PHASED APPLICATION AWARDS IN CANCER PROGNOSIS AND PREDICTION

RELEASE DATE:  April 8, 2003

PA NUMBER:  PAR-03-098 (see replacement PA-04-102)

EXPIRATION DATE:  December 12, 2003, unless reissued

National Cancer Institute (NCI)  
 (http://www.nci.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.394

LETTER OF INTENT RECEIPT DATES:  May 14, 2003 and November 13, 2003

APPLICATION RECEIPT DATES:  June 11, 2003 and December 11, 2003 

This Program Announcement (PA) replaces PAR-01-061, which was published in the 
NIH Guide on March 1, 2001.

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 Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Receipt and Review Schedule
o Required Federal Citations

THIS PROGRAM ANNOUNCEMENT (PA) INCLUDES DETAILED MODIFICATIONS TO STANDARD 
APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING APPLICATIONS IN 
RESPONSE TO THIS PA. 

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 Program Announcement (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.

Small businesses are encouraged to consider a parallel program announcement of 
identical scientific scope PAR-03-099 at  
(http://grants.nih.gov/grants/guide/pa-files/PAR-03-099.html) that utilizes 
the SBIR and STTR award mechanisms.

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 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 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.

Applications involving collaborations with industrial partners either through 
this PAR or the parallel SBIR/STTR solicitation PAR-03-099 at 
(http://grants.nih.gov/grants/guide/pa-files/PAR-03-099.html) are encouraged.

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 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. 

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.

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.  Milestones will be negotiated and may be modified 
in response to reviewers' recommendations (see below, AWARD CRITERIA).

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-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-01-030 (Exploratory Developmental Grants for 
Diagnostic Cancer Imaging or PAR-01-101 (Development of Novel Technologies for 
In Vivo Imaging: 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.  

MECHANISMS OF SUPPORT 

This PA will use the National Institutes of Health (NIH) 
Exploratory/Developmental Research Grant (R21) and the 
Exploratory/Developmental Research Grant Phase 2 (R33).  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. The NIH Grants 
Policy Statement applies to all awards.

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 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.

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 
indirect costs to subcontracts to the project.  
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 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.

Through a separate program announcement PAR-03-099 at 
(http://grants.nih.gov/grants/guide/pa-files/PAR-03-099.html), 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 review, and cost allowance 
policies and procedures will be identical to this PA.  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.

ELIGIBLE INSTITUTIONS 

Applications may be submitted by:

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
o Domestic or foreign 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 

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 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, 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., Room EPN 6035A
Bethesda, MD  20892
Telephone:  (301) 496-1591
FAX: 301-402-7819
Email: lugot@mail.nih.gov
(for general inquiries and for projects specifically related to breast cancer, 
gynecologic cancers, gastric cancer, pancreatic cancer 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
Telephone:  (301) 496-1591
FAX: 301-402-7819
Email: thurinm@mail.nih.gov
(for projects related to colon 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
Telephone:  (301) 496-1591
FAX: 301-402-7819
Email: tricolij@mail.nih.gov
(for projects related to prostate cancer, renal or bladder cancer, liver 
cancer, lymphomas or chronic leukemias)

Barbara Conley, M.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Blvd., Room EPN 6035A
Bethesda, MD  20892
Telephone:  (301) 496-1591
FAX: 301-402-7819
Email: conleyb@mail.nih.gov
(for projects related to lung cancer, head and neck cancer or esophageal 
cancer)

o Direct your questions about peer review issues to:

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Telephone: (301) 496-3428
FAX: (301) 402-0275 
Email:  ncirefof@dea.nci.nih.gov

o Direct your questions about financial or grants management matters to:

Ms. Eileen Natoli
Section Chief
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd.
EPS – Room 243
Bethesda, Maryland 20892
Phone: (301) 496-8791
Fax: (301) 496-8601
E-mail: natolie@gab.nci.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this PA 

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 NCI staff to estimate the potential review workload and plan 
the review.
 
The letter of intent is to be sent by the date listed at the beginning of this 
document.  The letter of intent should be sent to:

Tracy G. Lugo, 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: lugot@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001 or most recent version).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, Telephone 
(301) 435-0714, Email: GrantsInfo@nih.gov.  This PA does not use the "modular 
grant" application process.

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 special 
receipt dates and an expedited transition procedure. Refer to the INQUIRIES 
sections of this program announcement for NCI staff contacts.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted by the receipt dates listed on the first page of 
this program announcement.  

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 are 
limited to a maximum of $100,000 per year for up to 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. 
Insert the total costs requested for first year of R21 support in item 7a.

Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:
The R21 phase may be either one or two years in duration. For the R21 phase, 
direct costs requested for the proposed period may not exceed $200,000 for two 
years of support.  The requested budgets can exceed this cap to accommodate 
indirect costs to subcontracts to the project.  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 provide a DETAILED BUDGET for 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 justification for each item requested.  The modular budget format is NOT to 
be used.

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% 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% 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:
The application should provide a DETAILED BUDGET for the Initial Budget Period 
(form page 4) as well as a budget for the entire proposed period of support 
(form page 5).  Budget should include a justification of all items requested. 
The modular budget format is NOT to be used.

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.

FOR ALL APPLICATIONS:

Appendix: All instructions in the Form 398 kit apply.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and three 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 express/courier service)

To expedite the review process, at the time of submission, send two additional 
copies of the application to:

Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)

APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE 
WILL NO LONGER BE ACCEPTED.  This policy does not apply to courier deliveries 
(i.e., FEDEX, UPS, DHL, etc.) http://grants.nih.gov/grants/guide/notice-
files/NOT-CA-02-002.html.  This change in practice is effective immediately.  
This policy is similar to and consistent with the policy for applications 
addressed to Centers for Scientific Review (CSR) as published in the NIH Guide 
Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html 

APPLICATION PROCESSING: Applications must be received by the receipt dates 
listed at the beginning of the PAR.  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 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

Upon receipt, applications will be reviewed for completeness by the CSR and 
for adherence to the guidelines of this PA by the NCI program staff.  
Applications not adhering to the guidelines of this PA, 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 PA will be 
evaluated for scientific and technical merit by an appropriate peer review 
group convened by the Division of Extramural Activities of the NCI in 
accordance with the review criteria stated below. 

As part of the initial merit review, all applications will:

o  Receive a written critique
o  Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score
o  Those applications that receive a priority score will undergo a second 
level review by the National Cancer Advisory Board (NCAB).

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 discuss the following aspects 
of your application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals. 

o Significance 
o Approach 
o Milestones
o Innovation
o Investigator
o Environment
  
The scientific review group will comment on each of these criteria in 
assigning your application's overall score, weighting them as appropriate for 
each application.  Your 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, you 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 the study address an important problem? If the aims of the application 
are achieved, how do they advance scientific knowledge?  What will be the 
effect of these studies on the concepts or methods that drive this field?  
What is the throughput and cost effectiveness of the proposed assay(s)? What 
will be the impact on 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 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?  

(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 methodologies or technologies? How is the proposed diagnostic 
strategy superior to existing alternatives? What additional uses can be 
projected from the proposed assay(s), or what additional groups of patients 
might benefit from the new diagnostic strategy?

(5) INVESTIGATOR: 
Are the researchers appropriately trained and well suited to carry out this 
work?  Is the work proposed appropriate to the experience level of the 
principal investigator and to that of other researchers, including consultants 
and collaborators (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 REVIEW CRITERIA:  In addition to the above criteria, the 
application will also be reviewed with respect to the following:

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.  

BUDGET:  
The reasonableness of the proposed budget and the requested period of support 
in relation to the proposed research.

OTHER:
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, in rare instances this might result in a recommendation that only 
the R21 phase be supported. 

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 
o  Relevance to program priorities

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.  

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.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Dates:  May 14, 2003 and November 13, 2003
Application Receipt Dates:  June 11, 2003 and December 11, 2003
NCAB Review Dates:  February 18, 2004 and June 8, 2004
Earliest Anticipated Award Date:  April 1, 2004 and July 1, 2004

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.

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving clinical trials, including Phase I and Phase II trials, must include 
provisions for assessment of patient eligibility and status, rigorous data 
management, quality assurance, and auditing procedures.  In addition, it is 
NIH policy that all clinical trials require data and safety monitoring, with 
the method and degree of monitoring being commensurate with the risks (NIH 
Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, 
June 12, 1998: 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.  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.  Information concerning essential elements of 
data safety monitoring plans for clinical trials funded by the NCI is available:  
http://www.cancer.gov/clinical_trials/.

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 AMENDMENT "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. 
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 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). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

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 No. 93.394 see 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 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 described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92.

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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