TECHNOLOGIES FOR COMPREHENSIVE, SENSITIVE, AND QUANTITATIVE PROTEIN ANALYSIS IN 
HUMAN TUMORS: PHASED INNOVATION
 
Release Date:  August 30, 2000
 
RFA:  CA-01-011

National Cancer Institute
National Human Genome Research Institute

Letter of Intent Date:     December 11, 2000
Application Receipt Date:  January 18, 2001

PURPOSE

The Technology Development Branch of the Cancer Diagnosis Program, Division of 
Cancer Treatment and Diagnosis, National Cancer Institute (NCI), and the 
Functional Analysis of the Genome Program, Division of Extramural Research, 
National Human Genome Research Institute (NHGRI), invite grant applications 
proposing the development of innovative technologies for the sensitive 
quantitation of the comprehensive spectrum of proteins present in human 
tissues.  In combination with protein identification strategies, sensitive, 
efficient, and reproducible protein quantitation technologies are needed to 
more accurately and rapidly determine altered levels of the spectrum of 
proteins in human tumor specimens.  The approaches proposed should take into 
account the need to identify and quantitate a broad range of proteins 
including proteins present in low abundance and proteins that are membrane-
associated or not readily soluble.  Approaches should be sensitive enough to 
detect modest changes in the concentration of individual proteins since these 
changes may have significant biological consequences.

This solicitation will utilize the newly created Phased Innovation Award 
Mechanism (R21/R33).  Specific Features of this mechanism will include:

o  Support for either R21 or R33 or combined R21/R33 applications.
o  Single submission and evaluation of both the R21 and R33 as one 
application.
o  Expedited transition from feasibility phase to development phase.
o  Flexible budgets.
o  Flexible staging of feasibility and development phases.

RESEARCH OBJECTIVES

Background

Profiling of gene expression in tumors promises to improve the clinical 
management of cancer patients.  Technologies for the comprehensive evaluation 
of DNA and RNA alterations in tumors are rapidly being developed, but 
development of comparable technologies for the evaluation of protein 
expression in human tumor specimens has been slower due to the inherent 
difficulties of analyzing complex mixtures of proteins.  

Protein profiling technologies currently in use or under development are based 
on identification of proteins and/or analysis of the properties and 
characteristics of proteins.  The research community has highlighted the 
importance of developing sensitive, quantitative protein analysis technologies 
to complement these approaches.  No current technology allows both 
comprehensive identification and sensitive quantitation of proteins in human 
tissues.  Investigators are forced to choose between technologies that provide 
a non-quantitative, comprehensive profile of proteins and technologies that 
provide a quantitative measurement of a limited subset of proteins in a 
specimen.

Protein profiling will require knowledge of both the identity and relative 
abundance of all or a significant subset of proteins in tumors.  This 
knowledge will greatly enhance our understanding of molecular pathways 
involved in cancer development.  Measuring changes in the abundance of 
membrane-bound receptor proteins in human tumors is important since these 
proteins are involved in signaling cascades during cancer initiation or 
progression.  Detecting subtle changes in the abundance of proteins in tumors 
is also important because these changes may be key to biological processes in 
cancer development.  However, major technical challenges remain.  These 
include the quantitation of hydrophobic, membrane-bound proteins and the 
improvement in detection sensitivity for measurement of very low-abundance 
proteins.   Overcoming these technical challenges will allow the generation of 
informative protein profiles that have the potential to improve clinical 
decisions regarding diagnosis, prognosis, and selection of therapy for 
individual cancer patients.

Post-translational modifications of proteins are critical to their function.  
Certain key information about the functional status of these proteins can be 
obtained only from the identification and quantitation of biologically active, 
properly modified proteins following the processing of inactive or unmodified 
translation products.  Quantitative information about differentially 
phosphorylated proteins, differentially glycosylated membrane-bound proteins, 
and processing of precursor proteins into functional proteases, cytokines, and 
growth factors will allow investigators to gain increased understanding of the 
altered biological processes associated with the various stages of cancer 
development.

Research Goals and Scope

This Request for Applications (RFA) is intended to stimulate the initiation 
and/or continued development of high-risk/high-impact technologies that target 
the sensitive quantitation of the wide spectrum of proteins in human tissues.  
Investigators are invited to propose the development of technologies for both 
comprehensive identification and sensitive quantitation of proteins translated 
and modified in human tumor specimens.  They are challenged to develop 
sensitive, efficient, and reproducible technologies that reliably measure 
altered concentrations of individual proteins.  The proposed approaches should 
address the current needs of identifying and quantitating proteins that are 
difficult to analyze, including low-abundance proteins and membrane-bound or 
hydrophobic proteins.

Comprehensive protein analysis is defined, for purposes of this RFA, as 
analysis of a large subset of proteins.  It is not necessary for applicants to 
propose strategies to analyze all proteins in a cell or tissue.  Investigators 
may choose to identify and quantitate the proteins present in subcellular 
compartments of human tissues.  For example, proteins associated with 
membranes, nuclei, mitochondria, microsomes, or cytoplasm could be analyzed 
separately.  Technical approaches to quantitating subsets of proteins that are 
grouped on the basis of their chemical properties may also be proposed.

Quantitative protein analysis technologies are intended to enable the 
measurement of relative differences in the abundance of individual proteins 
present in human tumors at various stages of cancer development.  This is 
intended to include proteins in all ranges of concentrations within a tissue.  
Accurate information about relative quantitation of these proteins will allow 
the evaluation of the biological consequences of changes in protein 
expression.  The proposed quantitation technologies should also be able to 
determine relative concentrations of differentially modified or processed 
proteins.  

Sensitive protein analysis technologies are intended to enhance the detection 
of very low-abundance proteins and the detection of changes in concentrations 
of these proteins.  Subtle changes in the abundance of these proteins may have 
profound biological consequences and may play a major role in tumor initiation 
and progression.

It is anticipated that investigators will develop general technologies that 
are applicable to quantitating proteins in the majority of human tissues.  
However, in all cases, applicants will have to carefully consider the sample 
preparation methods that will be used.  It may be necessary to integrate 
tissue-specific sample preparation methodologies with the protein analysis 
technologies depending upon the tissues that are selected for analysis.

Investigators may design novel adaptation or modification schemes that are 
compatible with available technologies as an alternative to proposing new 
approaches to the comprehensive, sensitive profiling of proteins in human 
tissues.  For example, investigators who are currently developing approaches 
to comprehensive quantitation of proteins in model systems, such as yeast and 
cell lines, may propose adaptation strategies for applying their technology to 
profiling the broad spectrum of proteins present in human tissues.  
Investigators may also propose to explore modifying comprehensive, but non-
quantitative proteomics technologies to add quantitation procedures to the 
analysis.  If necessary, a single application could propose two or more 
complementary approaches to efficiently analyze the spectrum of proteins 
selected for study.

While the purpose of this initiative is the development of sensitive, 
quantitative technologies for analysis of a wide spectrum of proteins in human 
tissues, identification of each protein is also important.  Investigators 
should address the methodologies for linking data generated from the 
developing protein analysis technologies to existing databases, including 
peptide mapping databases, messenger RNA (mRNA) expression databases, three-
dimensional protein structure databases, and/or protein function databases.  
Proteins that can not be clearly identified from available databases will need 
to be further characterized, but these studies are beyond the scope of this 
RFA. 

The intent of this initiative is to provide the proteomics research community 
with the opportunity to test and develop innovative strategies for 
comprehensive, sensitive, and quantitative protein profiling, not to support 
modest incremental advances in current technologies.  Submissions proposing 
the application of existing protein analysis technologies to address 
biological questions will not be supported under this RFA.  The R21/R33, 
exploratory/developmental Phased Innovation Award mechanism, will be used to 
support meritorious applications that are responsive to this RFA.  The R21 
phase will be used to demonstrate the feasibility of novel or improved 
technologies in comprehensive, sensitive, and quantitative analysis of 
proteins present in human tumor specimens.  The R33 phase will be used for 
further development of the proposed approaches into comprehensive, sensitive, 
efficient, and reproducible quantitation technologies that work in conjunction 
with protein identification strategies.

Summary
 
This RFA is to encourage and stimulate the development of substantially 
improved or new technologies that can achieve both a comprehensive 
identification and a sensitive, quantitative analysis of an extensive range of 
proteins in human tumor specimens.  This initiative is intended to take 
advantage of the increasing interest in the development of proteomics 
technologies, and specifically to meet the need identified by the research 
community for the ability to carry out sensitive and quantitative protein 
analysis.  Investigators in both academic and commercial institutions are 
invited to propose projects in response to this RFA.

Comprehensive, quantitative protein profiles of tumors at various stages of 
cancer development could ultimately permit the identification of multiple 
tumor-specific markers that will aid in identification of cancer therapeutic 
targets and of new approaches to cancer diagnostics.  Comprehensive 
information about the identification and quantitation of proteins will allow 
investigators to correlate expression levels of mRNAs and biologically active 
proteins in human tumors.  This information will augment our knowledge of 
molecular pathways underlying the development of cancer, and ultimately 
improve clinical decisions regarding early detection, diagnosis, prognosis, 
and treatment of cancer.

MECHANISM OF SUPPORT

Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  Except as otherwise stated in 
this solicitation, awards will be administered under NIH grants policy as 
stated in the NIH Grants Policy Statement, NIH Publication No 99-8, October 
1998.

Support for this program will be through the National Institutes of Health 
(NIH) Exploratory/Developmental Research Grant (R21) and the 
Exploratory/Developmental Research Grant Phase 2 (R33).  The R33 is a newly 
established NIH grant mechanism to provide a second phase for the support of 
innovative exploratory and developmental research initiated under the R21 
mechanism.  Transition of the R21 to the R33 phase will be expedited and is 
dependent on completion of negotiated milestones.

Under this RFA, applicants can choose one of three options in submitting 
applications, as described in the APPLICATION PROCEDURES section of this 
solicitation: an R21 application alone, a combined R21/R33 application (Phased 
Innovation Award application), or an R33 application alone if feasibility of 
the project can be documented.  Applicants requesting the support of an R21 
phase alone under this initiative will be allowed up to two years to explore 
the feasibility of their high-risk, challenging applications.  The total 
project period for a combined R21/R33 applications may not exceed 4 years, 
i.e., applicants can propose either two years of R21 and two years of R33 or 
one year of R21 and three years of R33 funding.  Applicants who request the 
support of an R33 phase alone will be allowed up to three years for the 
completion of their studies.

For combined R21/R33 applications, the R21 phase may not exceed $100,000 
direct costs per year.  R21 budgets can exceed this cap to accommodate 
Facility and Administrative (F&A) costs to subcontracts to the project.  
Although the R33 application has no official budgetary limit, applications 
requesting in excess of $500,000 dollars direct costs in any single year of 
the grant period require prior approval before submission.  It is strongly 
recommended that applicants contact program staff at an early stage of 
application development to convey critical information, such as potentially 
large budget requests or to discuss programmatic adherence to the guidelines 
of the proposed project.  Early contact with program staff is particularly 
critical relative to this RFA because it uses a new grant mechanism R33 as 
well as an expedited review procedure between a successful R21 and the R33 
phases.  Refer to the INQUIRIES sections of this solicitation for program 
staff contacts.

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

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

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

To be eligible for the Phased Innovation Award, the R21 phase must include 
well defined quantifiable milestones that will be used to judge the success of 
the proposed research, as well as a credible plan for the development of 
technology for the R33 phase. The Phased Innovation Award must have a section 
labeled Milestones at the end of the Research Plan of the R21 application. 
This section must include well-defined quantifiable milestones for completion 
of the R21 part of the 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.

FUNDS AVAILABLE

The NIH intends to commit approximately $1,750,000 in FY 2001 to fund 4 to 6 
new grants in response to this RFA. Because the nature and scope of the 
research proposed may vary, it is anticipated that the size of each award will 
also vary.  Although the financial plan of the NCI and NHGRI provides 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.   At this time, it is not known if competing renewal 
applications will be accepted and/or if this RFA will be reissued.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and 
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 
investigators

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:

Min H. Song, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
Executive Plaza North, Room 6035
Bethesda, MD 20892
Telephone:  (301) 402-4185
FAX:  (301) 402-7819
E-mail:  ms425z@nih.gov

Elise A. Feingold, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
Building 31, Room B2B07
Bethesda, MD 20892-2033
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
E-mail:  ef5j@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Kathleen Shino
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD 20892-7150
Telephone:  (301) 496-8635
FAX:  (301) 496-8601
E-mail:  shinok@gab.nci.nih.gov

Jean Cahill
Grants Administration Branch
National Human Genome Research Institute
Building 31, Room B2B34
Bethesda, MD 20892-2031
Telephone:  (301) 435-7858
FAX:  (301) 402-1951
E-mail:  jc166o@nih.gov

Direct inquiries regarding review matters to:

Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Telephone:    (301) 496-3428
FAX:    (301) 402-0275

LETTER OF INTENT

Prospective applicants are asked to submit, by the date listed on the first 
page of this RFA, a letter of intent that includes a descriptive title of the 
proposed research, the name, address, and telephone number of the Principal 
Investigator, the identities of other key personnel and participating 
institutions, and the number and title of the RFA in response to which the 
application is being submitted.  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 to Dr. Min H. Song listed under INQUIRIES 
by the letter of intent receipt date listed in the heading of this RFA.

SCHEDULE
 
Letter of Intent Receipt:                      December 11, 2000
Application Receipt Date:                      January 18, 2001
Peer Review Date:                              April/May 2001
Review by Institutes’ Advisory Board/Council:  August/September 2001
Earliest Anticipated Start Date:               September 1, 2001

APPLICATION PROCEDURES

SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION 
AWARD APPLICATION

Applications for R21/R33 grants are to be submitted on the grant application 
form PHS 398 (rev. 4/98) and prepared according to the instructions provided 
unless specified otherwise within this section.  Application kits are 
available at most institutional offices of sponsored research and may be 
obtained from the Division of Extramural Outreach and Information Resources, 
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-
0714, email: grantsinfo@nih.gov.  For those applicants with internet access, 
the 398 kit may be found at: http://grants.nih.gov/grants/forms.htm.

The R21/R33 application must include the specific aims for each phase and the 
feasibility milestones that would justify transition to the R33 phase.  
Applications must include a specific section labeled Milestones following the 
Research Plan of the R21 phase.  Milestones should be well described, 
quantifiable and scientifically justified.  A discussion of the milestones 
relative to the progress of the R21 phase, as well as, the implications of 
successful completion of the milestones for the R33 phase should be included.  
This section should be indicated in the Table of Contents.  Applications 
lacking this information as determined by the program staff, will be returned 
to the applicant without review.  For funded applications, completion of the 
R21 milestones will elicit an expedited review by the Institutes 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 Phased Innovation Award application must be submitted as a single 
application, with one face page.  Although it is submitted as a single 
application, it should be clearly organized into two phases.  To accomplish a 
clear distinction between the two phases, applicants are directed to complete 
Sections a-d of the Research Plan twice: one write-up of Sections a-d and 
milestones for the R21 phase and sections a-d again for the R33 phase.  The 
Form 398 Table of Contents should be modified to show sections a-d for each 
phase as well as the milestones.  There is a page limit of 25 pages for the 
composite a-d text (i.e., section a-d and milestones for the R21 and sections 
a-d for the R33 phase must be contained within the 25 page limit.)

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

1.  Face Page of the application:

Item 2.  Check the box marked “YES” and type the number and title of this RFA.  
Also indicate that the application is an R21/R33.

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

For the R21 phase of the combined R21/R33 application, direct costs are 
limited to a maximum of $100,000 per year for a maximum of two years and the 
award may not be used to supplement an ongoing project.  The requested budgets 
can exceed this cap to accommodate for F&A 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 in item 8a.

2.  Description:

As part of the description, identify concisely the technology or methodology 
to be developed, its innovative nature, its relationship to presently 
available capabilities, and its expected impact on comprehensive, sensitive, 
and quantitative protein analysis in human tumors.

3.  Budget:

The application should provide a detailed budget for Initial Budget Period 
(form page 4), for each of the initial years of the R21 and R33 phases as well 
as a budget for the entire proposed period of support (form page 5).  Form 
pages should indicate which years are R21 and R33.  All budgets should include 
a written justification. 

Investigators funded through this program will be invited to an annual meeting 
of investigators funded by the Phased Innovation Award mechanism under NCI’s 
Program Announcements.  The annual meeting will facilitate sharing of progress 
and research insights with other investigators.  Applicants should request 
travel funds in their budgets for the principal investigator and one 
additional senior investigator to attend this annual meeting.

4.  Research Plan:

Item a., Specific Aims.

The applicants 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 develop innovative technologies, biological 
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 and R33 phase, research that 
develops 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 within this 
section are essential.

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.

Item c., Preliminary Studies/Progress Report

While preliminary data are not required for submission of the R21 phase, this 
section should provide current thinking or evidence in the field to 
substantiate feasibility of the R21 phase.  The R33 need not repeat 
information already provided in the R21.  In the event that an applicant feels 
that technology is too proprietary to disclose, applicants at a minimum should 
provide a demonstration (results) of the capabilities of the proposed 
technology.  
 
Item d., Research Design and Methods

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

Applications must include a specific section labeled Milestones following the 
Research Design and Methods of the R21 phase.  Milestones should be well 
described, quantifiable, and scientifically justified and not be simply a 
restatement of the specific aims.  A discussion of the milestones relative to 
the success of the R21 phase, as well as the implications of successful 
completion of the milestones for the R33 phase, and the page number of the 
milestones section should be listed.  This section should be indicated in the 
Table of Contents.  Applications lacking this information, as determined by 
the program staff, will be returned to the applicant without review.  For 
funded applications, completion of the R21 milestones will elicit an expedited 
review by the Institutes that will determine whether or not the R33 should be 
awarded.  The release of R33 funds will be based on successful completion of 
milestones, program priorities and on the availability of funds.  The 
expedited review may result in additional negotiations of award.

SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R21 APPLICATION WHEN SUBMITTED 
WITHOUT THE R33 PHASE.

Applications for R21 grants are to be submitted on the grant application form 
PHS 398 (rev. 4/98) and prepared according to the instructions provided for 
R21 applications in the previous section except that Milestones and discussion 
of the implication of the milestones to the R33 phase are not required.  
Application kits are available at most institutional offices of sponsored 
research and may be obtained from the Division of Extramural Outreach and 
Information Resources, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-
7910, telephone 301/435-0714, email: grantsinfo@nih.gov.  For those applicants 
with internet access, the 398 kit may be found at: 
http://grants.nih.gov/grants/forms.htm.

1.  Face Page of the application:

Item 2. Check the box marked “YES” and type the number and title of this RFA.  
Also indicate that the application is an R21.

SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED 
WITHOUT THE R21 PHASE.

Applications for R33 grants are to be submitted on the grant application form 
PHS 398 (rev. 4/98) and prepared according to the instructions provided unless 
specified otherwise within items 1-5 below.  Application kits are available at 
most institutional offices of sponsored research and may be obtained from the 
Division of Extramural Outreach and Information Resources, 6701 Rockledge 
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
grantsinfo@nih.gov.

1.  Face Page of the application:

Item 2. Check the box marked “YES” and type the number and title of this RFA.  
Also indicate that the application is an R33.

2.  Description:

As part of the description, identify concisely the technology or methodology 
to be developed, its innovative nature, its relationship to presently 
available capabilities and its expected impact on comprehensive, sensitive, 
and quantitative protein analysis in human tumors.

3.  Research Plan:

Item a., Specific Aims.

The instructions in the PHS 398 booklet for this section of research grant 
applications suggest that the applicant state the hypotheses to be tested.  
Because the goal of this RFA is to develop innovative technologies, biological 
hypothesis testing per se may not be the driving force in developing such a 
proposal and, therefore, may not be applicable.

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.

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 application must clearly describe how the 
exploratory/developmental study is ready to scale up to an expanded 
development stage.  In the event that an applicant feels that the technology 
is too proprietary to disclose, applicants at a minimum should provide a 
demonstration (results) of the capabilities of the proposed technology.  

FOR ALL APPLICATIONS

Appendix:   All instructions in the Form 398 application kit apply.

Submit a signed, typewritten original of the application, including the 
checklist, and three signed, exact, single-sided photocopies, in one package 
to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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

Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Telephone:    (301) 496-3428
FAX:    (301) 402-0275

Applications must be received by the receipt date listed at the beginning of 
this RFA.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by the program staff.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration.

Applications that are complete and responsive to this RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the Division of Extramural Activities, NCI, in accordance with the 
review criteria stated below.  As part of the initial merit review, all 
applicants will receive a written critique and may undergo a process in which 
only those applications deemed to have the highest scientific merit generally 
the top half of the applications will be discussed, assigned a priority score, 
and receive a second level review by the National Cancer Advisory Board and/or 
the National Advisory Council for Human Genome Research.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  The 
reviewers will comment on the following aspects of the application in their 
written critiques in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered by the reviewers in assigning the 
overall score weighting them as appropriate for each application.  Note that 
the application does not need to be strong in all categories to be judged 
likely to have a major scientific impact and thus deserve a high priority 
score.  For example, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a technology 
forward.

1.  Significance.  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?  To what degree does the technology support the needs of the 
targeted research community?  For systems intended for clinical research the 
additional criteria will be considered: to what degree is the analysis system 
appropriate for clinical research and likely to have utility for the analysis 
of clinical specimens or patients?

2.  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?  What is the time frame for developing the proposed 
technologies and suitability of this time frame for meeting the scientific 
community’s needs?  How easy will it be to use the proposed technology?  Are 
the plans for proposed technology dissemination adequate?

3.  Milestones.  How appropriate are the proposed milestones against which to 
evaluate the demonstration of feasibility for transition to the R33 
development phase?

4.  Innovation.  Does the project employ novel concepts, approaches or method?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

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

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

Additional Considerations

For the R21/R33 Phased Innovation Award Application, the initial review group 
will evaluate the specific goals for each phase and the feasibility milestones 
that would justify expansion to the R33 phase.  A single priority score will 
be assigned to each scored application.  As with any grant application, the 
initial review group has the option of recommending support for a shorter 
duration than that requested by the applicant, and basing the final merit 
rating on the recommended portion of the application.  For the R21/R33 
application, this may result in a recommendation that only the R21 phase be 
supported, based on concerns related to the applicant’s specific goals and the 
feasibility milestones justifying expansion to the R33 phase.  Deletion of the 
R33 phase by the review panel or inadequate milestones will affect the merit 
rating of the application.

The initial review group will also examine: the appropriateness of the 
proposed project budget and duration; the adequacy of plans to include both 
genders and minorities and their subgroups, and children as appropriate for 
the scientific goals of the research and plans for the recruitment and 
retention of subjects; the provisions for the protection of human and animal 
subjects; and the safety of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other recommended 
applications received in response to this RFA.  The following will be 
considered in making funding decisions: quality of the proposed project as 
determined by peer review, availability of funds, and program priority.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub- populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000  
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are clear and compelling scientific and ethical reasons not 
to include them.  This policy applies to all initial (Type 1) applications 
submitted for receipt dates after October 1, 1998. 

All investigators proposing research involving human subjects should read the 
“NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects” that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address:  http://grants.nih.gov/grants/guide/notice-files/not98-024.html 

Investigators also may obtain copies of the policy from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES 

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

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, Technologies for Comprehensive, 
Sensitive, and Quantitative Protein Analysis in Human Tumors, is related to 
the priority area of cancer.  Potential applicants may obtain a copy of 
“Healthy People 2010” at http://www.health.gov/healthypeople/.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.394 (Cancer Detection and Diagnosis Research) and No. 93.172 (Human Genome 
Research).  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

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

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