INNOVATIVE TECHNOLOGIES FOR MOLECULAR ANALYSIS OF CANCER
 
RELEASE DATE:  December 17, 2003
 
RFA Number:  RFA-CA-05-002 (This RFA has been reissued, see RFA-CA-06-002)
                           (see NOT-CA-04-013)

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):  93.392, 93.393, 93.394, 
93.395, 93.396 

LETTER OF INTENT RECEIPT DATES: January 16, 2004; May 17, 2004; September 17, 
2004

APPLICATION RECEIPT DATES: February 17, 2004; June 17, 2004; October 18, 2004 
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanisms of Support 
o Funds Available
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 Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The National Cancer Institute (NCI) invites applications for research 
projects proposing the development of highly innovative cancer relevant 
technologies.  Technology encompasses methods and tools that enable research, 
including, but not limited to, instrumentation, techniques, and devices.  
Technology is distinct from resources such as databases, reagents, and tissue 
repositories.  Applications for support of such resources will not be 
considered responsive to this RFA.  Technologies solicited include, but are 
not necessary limited to, those that are suitable for the detection of 
alterations and instabilities of genomic DNA; measurement of the expression 
of genes and gene products, including proteins; analysis and detection of 
gene and/or cellular products, including post-translational modification and 
function of proteins; identification and characterization of exogenous 
infectious agents in cancer; and assaying the function of major signal 
transduction networks involved in cancer.  Developing technologies would 
include those that will support molecular analysis in vitro, in situ, or in 
vivo in discovery processes as well as in pre-clinical models and clinical 
research.

This initiative is part of a broader technology development program within 
the NCI to harness technology in the fight against cancer.  The NCI 
technology program underscores the desire of NCI to develop and integrate 
novel and emerging technologies in the support of cancer research, diagnosis, 
and treatment.  In the research continuum of discovery, development, and 
delivery, this program accelerates development and delivery.  This specific 
initiative will serve as the discovery tool of the larger program by 
soliciting and funding highly innovative, high risk and cancer-relevant 
technology development projects associated with the molecular analysis of 
cancer.  

This initiative capitalizes on both the success and intent of the original 
NCI sponsored Innovative Molecular Analysis Technologies (IMAT) program in 
bringing together a multi-disciplinary group of scientists and engineers to 
work on cancer and the expansion of interest in technology development across 
the NCI and other NIH institutes.  This continuation of the IMAT program 
consists of the following three initiatives: Innovative Technologies for the 
Molecular Analysis of Cancer; Innovations in Cancer Sample Preparation; and 
Application of Emerging Technologies for Cancer Research.  This RFA is 
designed to support technology development projects.  Technologies developed 
or adapted for sample preparation methodology may be most suitable for 
RFA CA-05-004, Innovations in Cancer Sample Preparation 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-004.html).  Research 
projects to evaluate emerging technologies that are ready for initial 
clinical or biological application in cancer research may be most suitable 
for RFA CA-05-003, Application of Emerging Technologies for Cancer Research 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-003.html).  
Applicants from small businesses are encouraged to submit applications to the 
parallel RFAs for each IMAT initiative, which utilize the SBIR and STTR grant 
mechanisms (see MECHANISM OF SUPPORT).  Researchers who emphasize the 
assessment of in vivo imaging technologies as the primary focus of their 
grant applications should contact the Cancer Imaging Program 
(http://www3.cancer.gov/bip/) for information on appropriate funding 
opportunities.  Researchers focusing on applying new bioinformatics or 
statistical techniques as the primary focus of their applications should 
consider one of the BISTI initiatives 
(http://www.bisti.nih.gov/bistic_funding.cfm).  
 
RESEARCH OBJECTIVES
 
Background

In order to meet the goal of eliminating death and suffering due to cancer, 
the NCI will continue to support the development of creative methods to 
understand, prevent, diagnose, and treat cancer.  In the past several 
decades, basic discovery research has revealed that cancer is a complex 
disease involving myriad molecular and cellular processes, and that cancers 
arise as the result of the gradual accumulation of genetic changes in 
specific cells.  Identifying which subset of the genes encoded within the 
human genome can contribute to the development of cancer remains a challenge.  
Even more challenging is the subsequent understanding of the proteins and 
other functional products encoded by these genes.  The identification and 
characterization of these cancer genes and their associated gene products 
remains a high priority in cancer research.  New technologies and approaches 
not only address specific questions in basic research and clinical practice 
but are also beneficial in uncovering and developing new directions and 
paradigms in cancer research.  Taken together, these points highlight the 
leading and critical role technological advances play throughout the NCI’s 
mission.

The Innovative Molecular Analysis Technologies (IMAT) program was originally 
designed in 1999 with three objectives:  to focus technology development on 
cancer, to solicit highly innovative technology development projects, and to 
accelerate the rate of maturation of meritorious technologies from 
feasibility through development of the technology.  Through solicitation, 
outreach, and communication with the investigator community, the IMAT program 
has been successful in focusing a diverse spectrum of new and emerging 
technologies onto cancer applications.  The program has focused on both the 
inception and development of cancer-related technologies.  Some of the 
technologies originally generated with IMAT funding have gone on to support 
the acquisition of basic knowledge about cancer, which feeds the discovery 
pipeline.  Other IMAT supported technologies have been applied to questions 
of clinical importance.  Through the R21/33 Phased Innovation Award, 
originally invented and piloted by this program, IMAT has also been 
successful in accelerating meritorious technology development projects by 
minimizing the funding gap between feasibility and development phases.  While 
the overall NCI technology program maintains these general goals, this 
initiative will be more focused on the R21 or high-risk portion of an 
investigator’s scientific effort, with emphasis on the extent to which the 
idea is novel and innovative.  Therefore, this RFA will not support the 
Phased Innovation Award (combined R21/R33), but only R21 alone and R33 alone 
applications, as outlined in the Mechanisms of Support section.

This solicitation is intended to support the development of molecular 
analysis tools that will not only allow for the more careful examination of 
the molecular basis and profiles of cancer but will also provide the ability 
to identify the molecular characteristics of individuals that influence 
cancer development and prognosis.  These tools will allow for an examination 
of genetic factors that influence individuals’ risk of developing cancer or 
their ability to respond to damaging external agents such as radiation, 
carcinogens, and therapeutic regimes.  

In order to fully understand cancer and define the molecular responses of the 
host to cancer, it will be critical not only to have knowledge at the DNA 
level but also to have a complete understanding of the processing of genetic 
information in cellular function. Current discoveries indicate that 
alterations in many of the cellular processes, pathways, or networks may 
contribute to the genesis of cancer and that these alterations could be 
exploited for therapeutic or prevention intervention.  Therefore, it is 
important to invoke technologies that can detect molecular changes in the 
cell without preconceived ideas about what changes would be the most valuable 
to monitor.  In the discovery phase, the emphasis will be on technologies 
that can effectively scan, through highly multiplexed analysis, structural 
variations or functional changes in many or all members of the populations of 
DNA, RNA, or proteins present in cells.  Current technologies for the 
multiplexed analysis of molecular species are at a stage where the greatest 
utility exists for the analysis of large numbers of relatively homogeneous 
cell populations that can be assayed in vitro. While many of the existing 
technologies have relatively sophisticated multiplexing capabilities in the 
assay format, none are comprehensive for any particular molecular species 
(DNA, RNA, or protein).  Therefore, opportunities exist for further 
development to insure that the resulting technologies provide enhanced assay 
potential, adequate sensitivity and discrimination, robust data analysis 
tools, and easy adaptation to the basic, preclinical, and clinical research 
settings.

Objectives and Scope

The purpose of this RFA is to encourage applications from individuals and 
groups interested in developing novel technologies suitable for the molecular 
analysis of cancers and their host environment in support of basic, clinical, 
and epidemiological research.  Technologies to support research in the 
following areas are considered to be appropriate.  Examples given below are 
not intended to be all-inclusive but are illustrative of the types of 
capabilities that are of interest.

New tools that allow development of more complete molecular profiles of 
normal, precancerous, and cancerous cells, as well as the process of 
carcinogenesis, are needed to support the basic discovery process.  The same 
sort of technological approaches will also be needed to examine the tumor 
micro-environment, including stromal and vascular interaction.  These tools 
will also allow more thorough examination of the variations that influence 
predisposition to cancer and individual variability in response to 
therapeutic and prevention agents.  Of interest are technologies and data 
analysis tools for:

o  In vitro scanning for and identification of the sites of chromosomal 
aberrations that reflect inherited aberrations or somatic alterations 
resulting from aging, oxidation, or exposure to radiation or carcinogens, 
including those that are suitable for scaling for use across whole genomes, 
detecting DNA adducts, or detecting rare variants in mixed populations;

o  In vitro scanning for and identification of sites of mutations and 
polymorphisms that reflect inherited aberrations or variations, or somatic 
alterations resulting from aging, oxidation, or exposure to radiation or 
carcinogens, including those that are suitable for scaling for screening 
whole genomes, detecting DNA adducts, or identifying infrequently represented 
mutations in mixed populations of DNA molecules;

o  Technologies for detection and characterization of nucleic acid sequences 
of novel exogenous infectious agents that may be present in human cancer;

o  Highly specific and sensitive detection of specific mutations;

o  Detecting mismatch and recombinational DNA repair related to cancer 
susceptibility and drug sensitivity;

o  In vitro multiplexed analysis of the expression of genes;

o  In vitro detection of expression of proteins and their modified forms, 
including technologies suitable for expansion to profiling of all proteins 
expressed in cells, detecting rare variants in mixed populations, and 
detecting protein adducts involved in chemical mutation;

o  Monitoring the function of proteins and genetic pathways, including 
measurement of ligand-protein complexes and technologies for monitoring 
protein function of all members of a class of proteins or a complete genetic 
pathway;

o  Delineating molecular expression, function, and analysis at the cellular 
level in the context of both the whole body and in situ, including molecular 
imaging technologies suitable at this scale, contrast agents, gene 
amplification techniques, and related data analysis tools;

o  Detection technologies and sensors, including signal to noise optimization 
and rare cell/molecule detection, of cancer and the structures and molecules 
important in its development and diagnosis;

o  Technologies to elucidate molecular modifications of macromolecules that 
may be indicative of and critical to the transformation process;

o  Delivery technologies and approaches to enable faster and more accurate 
delivery of molecular and cellular labels and drugs to and within cells for 
research and treatment, the overall goals being speed, accuracy, and 
biocompatibility; and/or

o  Development of high-throughput, quantitative assays for epigenetic 
alternations, e.g., acetylation and methylation, in promoter region of genes 
and histone proteins isolated from biological fluids and tissues.

For all technologies proposed, it will be important to substantiate the 
ultimate value of and role for the technology in deciphering the molecular 
anatomy of cancer cells or analyzing the molecular profile of the individual.  
It is also important for applicants to discuss the ultimate potential for the 
transfer of ensuing technology to other laboratories or the clinic and, for 
more mature technologies, plans to ensure dissemination of the technology.  
In the case of technologies intended for use on clinical specimens or in 
patients, applications from or collaborations with investigators involved in 
the clinical research of cancer are encouraged.

MECHANISM OF SUPPORT

Support for this program will be through the National Institutes of Health 
(NIH) Exploratory/Developmental Research Grant (R21) and the 
Exploratory/Developmental Research Grant Phase 2 (R33).  The R33 mechanism 
provides a second phase for the support of innovative exploratory and 
developmental research that may or may not have been initiated under the R21 
mechanism.  Except as otherwise stated in this RFA, awards will be 
administered under NIH grants policy as stated in the NIH Grants Policy 
Statement, March 2001, available at: 
http://grants.nih.gov/grants/policy/nihgps_2001/.  Hard copies are not 
available. Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.

This initiative will employ separate discovery (R21) and development (R33) 
awarding mechanisms.  The R21 application will emphasize the high risk, high 
innovation feasibility phase and potential impact.  The development (R33) 
phase application will have to contain proof of the feasibility of the 
proposed technology.  In addition, the R33 application will contain an 
outline of a plan for further development of the technology towards its 
ultimate use and application.

Unlike the previous IMAT announcements of 1999 and 2002 (PAR-01-104) and the 
other two RFA solicitations of the current program, this RFA does not solicit 
and will not accept combined R21/R33 applications.  Under this RFA, 
applicants must submit either an R21 application or a fully developed R33 
application, according the guidelines below.  

The R21 application will emphasize the innovative and high-risk nature of the 
proposed research and be conceptual in nature, with no preliminary data 
required.  In addition to the concept and discussion of the proposed 
technology that is common to all R21 applications, the application must also 
include a brief section describing the potential use and impact of the 
proposed technology.  The specifics of the R21 application are described in 
the SUPPLEMENTARY INSTRUCTIONS section of this RFA.  The R21 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 proposed R21 
project period may be up to a maximum of 2 years funding.

Under this RFA, applicants may also submit an R33 application if feasibility 
can be documented, as described in the SUPPLEMENTARY INSTRUCTIONS section of 
this RFA.  R33 applicants must present detailed preliminary data in support 
of the feasibility of the proposed technology or approach that is proposed 
for development.  These applications will also have the added burden of 
demonstrating the innovation of the particular technology or approach.  The 
proposed R33 project period may be up to a maximum of 3 years.

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 of 
the proposed project to the RFA guidelines.  Early contact with NCI staff is 
particularly critical relative to this RFA because of the kinds of funding 
mechanisms permitted, i.e., either R21 or R33, with R21/R33 applications not 
accepted.  Refer to the INQUIRIES sections of this program announcement for 
NCI staff contacts.

This program will run in parallel with a program of identical scientific 
scope CA-05-006 that will utilize the Small Business Innovation Research 
(SBIR) and Small Business Technology Transfer (STTR) mechanisms.

This RFA uses just-in-time concepts.  It also uses the modular as well as 
non-modular budgeting format. (See 
http://grants.nih.gov/grants/funding/modular/modular.htm).   Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  This program does not require cost sharing 
as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE
 
NCI intends to commit approximately $3,000,000 in FY 2005 to fund 10 to 15 
new and/or competitive continuation grants in response to this RFA. An 
applicant may request a project period of up to 2 years and a budget for 
direct costs of up to $100,000 per year, in keeping with standard R21 
mechanism guidelines, or 3 years for an R33.  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, especially in the case 
of R33 awards, will also vary.  Budgets for R33 applications should be 
appropriate for the science proposed.  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

An annual meeting of all investigators funded through this program will be 
held to share progress and research insights that may lead to further progress 
in the program.  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 inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into four 
areas:  scientific/research, intellectual property, peer review, and 
financial or grants management issues:

o Direct your questions about scientific/research issues to:

Gregory J. Downing, D.O., Ph.D.
Office of Technology and Industrial Relations
National Cancer Institute
Building 31, Room 10A52
Bethesda, MD  20892
Telephone:  (301) 496-1550
FAX:  (301) 496-7807
Email: downingg@mail.nih.gov

o Questions regarding intellectual property management plans should be 
directed to:    
   
Wendy Patterson, J.D. 
National Cancer Institute
Technology Transfer Branch
6120 Executive Boulevard, EPS Room 450
Bethesda, MD 20892-8329
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-0477
Email: pattersw@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
Rockville, MD 20852 (for express/courier service)
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:

Shane Woodward 
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, EPS Room 243
Bethesda, MD 20892-7150
Rockville, MD 20852 (for express/courier service)
Telephone:  301-846-1017 
Fax:  301-496-8601
Email:  woodwars@mail.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 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 at least one month prior to the targeted 
receipt date.  The receipt dates and respective letter of intent dates are 
listed at the beginning of this document.  The letter of intent should be 
sent to:

Gregory J. Downing, D.O., Ph.D.
Office of Technology and Industrial Relations
National Cancer Institute
Building 31, Room 10A52
Bethesda, MD  20892
Telephone:  (301) 496-1550
FAX:  (301) 496-7807
Email: downingg@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.

SUPPLEMENTARY INSTRUCTIONS

SPECIFIC INSTRUCTIONS FOR PREPARING THE ENHANCED R21 AND R33 APPLICATIONS

Applications for R21 or R33 grants (no combined R21/R33 applications will be 
accepted under this RFA) are to be submitted on the grant application form PHS 
398 and prepared according to the instructions provided unless specified 
otherwise within this section.  

1.  Face Page of the application:

Item 2.  Check the box marked YES and type the number and title of this RFA.  
Also indicate if the application is an R21 or R33.

3.  Budget: 
The application should contain a modular budget for the Initial Budget Period 
(form page 4), for each of the initial years of the R21 or R33 phases (or a 
detailed budget for R33 years that exceed $250,000 direct costs), as well as a 
budget for the entire proposed period of support (form page 5).  All budgets 
should include a written justification. 

Item b: Background and Significance

Elaborate on the innovative nature of the proposed research.  Clarify how the 
technology development proposed in this project is a significant improvement 
over existing approaches.  Explain the potential of the proposed technology 
for having a broad impact on cancer research.  Clearly identify how the 
project, if successful, would result in new capabilities for research, the 
immediacy of the opportunity and how these proposed technologies would differ 
from existing technologies.

SPECIFIC INSTRUCTIONS FOR PREPARATION OF AN R21 APPLICATION

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 RFA is to develop innovative technologies, hypothesis 
testing per se may not be the driving force in developing such a proposal and, 
therefore, may not be applicable.  Furthermore, preliminary data are not 
required, although they should be included when available.

Item d: Research Design and Methods

Follow the instructions in the PHS 398 booklet.  Along with sections a-d, a 
one page section entitled Technical Vision should be included describing the 
potential application of the proposed technology.  

The R21 application must also include quantitative feasibility milestones 
that, when accomplished, would justify a future continuation to an R33 phase.  

The milestones and Technical Vision sections must be contained within the 
standard 25 page limit for sections a-d text for an R21 application.  

An application lacking these sections, as determined by the NCI program staff, 
will be returned to the applicant without review.

SPECIFIC INSTRUCTIONS FOR PREPARATION OF AN R33 APPLICATION

Applications for R33 grants are to be submitted on the grant application form 
PHS 398 and prepared according to the instructions provided unless specified 
otherwise within the items below.  

1.  Face Page of the application:

Item 2.  Check the box marked a YES and type the number and title of this 
program announcement and indicate R33.

2.  Research Plan:

Item c: Preliminary Studies/Progress report

This section must document that feasibility studies have been completed, and 
progress achieved, equivalent to that expected through the support of an R21 
project.  The applicant must clearly describe how the 
exploratory/developmental study is ready to be scaled up to an expanded 
application stage.  In the event that an applicant feels that the technology 
is too proprietary to disclose, the applicant must at a minimum provide a 
demonstration (results) of the capabilities of the proposed technology.  
Preliminary data relevant to both the technology evaluations and the pilot 
biological study should be presented.

INTELLECTUAL PROPERTY MANAGEMENT PLAN:  Certain research plans will require 
collaboration and coordination between investigators at different 
institutions, some of whom may not be NIH funding recipients and who may have 
pre-existing intellectual property obligations to third parties.  It is 
anticipated that commercial embodiments of the results of such research may 
incorporate single inventions shared by several institutions, or multiple 
inventions each from a separate institution.  Therefore, prior to funding, 
R33 grant applicants must address how they will coordinate patent prosecution 
and licensing activities, if necessary to enable a licensee to access the 
bundle of intellectual property needed to take a product to market on 
commercially viable terms.  Suggested strategies include: (1) assigning 
intellectual property rights to related inventions to an invention management 
firm; (2) designating one organization to take the lead on patenting and 
licensing related inventions; and (3) agreeing in advance that if multiple 
parties are to independently license related inventions, the total of stacked 
royalties will not exceed a predetermined percentage rate. 

The technology transfer/intellectual property management/licensing officer or 
equivalent of the principal investigator’s institution is to submit an 
intellectual property management plan including at least those elements 
above.  Alternatives to the suggested strategies that accomplish the same 
goals will be considered.  Intellectual property management plans are a just-
in-time requirement; it is not necessary to include the plan in the grant 
application but plans will be required before an R33 grant can be awarded.

The applicant’s institution should avoid exclusively licensing those 
inventions that are research tools, unless either: (1)  the field of use of 
the exclusive license is restricted to commercial use, or (2) the exclusive 
licensee will make the research tool available on reasonable terms.  The 
applicant’s attention is directed to the NIH policy on the dissemination of 
biological research resources (“research tools”) which can be found at 
http://www.ott.nih.gov/policy/rt_guide_final.html.   

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

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/label-bk.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 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)

Appendices 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.  This 
does not preclude the submission of a substantial revision of an unfunded 
version of an application already reviewed, but such an application must 
include an Introduction addressing the previous critique. An application 
submitted through this RFA that is unsuccessful may be resubmitted as amended 
at the next subsequent receipt date.

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 these criteria in assigning the 
application’s overall score, weighting them as appropriate for each 
application.  

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

SIGNIFICANCE: Does this study address an important problem? If the aims of 
the application are achieved, how will scientific knowledge be advanced? What 
will be the effect of these studies on the concepts or methods that drive 
this field?

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

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

INVESTIGATOR: Is the investigator appropriately trained and well suited to 
carry out this work? Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?

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

ADDITIONAL REVIEW CRITERIA:

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

R21 applications: the adequacy of the proposed quantitative feasibility 
milestones and the Technical Vision statement.

R33 applications: R33 applicants must present detailed preliminary data in 
support of the feasibility of the proposed technology or approach that is 
proposed for development.  They will also have the added burden of 
demonstrating the innovation of the particular technology or approach. 
Feasibility means that some preliminary experiments have been performed and 
that there is sufficient technical data to support proof of principle of the 
technology/hypothesis.   

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

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

ADDITIONAL CONSIDERATIONS 

DATA SHARING:  The adequacy of the proposed plan to share 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.  
 
BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research will be assessed after the 
determination of the priority score.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Dates: January 16, 2004; May 17, 2004; September 17, 
2004 

Application Receipt Dates:  February 17, 2004; June 17, 2004; October 18, 
2004

Peer Review Dates: June 2004; November 2004; March 2005;

Council Reviews: September 2004; February 2005; June 2005

Earliest Anticipated Start Dates: December 2004; April 2005; July 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; and
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 more than $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: (if 
applicable) 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/.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://stemcells.nih.gov/index.asp and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s) for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review.

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:  (if 
applicable) 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.healthypeople.gov.

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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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