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 301/435-0714, 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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