plans for the study;
2) Obtain agreement from the IC staff that the IC will accept your
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff member
and IC who agreed to accept assignment of the application
This policy applies to all investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended or revised
version of these grant application types. Additional information on this
policy is available in the NIH Guide for Grants and Contracts, October 19,
2001, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of
the application, including the checklist, and five signed 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 courier/express service)
APPLICATION PROCESSING: Applications must be mailed on or before the receipt
dates described at
http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will
not accept any application in response to this PA 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 a substantial revision of an unfunded version of an application
already reviewed, but such application must include an Introduction
addressing the previous critique.
Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and funding
assignment within 8 weeks.
PEER REVIEW PROCESS
Applications submitted for this PA will be assigned on the basis of
established PHS referral guidelines. Appropriate scientific review groups
convened in accordance with the standard NIH peer review procedures
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific
and technical merit.
As part of the initial merit review, all applications will:
o Undergo a selection process in which only those applications deemed to have
the highest scientific merit, generally the top half of applications under
review, will be discussed and assigned a priority score
o Receive a written critique
o Undergo a second level review by an appropriate national advisory council
or board.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments, reviewers will be asked to evaluate the application in
order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals. The scientific review
group will address and consider each of these criteria in assigning the
application’s overall score, weighting them as appropriate for each
application.
o Significance
o Approach
o Innovation
o Investigator
o Environment
The application does not need to be strong in all categories to be judged
likely to have 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 analyses
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 methods?
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?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following
items will be considered in the determination of scientific merit and the
priority score:
MILESTONES: How appropriate are the proposed milestones to judge the success
of the proposed R21 project and to determine whether the R33 grant should be
awarded? Do they set forth specific criteria, in sufficient detail, that will
permit a straightforward decision about whether or not they have been
accomplished? Do the milestones establish feasibility for all aspects of the
proposed R33 work?
For the R21/R33 Phased Innovation Award Application, the initial review group
will evaluate the specific goals for each phase and the feasibility
milestones that would justify expansion to the R33 phase. A single priority
score will be assigned to each scored application. As with any grant
application, the initial review group has the option of recommending support
for a shorter duration than that requested by the applicant and basing the
final merit rating on the recommended portion of the application. For the
R21/R33 application, this may result in a recommendation that only the R21
phase be supported, based on concerns related to the application's specific
goals and the feasibility milestones justifying expansion to the R33 phase.
Deletion of the R33 phase by the review panel or presentation of inadequate
milestones in the application may affect the merit rating of the application.
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human
subjects and protections from research risk relating to their participation
in the proposed research will be assessed. (See criteria included in the
section on Federal Citations, below.)
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of
plans to include subjects from both genders, all racial and ethnic groups
(and subgroups), and children as appropriate for the scientific goals of the
research will be assessed. Plans for the recruitment and retention of
subjects will also be evaluated. (See Inclusion Criteria in the sections on
Federal Citations, below.)
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to
be used in the project, the five items described under Section f of the PHS
398 research grant application instructions (rev. 5/2001) will be assessed.
ADDITIONAL REVIEW CONSIDERATIONS
SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct
costs in any year of the proposed research are expected to include a data
sharing plan in their application. The reasonableness of the data sharing
plan or the rationale for not sharing research data will be assessed by the
reviewers. However, reviewers will not factor the proposed data sharing plan
into the determination of scientific merit or priority score. (See below,
SHARING RESEARCH DATA.)
BUDGET: The reasonableness of the proposed budget and the requested period
of support in relation to the proposed research.
AWARD CRITERIA
Applications submitted in response to a PA will compete for available funds
with all other recommended applications. The following will be considered in
making funding decisions:
o Scientific merit of the proposed project as determined by peer review;
o Availability of funds; and
o Relevance to program priorities.
REQUIRED FEDERAL CITATIONS
HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and
others, and the importance of the knowledge gained or to be gained. See
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.
DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy,
effectiveness and comparative trials (phase III). The establishment of data
and safety monitoring boards (DSMBs) is required for multi-site clinical
trials involving interventions that entail potential risk to the
participants. (See NIH Policy for Data and Safety Monitoring, NIH Guide for
Grants and Contracts, June 12, 1998, at
http://grants.nih.gov/grants/guide/notice-files/not98-084.html.)
Clinical trials supported or performed by NCI require special considerations.
The method and degree of monitoring should be commensurate with the degree of
risk involved in participation and the size and complexity of the clinical
trial. Monitoring exists on a continuum from monitoring by the principal
investigator/project manager or NCI program staff or a Data and Safety
Monitoring Board (DSMB). These monitoring activities are distinct from the
requirement for study review and approval by an Institutional review Board
(IRB). For details about the Policy for the NCI for Data and Safety
Monitoring of Clinical, trials see
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II
clinical trials, investigators must submit a general description of the data
and safety monitoring plan as part of the research application. For
additional information see NIH Guide Notice on Further Guidance on a Data
and Safety Monitoring for Phase I and II Trials at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.
Information concerning essential elements of data safety monitoring plans for
clinical trials funded by the NCI is available at
http://www.cancer.gov/clinical_trials/.
ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities
involving live, vertebrate animals must comply with PHS Policy on Humane Care
and Use of Laboratory Animals
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as
mandated by the Health Research Extension Act of 1985
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA
Animal Welfare Regulations
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.
SHARING RESEARCH DATA: Investigators submitting an NIH application seeking
more than $500,000 or more in direct costs in any single year are expected to
include a plan for data sharing
(http://grants.nih.gov/grants/policy/data_sharing) or state why this is not
possible. Investigators should seek guidance from their institutions, on
issues related to institutional policies, local IRB rules, as well as local,
State, and Federal laws and regulations, including the Privacy Rule.
Reviewers will consider the data sharing plan but will not factor the plan
into the determination of the scientific merit or the priority score.
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a
clear and compelling justification is 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 clinical research should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical Research -
Amended, October, 2001," published in the NIH Guide for Grants and Contracts
on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: (a)
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
The NIH maintains a policy 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 scientific and ethical reasons not to include
them.
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 is available at
http://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject participants for
all investigators submitting NIH proposals for research involving human
subjects. You will find this policy announcement in the NIH Guide for Grants
and Contracts Announcement, dated June 5, 2000, at
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 available online at: http://cme.nci.nih.gov/.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a
project that is supported in whole or in part with Federal funds and (2)
cited publicly and officially by a Federal agency in support of an action
that has the force and effect of law (i.e., a regulation) may be accessed
through FOIA. It is important for applicants to understand the basic scope
of this amendment. NIH has provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the
application. In addition, applicants should think about how to structure
informed consent statements and other human subjects procedures given the
potential for wider use of data collected under this award.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The
Department of Health and Human Services (DHHS) issued final modification to
the Standards for Privacy of Individually Identifiable Health Information,
the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal
regulation under the Health Insurance Portability and Accountability Act
(HIPAA) of 1996 that governs the protection of individually identifiable
health information, and is administered and enforced by the DHHS Office for
Civil Rights (OCR).
Decisions about applicability and implementation of the Privacy Rule reside
with the researcher and his/her institution. The OCR website
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including
a complete Regulation Text and a set of decision tools on Am I a covered
entity? Information on the impact of the HIPAA Privacy Rule on NIH
processes involving the review, funding, and progress monitoring of grants,
cooperative agreements, and research contracts can be found at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
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. Furthermore,
we caution reviewers 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
is related to one or more of the priority areas. 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 at http://www.cfda.gov/ and is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review. Awards are made under the authorization of Sections
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All
awards are subject to the terms and conditions, cost principles, and other
considerations described in the NIH Grants Policy Statement. The NIH Grants
Policy Statement can be found at
http://grants.nih.gov/grants/policy/policy.htm.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and discourage the 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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NIH Funding Opportunities and Notices
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