INNOVATIONS IN CANCER SAMPLE PREPARATION
 
RELEASE DATE:  December 17, 2003
 
RFA Number:  RFA-CA-05-004 (This RFA has been reissued, see RFA-CA-06-004)
                           (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 Requirement
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 involving the development and significant enhancement or adaptation 
of sample preparation methodologies and technologies, the development of 
assays to assess sample quality, and studies designed to elucidate the 
criteria by which to judge sample quality.  The outcome will be products and 
methods designed to optimize sample utility.   Samples may originate from 
residual material not necessary for patient care or from cell lines, model 
organisms, or other sources relevant to cancer research.

The development of new and/or improved cancer sample preparation 
methodologies and technologies, the development of assays to assess sample 
quality, and studies to elucidate the criteria needed to judge sample quality 
covers a wide range of project sizes and innovation levels.  This RFA will 
allow the submission of applications involving R21, R21/R33, and R33 
mechanisms.  R21 applicants may propose small, highly innovative feasibility 
studies or small, short-term exploratory studies to meet one of the RFA 
goals.  R21/R33 applicants should propose projects that require a small 
feasibility study followed by a well-defined development plan.  Successful 
completion of the R21 feasibility study and the resulting transition to the 
R33 phase will be judged by NCI staff per NCI R21/R33 policy.  Projects for 
which feasibility has already been established may be proposed as R33 
applications.  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.   

This initiative is part of a broader technology development program within 
the NCI.  That program underscores the desire of NCI to develop and integrate 
novel technologies focused on the molecular analysis of cancers and their 
micro-environment in support of cancer research, diagnosis, and treatment.  
In the research continuum of discovery, development, and delivery, this 
program thus emphasizes the link between development and delivery.  This 
specific initiative aims to foster the development of sample preparation 
techniques and methodologies that are essential for effective research, 
technology development, and validation that will eventually lead to clinical 
applications.   

This RFA 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 research focused on sample preparation methods.  Projects 
focused on the development of novel technologies may be most suitable for 
RFA CA-05-002, Innovative Technologies for the Molecular Analysis of Cancer 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-002.html).  Projects 
focused on evaluating 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 RFA for each IMAT initiative, which utilizes the SBIR and STTR grant 
mechanisms (see MECHANISMS OF SUPPORT).  

RESEARCH OBJECTIVES

Background

High quality sample preparations are the foundation for effective technology 
validation as well as for meaningful biological and clinical research.  
Sample preparation covers the spectrum from preparation of molecules to cells 
to tissues.  Preparation of the highest quality samples can be hampered by 
technical issues, lack of standards by which to judge quality, and lack of 
standard practices.  Sample preparation methods vary.  Researchers often 
develop sample preparation methodologies in an ad hoc fashion as part of 
other projects.  This lack of information and standardization affects the 
quality and comparability of data across all fields of cancer research and 
across all technological platforms.  

Objectives and Scope

Sample preparation methods and technologies may be developed for sample 
collection, processing, isolation, storage, purification, preservation, and, 
in the case of stored tissues, reversal of adverse events resulting from 
storage and preservation.  Methods may be for preparation of molecules, 
fluids, tissues, or any other samples necessary for cancer research.  
Researchers may propose to develop methods to isolate cells or sub-cellular 
components, such as classes of molecules, organelles, or sub-cellular 
structures.  They may propose to isolate specific classes of molecules, such 
as membrane-bound proteins.  They may also propose studies to determine the 
effects of collecting, processing, and storage on molecular components of 
interest in stored specimens.  The goal is to develop products and 
methodologies that maximize the quality and utility of samples for research 
and, in the case of human specimens, maximize the quality of the samples for 
research and clinical needs without compromising patient care.

Sample preparation methods may impact the results or interpretation of 
biological studies.  Investigators may apply different methods of sample 
preparation using the same measurement technology.  In many cases of 
measuring biological response, no “gold standard” exists by which to compare 
research results obtained from the different sample preparation methods.  
There is a need for methods to assess the quality of samples prepared using 
different methodologies.   This RFA will support methods to assess sample 
quality and studies that elucidate the criteria needed to judge sample 
quality under different conditions.  This RFA will also support the 
development of technologies to make these assessments, such as the 
development of sample reference materials that can be used to calibrate the 
effectiveness of new fixatives or new detection methodologies. 

It is expected that many investigators who developed successful cancer sample 
preparation techniques under previous IMAT initiatives or under the new RFA 
(Innovative Technologies for Molecular Analysis of Cancer, RFA CA-05-002) 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-002.html) will 
propose projects for this RFA.  However, this RFA is not limited to 
techniques developed under the IMAT program.  Investigators are encouraged to 
use any sample preparation methodologies or techniques relevant to cancer.   

For all projects proposed, it will be important to substantiate the ultimate 
value of the innovation for analyzing samples, optimizing analysis, and/or 
evaluating sample quality for the purpose of research and eventually clinical 
applications.  Also of importance is the potential for ultimately 
transferring knowledge, technologies, and/or methodologies to other 
laboratories or the clinic.  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.

MECHANISMS OF SUPPORT
 
This RFA will use NIH Exploratory/Developmental Research Grant (R21), 
Exploratory/Developmental Phase II (R33), and the Phased Innovation Award 
(R21/R33) mechanisms.  Applicants will be solely responsible for planning, 
directing, and executing the proposed projects.  This RFA is a one-time 
solicitation.  Future unsolicited, competing-continuation applications based 
on this project will compete with all investigator-initiated applications and 
will be reviewed according to the customary peer review procedures. The 
anticipated award date is seven to nine months after the receipt date.  
Applications that are not funded in the competition described in this RFA may 
be resubmitted as amended applications for the receipt dates listed in this 
RFA and its future issuances, if any. 

This RFA uses just-in-time concepts.  It also uses both the modular budgeting 
as well as the non-modular budgeting formats (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 budget format.  Otherwise, 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/grants/policy/nihgps_2001/part_i_1.htm.  

The total project period for an application submitted in response to this RFA 
may not exceed the following durations: R21, 2 years; R33, 3 years; combined 
R21/R33 application, 4 years.  In the combined application, the R21 phase 
cannot extend beyond 2 years.

For R21 and R21/R33 applications, the R21 phase may not exceed $100,000 direct 
costs per year.  R21 budgets can exceed this cap to accommodate indirect costs 
to subcontracts to the project.  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, and to 
discuss programmatic adherence of the proposed project to the RFA guidelines.  
Refer to the INQUIRIES sections of this program announcement for NCI staff 
contacts.

The combined R21/R33 application offers two advantages over the regular 
application process:

1.  Single submission and evaluation of both the R21 and the R33 phases as one 
application.

2.  Minimal or no funding gap between R21 and R33 grants.  The award of R33 
funds will be based on program priorities, on the availability of funds, and 
on successful completion of negotiated scientific milestones as determined by 
NCI staff in the context of peer review recommendations.

An R21/R33 application must contain, within the R21 phase, well-defined 
quantitative milestones that will be used to judge the success of the proposed 
research, as well as a credible plan for the pilot application of the proposed 
technology in the R33 phase.  These must be presented in a section labeled 
“Milestones” at the end of the Research Plan of the R21 application.  A 
discussion of the suitability of the proposed milestones for assessing the 
success in the R21 phase, and a discussion of the implications of successful 
completion of these milestones for the proposed R33 study, should also be 
presented in this section.

This program will run in parallel with a program of identical scientific scope 
RFA CA-05-008 that will utilize the Small Business Innovation Research (SBIR, 
R43 and R44) and Small Business Technology Transfer (STTR, R41 and R42) 
mechanisms.

FUNDS AVAILABLE 
 
NCI intends to commit approximately $1,000,000 in FY 2005 to fund four to 
eight new and/or competitive continuation grants in response to this RFA. An 
applicant may request a project period of up to two years for an R21, up to 
three years for an R33, and up to four years for a combined R21/R33 of which 
the R21 portion may be no more than 2 years.  An applicant may request a 
budget for direct costs of up to $100,000 per year for R21 and the R21 
portion of R21/R33 applications.  Budgets for R33 and the R33 portion of 
R21/R33 grant applications should be appropriate for the science proposed.  
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 REQUIREMENT

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:

Ms. Catherine Blount
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, EPS Room 243
Bethesda, MD 20892-7150
Rockville, MD 20852 (express/courier service)
Telephone:  301-496-3179
Fax:  301-496-8601
Email:  blountc@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 COMBINED R21/R33 APPLICATION

Applications for R21/R33 grants are to be submitted on the grant application 
form PHS 398 and prepared according to the instructions provided unless 
specified otherwise within this section.  

The R21/R33 application must include the specific aims for each phase and the 
quantitative feasibility milestones that would, if successfully completed, 
justify transition to the R33 phase.  Applications must include a specific 
section labeled Milestones following the Research Plan of the R21 phase.  
Milestones should be well described, quantitative, and scientifically 
justified.  For funded applications, completion of the R21 negotiated 
milestones (potentially modified in the light of peer review and further 
discussion with the Program Director to whom the application is assigned) will 
elicit an NCI expedited review that will determine whether or not the R33 
should be awarded.  The release of R33 funds will be based on successful 
completion of negotiated scientific milestones, program priorities, and on the 
availability of funds.  The expedited review may result in additional 
negotiations of award.

The R21/R33 application must be submitted as a single application, with one 
face page.  Although it is submitted as a single application, it should be 
clearly organized into two phases.  To accomplish a clear distinction between 
the two phases, applicants are directed to complete Sections a-d of the 
Research Plan twice: one write-up of Sections a-d and milestones for the R21 
phase and sections a-d again for the R33 phase.  The Table of Contents form 
page in the PHS 398 instructions should be modified to show sections a-d for 
each phase as well as the milestones. There is a page limit of 25 pages for 
the combined sections a-d and milestones for the R21 phase and sections a-d 
for the R33 phase. 

In preparing the R21/R33 application, investigators should consider the fact 
that applications will be assigned a single priority score.  In addition, the 
initial review panel has the option of recommending only the R21 phase for 
support.  However, an R21/R33 application with an R33 Phase that is so 
deficient in merit that it is not recommended for support will reflect upon 
the judgment of the applicant.  For these reasons, the clarity and 
completeness of the R21/R33 application with regard to specific goals, and the 
quality of the feasibility milestones for the R21 phase, are critical.  The 
presentation of milestones that are judged not to be sufficiently 
scientifically rigorous for assessing progress in the R21 phase will reflect 
upon the scientific judgment of the applicant.

1.  Face Page of the application:

Item 2.  Check the box marked YES and type the number and title of this 
request for applications.  Also indicate if the application is an R21 only, a 
combined R21/R33, or an R33.

Item 7a: DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT:

For the R21 phase of the combined R21/R33 application, direct costs are 
limited to a maximum of $100,000 per year for a maximum of two years and the 
award may not be used to supplement an ongoing project.  The requested budgets 
can exceed this cap to accommodate indirect costs to subcontracts to the 
project.  Insert the first year of R21 support in item 7a.

Item 8a: DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:

For the R21 phase, direct costs requested for the proposed period may not 
exceed $200,000 for two years of support.  The statement in item 7a above 
pertaining to subcontract costs also applies here.  Insert sum of all years of 
requested support, both R21 and R33 years, in item 8a

2.  Page 2 - Description:
As part of the description, identify concisely and completely the technology 
or methodology to be applied, its innovative nature, its relationship to 
presently available capabilities, and its expected impact on the molecular 
analysis of cancer, as well as the study in which the technology will be 
applied.

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 
and 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).  Form pages should indicate which years are R21 and R33.  All budgets 
should include a written justification. 

4.  Research Plan:

Item a: Specific Aims

The applicant must present specific aims that the applicant considers to be 
scientifically appropriate for the relevant phases of the project.

The instructions in the PHS 398 booklet for this section of research grant 
applications suggest that the applicant state the hypotheses to be tested.  
Since the goal of this RFA is to support the pilot application of innovative 
technologies, hypothesis testing per se may not be the driving force in 
developing such an application and, therefore, may not be applicable.  
Furthermore, for R21 grant applications, preliminary data are not required, 
although they should be included when available.  For both the R21 phase and 
the R33 phase, research that supports the pilot application of new 
technologies is likely to require the application of principles of fields such 
as engineering, materials science, physics, mathematics, and computer science.  
Clear statements of these underlying principles are essential.  In particular, 
studies pursuing comprehensive analyses may result in hypothesis generation 
rather than hypothesis testing.  

Item d: Research Design and Methods

Follow the instructions in the PHS 398 booklet.  In addition, for the R21 
phase only, the following information must be included as a final section of 
Item d:

Applications must include a specific section labeled Milestones following the 
Research Design and Methods of the R21 phase.  Milestones should be well 
described, quantitative, and scientifically justified and they should not be 
simply a restatement of the specific aims.  A discussion of the milestones 
relative to the success of the R21 phase, as well as the implications of 
successful completion of the milestones for the R33 phase should be provided.  
The page number of the milestones section should be indicated in the Table of 
Contents.  

Applications lacking this information, as determined by the NCI program staff, 
will be returned to the applicant without review.  For funded applications, 
completion of the R21 negotiated milestones will elicit an NCI expedited 
review that will determine whether or not the R33 grant should be awarded.  
The release of R33 funds will be based on successful completion of negotiated 
milestones, program priorities, and on the availability of funds. The 
expedited review may result in additional negotiations of award.

SPECIFIC INSTRUCTIONS FOR PREPARING THE R21 APPLICATION (WITHOUT AN R33 PHASE)

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 an application 
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.  In addition to 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 the 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.  

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

SPECIFIC INSTRUCTIONS FOR PREPARING THE R33 APPLICATION (WITHOUT AN R21 
PHASE).

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.

FOR ALL APPLICATIONS

Appendix:   All instructions in the Form 398 application kit apply.
 
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, which 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.  
Applicants are 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/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)

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 
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 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?

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:

MILESTONES:  In the cases of R21 alone and R21/R33 applications, are 
appropriate and quantitative scientific milestones included that will show, 
when completed by the end of the R21 period, whether or not the project has 
shown feasibility to pursue the R33 portion of the project?  

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 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. 

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 2004; 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. See 
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); and 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 is 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/.

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:  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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