PHASED APPLICATION AWARDS IN CANCER PROGNOSIS AND PREDICTION
Release Date: March 1, 2001 (see replacement PAR-03-098)
PA NUMBER: PAR-01-061
National Cancer Institute
Letter of Intent Date: May 9, 2001, November 6, 2001, May 2, 2002,
and November 7, 2002
Application Receipt Date: June 13, 2001, December 11, 2001, June 11, 2002,
and December 11, 2002
THIS PROGRAM ANNOUNCEMENT (PAR) INCLUDES DETAILED MODIFICATIONS TO STANDARD
APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING APPLICATIONS IN
RESPONSE TO THIS PAR.
PURPOSE
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 Program Announcement (PAR) 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.
This solicitation will utilize the newly created Phased Application Award
Mechanism (R21/R33). Specific features of this mechanism include:
o Single submission and evaluation of both the R21 and R33 as one application.
o Expedited transition from feasibility phase to application phase.
o Flexible budgets.
o Flexible staging of feasibility and application phases.
Small businesses are encouraged to consider a parallel program announcement
(http://grants.nih.gov/grants/guide/pa-files/PAR-01-062.html) of identical
scientific scope that utilizes the SBIR and STTR mechanisms with accelerated
transitional review, as well as cost and duration requirements, comparable to
the Phased Application Awards.
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 Herceptin7, forerunner of a new class of therapeutic agents directed
against specific molecular targets. These markers are the exception, not the
rule. During the past five years the College of American Pathologists, 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. But 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 format 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 application 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
application 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.
Applications involving collaborations with industrial partners either through
this PAR or the parallel SBIR/STTR solicitation
(http://grants.nih.gov/grants/guide/pa-files/PA-01-062.html) are encouraged.
Applicants should justify their proposals on the strength of the study
proposed in the R33 component. Applications that include an R21 component
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 PAR.
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. Applicants who can provide
sufficient preliminary data are encouraged to apply for R33 grants.
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 PAR. Applicants who are interested in R21 projects
without an R33 phase should consider NCI Program Announcements such as PA-01-
010 (Exploratory Studies in Cancer Detection, Prognosis and Prediction) or PA-
01-015 (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-01-030 (Exploratory Developmental Grants for
Diagnostic Cancer Imaging) or PAR-00-089 (Development of Novel Imaging
Technologies-Phased Innovation Award), both sponsored by the NCI Biomedical
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. Examples
of possible milestones include:
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
o Provide evidence that the number of participants or specimens required by
the study design in the R33 phase can be accrued
MECHANISM OF SUPPORT
Responsibility for the planning, direction and execution of the proposed
project will be solely that of the applicant. Except as otherwise stated in
this program announcement, awards will be administered under NIH grants policy
as stated in the NIH Grants Policy Statement, rev. March 2001.
Support for this program will be through the National Institutes of Health
(NIH) Exploratory/Developmental Research Grant (R21) and the
Exploratory/Developmental Research Grant Phase 2 (R33). The R33 is a newly
established NIH grant mechanism to provide a second phase for the support of
innovative exploratory and developmental 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. Because of the combined use
of the R21/R33 the modular grant instructions will not apply to these
applications.
Under this PAR, applicants can submit either a combined R21/R33 application
(Phased Application Award application) or the R33 application alone, if
feasibility can be documented, as described in the APPLICATION PROCEDURES
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. The NIH Grants Policy Statement applies
to all awards.
For combined R21/R33 applications, the R21 phase may not exceed $100,000
direct costs per year. R21 budgets can exceed this cap to accommodate F&A
costs to subcontracts to the project. Although the R33 application has no
official budgetary limit, applications requesting in excess of $500,000
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 responsiveness of the proposed project. Early contact with NCI
staff is particularly critical relative to this PAR because it uses a new
grant mechanism (R33) as well as an expedited transition procedure. Refer to
the INQUIRIES section of this program announcement for NCI staff contacts.
The combined R21/R33 application offers two advantages over the regular
application process:
1. Single submission and evaluation of both the R21 and the R33 as one
application.
2. Minimal or no funding gap between funded R21 and R33 grants. 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 Application Award, the R21 phase must include
milestones that will be used to judge the feasibility of the research proposed
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 well-defined quantifiable milestones that are to be
completed by the end of the R21 part of the proposed project and a discussion
of the suitability of the proposed milestones for assessing the prospects for
success in the proposed R33 study.
Through a separate program announcement (PAR-01-062), the NCI is inviting
applications for SBIR and STTR support, focusing on the identical research
areas as described in the RESEARCH OBJECTIVES section of this solicitation.
For the SBIR/STTR solicitation, the expedited NCI review and cost allowance
policies and procedures will be identical to this PAR. Qualified applicants
are strongly encouraged to consider responding to the SBIR/STTR program
announcement. SBIR and STTR application information is available on the web
at: http://grants.nih.gov/grants/funding/sbir.htm
Potential applicants who believe that they may be eligible for the SBIR/STTR
award should consult the PHS SBIR and STTR Omnibus Solicitation prior to
discussions of their eligibility with NCI staff listed under INQUIRIES.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by foreign and domestic, for-profit and
non-profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government. Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as principal
investigators.
INQUIRIES
Inquiries are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Tracy G. Lugo, Ph.D.
Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Blvd., Room 6042
Rockville, MD 20892
Telephone: (301) 496-1591
FAX: (301) 402-7819
Email: TL82S@nih.gov
Direct inquiries regarding fiscal matters to:
Ms. Kathleen J. Shino
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd., EPS Room 243
Bethesda, MD 20892-7150
Telephone: (301) 846-1016
FAX: 301-846-5720
Email: shinok@gab.nci.nih.gov
Direct inquiries regarding review matters to:
Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: tf12w@nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit, by the dates listed on the first
page of this PAR, a letter of intent that includes a descriptive title of the
proposed research, the name, address and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of this PAR. Although a letter of
intent is not required, is not binding, and does not enter into the review of
a subsequent application, the information that it contains allows the NCI
staff to estimate the potential review workload and plan the review.
The letter of intent is to be sent to Dr. Tracy Lugo at the address listed
under INQUIRIES by the letter of intent receipt date.
APPLICATION PROCEDURES
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
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.
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 of their proposed
project to the goals of this PAR.
All clinical trials supported or performed by NCI require some form of
monitoring. 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 to 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 of the NCI for Data 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. See NIH Guide Notice on Further Guidance on a Data and Safety
Monitoring for Phase I and II Trials for additional information:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.
SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE COMBINED R21/R33 PHASED
APPLICATION AWARD APPLICATION
Applications for R21/R33 grants are to be submitted on the grant application
form PHS 398 (rev. 4/98) and prepared according to the instructions provided
unless specified otherwise within this section.
The R21/R33 application must include the specific aims for each phase and the
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. Successful completion of the milestones should
establish feasibility for the proposed R33 work. This section should be
indicated in the Table of Contents. Applications lacking this information, as
determined by the NCI program staff, will be returned to the applicant without
review. See the Research Objectives section above for examples of possible
milestones.
Prior to funding an application, the 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.
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.
The R21/R33 Phased Application Award application must be submitted as a single
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,
followed by the 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 composite a-d text (i.e., section a-d and milestones for the R21
and sections a-d for the R33 phase must be contained within the 25 page
limit.)
In preparing the R21/R33 application, investigators should consider the fact
that applications will be assigned a single priority score. In addition, as
discussed in the REVIEW CONSIDERATIONS section, the initial review panel has
the option of recommending only the R21 phase for support. However, a Phased
Innovation Award Application with an R33 Phase that is so deficient in merit
that it is not recommended for support will reflect upon the judgment of the
applicant. For these reasons, the clarity and completeness of the R21/R33
application with regard to specific goals for each phase and feasibility
milestones for the R21 phase are critical. The presentation of milestones that
are not sufficiently scientifically rigorous to be valid for assessing the
success of the R21 phase will reflect upon the scientific judgement of the
applicant in this proposal.
1. Face Page of the application:
Item 2. Check the box marked "YES" and type the number and title of this
program announcement. Also indicate that the application is 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 are
limited to a maximum of $100,000 per year for a maximum of two years and the
award may not be used to supplement an ongoing project. The requested budgets
can exceed this cap to accommodate indirect costs to subcontracts to the
project. The R21 phase may be either one or two years in duration. Insert
the first year of R21 support in item 7a.
Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:
For the R21 phase, direct costs requested for the proposed period may not
exceed $200,000 for two years of support. The statement in item 7a above
pertaining to subcontract costs also applies here. Insert sum of all years of
requested support (R21 plus R33) in item 8a.
2. Budget:
The application should provide a detailed budget for the Initial Budget Period
(form page 4), for each of the initial years of the R21 and R33 phases as well
as a budget for the entire proposed period of support (form page 5). Form
pages should indicate which years are R21 and R33. All budgets should include
a written justification. The Modular Budget approach is not to be used.
An annual meeting of all investigators funded through this program will be
held to share progress and research insights that may benefit the program.
Applicants should request travel funds in their budgets for the principal
investigator and one additional senior investigator to attend this annual
meeting.
3. Research Plan:
Item a., Specific Aims
The applicant must present specific aims that are scientifically appropriate
for each phase of the project. Clearly state the clinical question(s) 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 improvement over existing approaches. 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 submission of the R21 phase, they
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.
Item d., Research Design and Methods
Follow the instructions in the PHS 398 booklet. 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 suitability of the
milestones for judging the success of the R21 phase, as well as how their
successful completion establishes feasibility of the R33 phase must be
included. The page number of the milestones section should be indicated in
the Table of Contents. Applications lacking this information, as determined by
the NCI program staff, will be returned to the applicant without review.
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 on the grant application. 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.
For both the R21 and R33 phases, the Research Plans must include the following
sections:
Gender and Minority Inclusion for Research Involving Human Subjects -
Describe the composition of the proposed study population in terms of gender
and racial/ethnic group and provide a rationale for selection of such
subjects. Display this proposed composition using the Inclusion Report Format
provided in the PHS 398 form instructions.
Participation of Children - This section should provide either a description
of the plans to include children and a rationale for selecting or excluding a
specific age range of child, or an explanation of the reason(s) for excluding
children as participants in the research (see justifications for exclusions in
the PHS 398 form instructions).
4. Human Subjects
For each phase of the project provide a separate description of the
participation of human subjects in the research, addressing the six points in
the application form instructions.
5. Vertebrate Animals
For each phase of the project provide a separate description of the use of
vertebrate animals in the research, addressing the five points in the
application form instructions.
6. 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
Applications for R33 grants are to be submitted on the grant application form
PHS 398 (rev. 4/98) and prepared according to the instructions provided unless
specified otherwise within this section.
1. Face Page of the application:
Item 2. Check the box marked "YES" and type the number and title of this
program announcement. Also indicate that the application is an R33.
2. Budget:
The application should provide a detailed budget for Initial Budget Period
(form page 4) as well as a budget for the entire proposed period of support
(form page 5). All budgets should include a written justification. The
Modular Budget approach is not to be used.
An annual meeting of all investigators funded through this program will be
held to share progress and research insights that may benefit the program.
Applicants should request travel funds in their budgets for the principal
investigator and one additional senior investigator to attend this annual
meeting.
3. Research Plan:
Item a., Specific Aims
Clearly state the clinical question(s) 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 improvement over existing approaches.
Item c., Preliminary Studies/Progress Report
This section must document that feasibility studies have been completed .
Preliminary data relevant to both the laboratory assay(s) or test system(s)
and the clinical outcome measurements should be presented. An applicant may
use preliminary data obtained with the support of a previous R21 award.
Item d., Research Design and Methods
Follow the instructions in the PHS 398 booklet. 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 on the
grant application. 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.
The Research Plan must include the following sections:
Gender and Minority Inclusion for Research Involving Human Subjects - Describe
the composition of the proposed study population in terms of gender and
racial/ethnic group and provide a rationale for selection of such subjects.
Display this proposed composition using the Inclusion Report Format provided
in the PHS 398 form instructions.
Participation of Children - This section should provide either a description
of the plans to include children and a rationale for selecting or excluding a
specific age range of child, or an explanation of the reason(s) for excluding
children as participants in the research (see justifications for exclusions in
the PHS 398 form instructions).
4. Human Subjects: All instructions in the Form 398 application kit apply.
5. Vertebrate Animals: All instructions in the Form 398 application kit
apply.
6. Consultants/Collaborators
Include letters of support from collaborators in this section of the
application. Do not place them in the Appendix.
FOR ALL APPLICATIONS:
Appendix: All instructions in the Form 398 application kit apply.
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/courier service)
To expedite the review process, at the time of submission, send two additional
copies of the application to:
Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Applications must be received by the receipt dates listed at the beginning of
this PA.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed by the CSR for completeness and by
NCI program staff for responsiveness to the objectives of the PAR.
Applications not adhering to application instructions as described above and
those applications that are incomplete as determined by CSR or by NCI program
staff will be returned to the applicant without review.
Applications that are complete and adhere to the guidelines of this PAR will
be evaluated for scientific and technical merit by an appropriate peer review
group convened by the Division of Extramural Activities, NCI in accordance
with the review criteria stated below. As part of the initial merit review,
all applicants will receive a written critique and may undergo a process in
which only those applications deemed to have the highest scientific merit,
generally the top half of the applications, will be discussed, assigned a
priority score and receive a second level review by the National Cancer
Advisory 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. 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 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? How is the proposed diagnostic strategy superior to existing
alternatives? What will be the impact on the design of future clinical trials
or on clinical practice?
2. Approach. Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project? This includes the statistical rationale for the study design and the
choice of sample size. Does the applicant acknowledge potential problem areas
and consider alternative tactics? Has the applicant considered how the R33
study, if promising, could proceed into eventual definitive testing of the
diagnostic strategy?
3. Milestones. How appropriate are the proposed milestones for judging the
success of the proposed R21 work and determining whether the R33 grant should
be awarded? Do the milestones establish feasibility for all aspects of the
proposed R33 work?
4. 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 methods or technologies? What is the
throughput and cost effectiveness of the proposed assay(s)? What additional
uses can be projected for the proposed assay(s), or what additional groups of
patients might benefit from the new diagnostic strategy?
5. 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)?
6. 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?
Are the planned statistical and data management resources adequate?
Additional Considerations
For the R21/R33 Phased Innovation Award Application, the initial review group
will evaluate the specific aims for each phase and the feasibility milestones
that would justify transition 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 applicant's specific aims and the
feasibility milestones justifying expansion to the R33 phase. Deletion of the
R33 phase by the review panel or inadequate milestones will affect the merit
rating of the application.
The initial review group will also examine: the appropriateness of the
proposed project budget and duration; the adequacy of plans to include both
genders, 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
Applications will compete for available funds with all other recommended
applications assigned to the NCI. The following will be considered in making
funding decisions: quality of the proposed project as determined by peer
review, availability of funds, and program priority.
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 subpopulations 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 scientific and ethical 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 the policy 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
policy that was 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.
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 (see
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-004.html).
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, Phased Application Awards in
Cancer Prognosis and Prediction, is related to the priority area of 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.
93.394, (use appropriate program number). 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.
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