STRATEGIC PARTNERING TO EVALUATE CANCER SIGNATURES

RELEASE DATE:  January 29, 2004
 
RFA Number:  RFA-CA-04-015

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH) 
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION:
National Cancer Institute (NCI)
 (http://www.nci.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.394, and 93.395
  
LETTER OF INTENT RECEIPT DATE:  June 22, 2004
APPLICATION RECEIPT DATE:  July 22, 2004
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Pre-Application Meeting
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The purpose of this initiative is to build on recent demonstrations 
that molecular signatures correlate with important clinical parameters 
in cancer.  NCI invites investigators to form strategic partnerships 
that will bring together the multi-disciplinary expertise and resources 
needed to determine how the information derived from comprehensive 
molecular analyses can be used to improve patient care and ultimately, 
patient outcomes.  Applicants are asked to propose evaluation of 
potential clinical usefulness of molecular signatures already developed 
using a variety of molecular analysis technologies including DNA, RNA 
or protein-based technologies.  

Molecular signatures have been able, in retrospective studies, to 
identify subgroups of patients whose tumors are histopathologically the 
same but who have different clinical outcomes.  The challenge is to 
translate the information in these molecular signatures into tools that 
can be used in clinical decision-making.  To meet this challenge, 
signatures must be confirmed in independent studies.  Critical elements 
of signatures that correlate most strongly with the clinical endpoint 
of interest must be identified and confirmed.  Robust assays feasible 
for use in the clinical setting must be developed and validated.  This 
iterative process of signature refinement and confirmation and assay 
refinement requires diverse scientific expertise and access to 
significant patient and tissue resources. 

This initiative is an open competition that will provide the cancer 
research community the opportunity to establish collaborations focused 
on the translation of promising molecular profiles toward clinical 
application.  

NCI will continue the policy of requiring public release in a timely 
fashion of the rich data sets generated during these projects.  Access 
to these data sets will benefit the entire cancer research community.  
This initiative will help ensure that the NCI goal of eliminating the 
suffering and death from cancer by 2015 is met. 
 
RESEARCH OBJECTIVES

Background:  The projects funded by this RFA are intended to exploit 
the successes of the many research projects applying comprehensive 
molecular analysis in cancer.  Comprehensive molecular technologies 
have been demonstrated to provide a snapshot of the biological state of 
a tumor.  The ability of molecular profiles to provide useful clinical 
information is now being demonstrated in many projects throughout the 
cancer research community and needs to be evaluated further.  Projects 
are discovering molecular signatures by analysis of gene expression at 
the RNA level, gene expression following protein translation, gene 
mutations, DNA deletions, DNA amplifications, epigenetic changes of DNA 
and post-translational modification of proteins.  The challenge is to 
move beyond the initial discovery of potentially useful profiles, to 
decide what subset of the elements in the profiles needs to be 
measured, to confirm that the profiles are robust and can be 
reproducibly measured and to evaluate the clinical utility of the 
profiles.  

Objectives and Scope:  This RFA is open to all interested, qualified 
investigators.  The initiative is intended to support projects carrying 
out the extensive research needed to bridge the gap between discovery 
of molecular profiles and their integration into clinical decision-
making.  Applicants should propose projects that address clinical 
issues or needs in a specific cancer or a closely related set of 
cancers or in a group of patients whose cancers have related molecular 
alterations.  Collaborations must be established to provide all of the 
expertise and clinical resources required to achieve proposed project 
goals.  It is anticipated that these will be multi-institutional 
projects involving investigators with expertise in technology 
development and application, cancer biology, oncology, pathology, 
clinical cancer research, biostatistics, bioinformatics and, possibly, 
biomedical imaging.  

Applicants must propose projects that build on previously identified 
molecular profiles.

Applications proposing only profile discovery or technology development 
projects will not be considered responsive to this RFA.  The proposed 
studies should be designed to confirm and refine signatures that have 
been demonstrated to provide information that is potentially useful 
clinically and that may be used to aid in making clinical decisions.  
Applicants may propose to define critical components in the signature, 
to confirm that the selected components continue to provide the desired 
clinical information and to develop robust assays for measuring those 
components.  They may continue to develop and/or modify analytical 
technologies and algorithms for data analysis required to meet the 
goals of the proposed projects. 

Applicants must establish the collaborations necessary to bring 
together the expertise needed for the project.  

Successful completion of the project will require expertise in 
analytical technologies, cancer biology, oncology, pathology, clinical 
cancer research, biostatistics, bioinformatics and possibly biomedical 
imaging.  

Applicants must describe the clinical question(s) or need(s) they plan 
to address.  

The clinical questions posed should address a well-defined clinical 
need in one or a closely related set of tumors or in a group of 
patients whose cancers have related molecular alterations.  Examples of 
questions of interest may include, but are not limited to: risk of 
progression in early stage disease; prognosis at the time of diagnosis; 
identification of subsets within a tumor stage or grade where there is 
known heterogeneity in clinical behavior including differential 
response to standard therapies and/or radiation response; and selection 
of appropriate patients for or prediction of response to selected or 
targeted therapies.  

Applicants to this initiative should not propose projects addressing 
early detection of cancer in asymptomatic or high-risk populations or 
risk of progression of pre-malignant lesions.   

Applicants may propose the use of a variety of analytical platforms(s).

Applicants may propose to evaluate signatures the have previously been 
identified using analytical technologies such as, but not limited to, 
gene expression microarrays, SAGE, multiplex PCR or any of a large 
number of protein analysis technologies.  Genomic analysis technologies 
such as array CGH, comprehensive mutational analysis technologies, SNP 
analysis and analysis of epigenetic events are also appropriate.  
Applicants must demonstrate that they have experience with the 
analytical technologies that will be used in the project and 
demonstrate that the technologies can be used for analysis of standard 
pathological specimens.  Applicants are encouraged, but not required, 
to propose the use of multiple analytical strategies.  For example, 
projects may be proposed to analyze gene expression in both frozen 
tissue and paraffin-embedded tissue, to analyze gene expression at both 
the RNA and protein level or to analyze both epigenetic alterations and 
gene expression.  The integration of data to build clinically useful 
profiles that can be measured reproducibly in a clinical setting must 
be the focus of the project, no matter which technologies or analytic 
platforms are proposed.

Applicants must justify the numbers of specimens to be analyzed based 
on appropriate statistical designs for the proposed studies. 

Applicants must have established collaborations to ensure availability 
of the clinical materials required.  The availability of tissue 
resources with appropriate clinical annotation is critical to the 
successful completion of the projects.  Experience has demonstrated 
that the dimensionality of the molecular profiling data requires the 
analysis of hundreds, not tens, of specimens to get statistically 
significant results.  Applicants may propose to obtain tissues from a 
previous collection or prospectively, as long as the specific aims 
proposed can be accomplished within the period of the grant award.   
Demonstrated access to the requisite tissues will be critical to the 
successful review of the application.  It is recognized that tissue 
needs may change as the projects are carried out.  NCI staff will work 
with investigators to help identify additional tissue resources needed 
to meet project goals.  

Applicants should request sufficient resources to ensure that they will 
be able to collect, manage and analyze the data generated.  

Applicants must address issues related to obtaining, managing and 
controlling the quality of the clinical data needed for specimen 
annotation.  Continued development of strategies to more effectively 
address issues of data management and analysis will be an inter-project 
cooperative activity of the funded projects.

Applicants should request sufficient resources for their bioinformatics 
staff to be able to provide an appropriate interface with the NCI 
Center for Bioinformatics (NCICB).  

Sharing of the data between projects where appropriate and public 
release of data after publication will be a requirement for this 
initiative.  Gene expression data will be shared through the NCICB Gene 
Expression Database using the Gene Expression Data Portal and database.  
Proteomics data and other types of data can be shared through the NCICB 
site as the capabilities of the site are expanded.  They may also be 
shared through investigators’ websites or on other publicly available 
websites.  

The confirmation, refinement and evaluation of clinically useful 
molecular profiles and the development of robust clinical assays are 
the primary goals of this initiative.  Clinical utility of the 
signatures and performance of the clinical assays in the context of 
their intended clinical use must be validated before they can be 
integrated into clinical practice.  Final validation of the profiles in 
a clinical trial setting is beyond the scope of this initiative.  
However, it is anticipated that some of the projects may be ready to 
move profiles into clinical trials as early as the midpoint of the 
project period.  NCI staff will facilitate collaborations between the 
projects funded on this initiative and other clinical resources and 
clinical trials activities supported by NCI including: the clinical 
cooperative groups; the Program for the Assessment of Clinical Cancer 
Tests (PACCT); the SPORE programs and the NCI Cancer Centers.  

MECHANISM OF SUPPORT
 
This RFA will use the NIH cooperative agreement (U01) award mechanism.  
As an applicant you will be solely responsible for planning, directing, 
and executing the proposed project.  This RFA is a one-time 
solicitation.  The anticipated award date is April 1, 2005.  
Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications using 
the standard receipt dates for NEW applications described in the 
instructions to the PHS 398 application.  

This RFA uses just-in-time concepts.  It also uses the non-modular 
budgeting formats.  Follow the instructions for non-modular budget 
research grant applications.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. 

The NIH (U01) is a cooperative agreement award mechanism.  In the 
cooperative agreement mechanism, the Principal Investigator retains the 
primary responsibility and dominant role for planning, directing, and 
executing the proposed project, with NIH staff being substantially 
involved as a partner with the Principal Investigator, as described 
under the section "Cooperative Agreement Terms and Conditions of 
Award."  At this time, it is not known if this RFA will be reissued.    

FUNDS AVAILABLE 
 
NCI intends to commit approximately $10,000,000 in FY04 to fund three 
to four new grants in response to this RFA.  An applicant may request a 
project period of up to five years and a budget for total direct costs 
of up to $2,500,000 per year.  Because the nature and scope of the 
proposed research will vary from application to application, it is 
anticipated that the size and duration of each award will also vary. 
Although the financial plans of the NCI provide support for this 
program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of 
meritorious applications. 
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics:
   
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign institutions/organizations
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS

In order to ensure maximum progress in the projects funded by this 
initiative and to maximize progress toward the NCI 2015 goals, several 
special activities will be required of the funded investigators. An 
annual meeting of all funded investigators will be held to share 
progress and research insights that may benefit all of the projects.  
The annual scientific meeting will be initiated after the first year of 
funding.  One or more other focused meetings will be held each year to 
address arising issues or to take advantage of special scientific 
opportunities.  Applicants should request travel funds in their budgets 
for key personnel to attend two meetings per year.  

The funded investigators will be asked to work together on issues 
common to all funded projects.  Although each applicant will propose an 
independent project, all applicants are expected to face many of the 
same challenges and will benefit from the experiences of and 
interactions with the other funded investigators.  The interactions of 
the funded groups will be overseen by a Steering Committee made up of 
two investigators, the PI and one additional investigator, from each 
funded project and appropriate NCI staff members.  A Steering Committee 
organizing meeting will be held shortly after funding is initiated.  
The Steering Committee will focus on common problems and issues, 
especially issues of data management and analysis.  Applicants should 
state in their applications their commitment to participating on the 
Steering Committee and in interactions among the funded groups.

When proposed studies involve collection of human samples, specimens 
and/or clinical data, investigators should consider the issues raised 
and guidance provided in the NIH Brochure entitled "Research on Human 
Specimens: Are You Conducting Research Using Human Subjects?" 
(http://www-cdp.ims.nci.nih.gov/policy.html) and in the OHRP Guidance 
on Repositories, Tissue Storage Activities and Data Banks 
(http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm)  to ensure appropriate 
protection of human subjects in research.

Applicants must describe how they intend to meet the NIH policies for 
sharing of data or why data sharing is not possible.  In this regard, 
attention is drawn to the NIH Final Statement on Sharing Research Data 
(http://grants.nih.gov/grants/policy/data_sharing/index.htm and 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html), 
which was published in the NIH Guide on February 26, 2003 ("Data 
Sharing Guidelines"). This is an extension of NIH policy on sharing 
research resources, and reaffirms NIH support for the concept of data 
sharing. The new policy becomes effective with the October 1, 2003 
receipt date for applications or proposals to NIH.  Investigators 
submitting an NIH application will be required to include a plan for 
data sharing or to state why data sharing is not possible.  The 
statement required by this section should be prepared with reference to 
the provision below for Awardee Rights and Responsibilities within 
Terms and Conditions of Award, 

Intellectual property (IP) issues continue to provide challenges to the 
establishment of complex, collaborative projects.  This issue is being 
addressed and managed in different ways by many different projects 
supported by NCI.  The policy of the NIH is to make available to the 
public the results and accomplishments of the activities that it funds.  
NIH recognizes that certain research activities may result in 
inventions and that grantees are entitled to protect such inventions 
through patenting and licensing activities in accordance with the Bayh-
Dole Act, 35 USC § 200 et seq. and the implementing regulations, 37 CFR 
Part 401 (“Bayh-Dole Act”).  To address the interest in assuring that 
research resources are accessible, NCI requires applicants who respond 
to this RFA to submit a plan (1) for sharing the unique research 
resources generated through the grant; and (2) addressing how they will 
exercise IP rights, should any be generated through this grant, while 
making such research resources available to the broader scientific 
community.  The sharing of research resources and IP plans must make 
unique research resources readily available for research purposes to 
qualified individuals within the scientific community in accordance 
with the NIH Grants Policy Statement 
(http://grants.nih.gov/grants/policy/nihgps_2001/) 
and the Principles and Guidelines for Recipients of NIH Research Grants 
and Contracts on Obtaining and Disseminating Biomedical Research 
Resources: Final Notice, December 1999 
(http://www.ott.nih.gov/policy/rt_guide_final.html and 
http://ott.od.nih.gov/NewPages/64FR72090.pdf) (“NIH Research Tools 
Guidelines”).  These documents also define terms, parties, 
responsibilities, prescribe the order of disposition of rights, 
prescribe a chronology of reporting requirements, and delineate the 
basis for and extent of government actions to retain rights.  Patent 
rights clauses may be found at 37 CFR Part 401.14 and are accessible 
from the Interagency Edison web page (http://www.iedison.gov). 

If applicant investigators plan to collaborate with third parties, the 
research tools sharing plan must explain how such collaborations will 
not restrict their ability to share research materials produced with 
NIH funding.  All applicants will be expected to have addressed IP 
issues with their proposed collaborators before submitting their 
applications and to have documented the status of their arrangements by 
providing a copy of a signed agreement, a signed Memorandum of 
Understanding between collaborating institutions or a letter of 
collaboration countersigned by all relevant parties that describes the 
IP issues and provides applicants with all rights necessary to perform 
activities required by the research plans .   Successful applicants are 
expected to have resolved any outstanding IP issues before funding is 
awarded.   It is anticipated that successful applicants may subcontract 
with third party for profit institutions to perform certain aspects of 
the research plans described in their applications.  Successful 
applicants will be expected to ensure that they obtain sufficient 
rights in such subcontracts to enable them to meet their obligations 
under the NIH Research Tools Guidelines and the Data Sharing 
Guidelines, both of which are extensions of the distribution of unique 
research resources policy contained in the NIH Grants Policy Statement 
(page II-62).  In drafting these subcontracts, grantees will want to 
give some thought to the relative rights and responsibilities of the 
parties, particularly with respect to the dissemination and use of raw 
data, results and analyses.

The NCI Technology Transfer Branch staff works with NCI funded 
investigators on IP issues and has developed strategies for sharing IP.  
Staff of the NCI Technology Transfer Branch will provide their 
expertise as needed to the investigators funded under this initiative 
and their technology transfer and grants and contracts administration 
offices.  Addressing IP issues will be a component of the review of the 
projects

As discussed earlier, grantees will be required to publicly release 
data to the cancer research community through the NCI Center for 
Bioinformatics web site or through other appropriate public websites. 
Applicants should commit to the public release of data and request 
funds in their budgets to support bioinformatics staff interactions 
with the NCICB staff.  

Cooperative Agreement Terms and Conditions of Award 

These special Terms of Award are in addition to and not in lieu of 
otherwise applicable OMB administrative guidelines, HHS Grant 
Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, 
PHS, and NIH Grant Administration policy statements.  [Part 92 applies 
when state and local governments are eligible to apply as a "domestic 
organization."]

The administrative and funding instrument used for this program is a 
cooperative agreement (U01), an "assistance" mechanism (rather than an 
"acquisition" mechanism) in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during 
performance of the activity. Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient's activity by 
involvement in and otherwise working jointly with the award recipient 
in a partner role, but it is not to assume direction, prime 
responsibility, or a dominant role in the activity.  Consistent with 
this concept, the dominant role and prime responsibility for the 
activity resides with the awardee(s) for the project as a whole, 
although specific tasks and activities in carrying out the studies will 
be shared among the awardees, NCI Project Scientist and other NCI staff 
with required expertise.

1.  Awardee Rights and Responsibilities 

Awardees will have primary responsibility for the project as a whole, 
including research design and conduct, data collection, data quality 
control, data analysis and interpretation and preparation of 
publications, as well as collaborations with other awardees.  The NCI 
Project Scientist will coordinate and facilitate interactions and 
collaborations among the awardees.

The funded investigators will form a Network with a Steering Committee 
to coordinate Network activities.  While each of the projects will 
propose independent projects and work independently, each will also 
work with the other investigators to address issues common to all of 
the projects.    

Awardees will retain primary rights to the data developed under these 
awards, subject to Government rights of access consistent with current 
HHS, PHS, and NIH policies.   However, awardees will release the data 
to the cancer research community through collaboration with the NCI 
Center for Bioinformatics (NCICB) or through another appropriate 
publicly accessible website.  The release of data will occur after the 
individual investigators have had a reasonable period of time to 
evaluate their results and realize the appropriate benefits of their 
own research efforts.  Awardees will also share research results during 
meetings of the funded investigators.

2.   NCI Staff Responsibilities 

This program will be administered by the NCI Project Scientist who will 
have significant programmatic involvement in the project, above and 
beyond the normal programmatic stewardship responsibilities in the 
administration of grants, as described below.  Additional NCI staff who 
are subject matter experts will assist the Project Scientist, e.g., a 
Biostatistician, NCI Center for Bioinformatics (NCICB) staff, NCI 
Technology Transfer Branch staff.  The NCI Project Scientist will: 

- be voting members of the Steering Committee (SC).  Other designated 
NCI staff may attend SC meetings as non-voting members. 

- coordinate interactions with other NCI staff in assisting the 
projects, especially in public release of data generated in the 
individual projects.

- work with investigators to access tumor specimens to meet 
unanticipated research needs.  

- coordinate annual meetings to share progress and research insights 
that may benefit all of the projects

- facilitate collaborations with other NCI-funded research groups 
involved in clinical trials to help initiate clinical validation of 
promising profiles, if necessary. 

- assist the project PIs to identify members of an Expert Consultant 
Panel for the program, if necessary.

- assist the project PIs and the Expert Consultant Panel in developing 
strategies to meet the Network goals.

NCI staff from the NCI Technology Transfer Branch (TTB) will act as 
advisors to the Network on issues of Intellectual Property (IP).  

The NCI reserves the right to terminate or curtail the project (or an 
individual award) if there is inadequate progress or data reporting, or 
insufficient use of this resource.

An NCI Program Director will be responsible for normal stewardship of 
the award.  The Program Director may also serve as an NCI Project 
Scientist.  

3.  Collaborative Responsibilities

The Steering Committee, composed of the PI, a second member of each 
funded project and the NCI Project Scientist, will be responsible for 
developing strategies to address issues common to all of the projects 
funded by this initiative.  Investigators agree to follow common 
policies and procedures developed by the Steering Committee.  The 
Steering Committee will pay special attention to issues of data 
management, analysis and public release and may establish subcommittees 
as necessary.  The participants will select a chairperson for the 
Steering Committee.  NCI Program Staff cannot serve as chair. 

An Expert Consultant Panel will be appointed by NCI with concurrence of 
the Steering Committee.  The Panel will consist of no more than six 
members with expertise in comprehensive molecular technologies, 
oncology, statistics and data analysis and bioinformatics.  The Panel 
will advise the NCI staff and the Steering Committee and assist in the 
development of strategies to meet Network goals. Members of the Expert 
Consultant Panel will attend Network meetings and will advise the 
Steering Committee on an ad hoc basis as needed.  

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the award) between award recipients and the NCI 
may be brought to arbitration.  An arbitration panel will be composed 
of three members -- one selected by the Steering Committee or by the 
individual awardee in the event of an individual disagreement, a second 
member selected by NCI, and the third member selected by the two prior 
selected members.  This special arbitration procedure in no way affects 
the awardee's right to appeal an adverse action that is otherwise 
appealable in accordance with the PHS regulations at 42 CFR Part 50, 
Subpart D and HHS regulation at 45 CFR Part 16.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to 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:

James W. Jacobson, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN Room 6035A
Bethesda, MD  20892
Telephone:  (301) 402-4185
FAX:  (301) 402-7819
Email: jacobsoj@mail.nih.gov

or

Tracy Lugo, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute 
6130 Executive Boulevard, EPN Room 6035A
Bethesda, MD  20892
Telephone:  (301) 496-1591
FAX:  (301) 402-7819
Email: lugot@mail.nih.gov

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. Kelli Oster
Grants Administration Branch National Cancer Institute
6120 Executive Boulevard, Room 243
Bethesda, MD  20892-7150
Telephone:  (301) 496-8627
FAX:  (301) 496-8601
Email:  osterk@gab.nci.nih.gov 

PRE-APPLICATION MEETING

A meeting of interested investigators will be held on May 14, 2004 at 
9:00 AM in the Natcher Conference Center, NIH, Bethesda, MD.  The 
meeting is intended to answer questions potential applicants may have 
about the intent of the initiative.
 
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 RFA 

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:

James W. Jacobson, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN Room 6035A
Bethesda, MD  20892
Telephone:  (301) 402-4185
FAX:  (301) 402-7819
Email: jacobsoj@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). Applications must 
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements. The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/. The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form. The PHS 398 document is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.
 
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/labels.pdf.
 
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)
 
At the time of submission, two additional copies of the application and 
all copies of the appendix material must be sent to:

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

Appendix materials should be comprised of single-sided, unbound 
materials with separators between documents.

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 policy is similar to and consistent with the policy for 
applications addressed to Centers for Scientific Review 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 on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review. 

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.
 
The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes from the previous unfunded 
version of the application.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NCI.  Incomplete and/or non-responsive 
applications will not be reviewed.  

Applications that are complete and responsive to the RFA 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 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 Receive a written critique; and
o 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.  
In the written comments, reviewers will be asked to evaluate the 
application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals. The 
scientific review group will address and consider each of the following 
criteria in assigning the application’s overall score, weighting them 
as appropriate for each application

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The application does not need to be strong in all categories to be 
judged likely to have major scientific impact and thus deserve a high 
priority score.  For example, an investigator may propose to carry out 
important work that by its nature is not innovative but is essential to 
move a field forward.

SIGNIFICANCE: Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be 
advanced? What will be the effect of these studies on the concepts or 
methods that drive this field?  Do the proposed projects build on 
previously identified molecular profiles?  Does the proposed project 
address a well-defined clinical question or need?

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of 
the project? Does the applicant acknowledge potential problem areas and 
consider alternative tactics?

Has the investigator documented access to the patients and/or specimens 
with appropriate annotation in sufficient quantities to satisfy the 
statistical design and other goals of the proposed studies?   

INNOVATION: Does the project employ novel concepts, approaches or 
methods? Are the aims original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 
technologies?

INVESTIGATOR: Is the investigator appropriately trained and well suited 
to carry out this work? Has the investigator established appropriate 
collaborations to bring together the required expertise?  Is the work 
proposed appropriate to the experience level of the principal 
investigator and other researchers?  

ENVIRONMENT: Does the scientific environment in which the work will be 
done contribute to the probability of success? Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements? Is there 
evidence of institutional support?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the 
following items will be considered in the determination of scientific 
merit and the priority score:

INTELLECTUAL PROPERTY: Have the collaborating institutions provided 
evidence of or documented their commitment to an appropriate agreement 
on handling of IP arising from the proposed projects?  It is recognized 
that final IP agreements may not yet be executed because of the short 
time available for application preparation.  However, a memo of 
understanding or other documentation indicating an agreement in 
principle that IP issues will not hinder research progress should be 
presented.   

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.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the 
sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals 
are to be used in the project, the five items described under Section f 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.  

ADDITIONAL REVIEW CONSIDERATIONS 

Sharing Research Data 

Applicants requesting more than $500,000 in direct costs in any year of 
the proposed research must include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the 
reviewers. However, reviewers will not factor the proposed data sharing 
plan into the determination of scientific merit or priority score.  
(http://grants.nih.gov/grants/policy/data_sharing)
 
BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  June 22, 2004
Application Receipt Date:  July 22, 2004
Peer Review Date:  October 2004
Council Review:  February 16, 2005
Earliest Anticipated Start Date:  April 1, 2005

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities
 
REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated 
with reference to the risks to the subjects, the adequacy of protection 
against these risks, the potential benefits of the research to the 
subjects and others, and the importance of the knowledge gained or to 
be gained.  
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

DATA AND SAFETY MONITORING  PLAN: Data and safety monitoring is 
required for all types of clinical trials, including physiologic, 
toxicity, and dose-finding studies (phase I); efficacy studies (phase 
II); efficacy, effectiveness and comparative trials (phase III).  The 
establishment of data and safety monitoring boards (DSMBs) is required 
for multi-site clinical trials involving interventions that entail 
potential risk to the participants.   (NIH Policy for Data and Safety 
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/

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing.  Investigators should 
seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule. Reviewers 
will consider the data sharing plan but will not factor the plan into 
the determination of the scientific merit or the priority score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the 
policy of the NIH that women and members of minority groups and their 
sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research. This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 
103-43).

All investigators proposing clinical research should read the "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: The NIH maintains a policy that children (i.e., individuals 
under the age of 21) must be included in all human subjects research, 
conducted or supported by the NIH, unless there are scientific and 
ethical reasons not to include them. 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 RFA 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 RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92. All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at http://grants.nih.gov/grants/policy/policy.htm 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products.  In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits 
smoking in certain facilities (or in some cases, any portion of a 
facility) in which regular or routine education, library, day care, 
health care, or early childhood development services are provided to 
children.  This is consistent with the PHS mission to protect and 
advance the physical and mental health of the American people.


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