APPLICATIONS OF INNOVATIVE TECHNOLOGIES FOR THE MOLECULAR ANALYSIS OF CANCER:  
PHASED INNOVATION AWARD
 
Release Date:  May 31, 2001
 
PA NUMBER:  PAR-01-106 (see replacement RFA-CA-05-003)

National Cancer Institute

Letter of Intent Date:     June 15, 2001; October 17, 2001; February 14, 2002; 
                           June 10, 2002; October 18, 2002; February 14, 2003; 
                           and June 16, 2003

Application Receipt Date:  July 20, 2001; November 21, 2001; March 21, 2002; 
                           July 22, 2002; November 22, 2002; March 21, 2003; 
                           and July 21, 2003

This Program Announcement (PA) replaces PAR-99-102, which was published 
in the NIH Guide on May 14, 1999.

THE PA INCLUDES MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT 
MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. THIS 
PA DOES NOT USE THE MODULAR GRANT CONCEPT.

PURPOSE

The National Cancer Institute (NCI) invites applications for research 
projects to evaluate the utility and pilot the application of molecular 
analysis technologies in studies relevant to cancer research.  
Molecular analysis technologies of interest include those that are 
entirely novel, or emerging but not currently in broad scale use where 
the technologies have not yet been demonstrated to be robust or 
reproducible in supporting molecular analysis in cancer research, or 
technologies currently in use for one application or set of 
applications, that are being evaluated for utility for alternative 
applications.  The Program Announcement (PA) provides support for a 
first phase for technology evaluation and a second phase for pilot 
application of the technology in a study of biological interest to 
cancer research. The first (evaluation) phase should include proof of 
principle experiments that will demonstrate the utility of the 
technology on samples comparable to those that will be used in the 
second phase study.  Applicants will be expected to demonstrate the 
utility of all components of the process required for a fully 
integrated system, including sample preparation, molecular analysis 
assay, and data capture and analysis.  The second (application) phase 
supports the transition of the technology optimized in the first 
(evaluation) phase to pilot application in a study of biological 
interest to cancer research.  The design of the second phase study 
should allow the demonstration that the technology can reproducibly 
obtain molecular data from the selected sample type and produce 
information of biological interest to cancer research.  Studies might 
appropriately target analysis of precancerous, cancerous, or metastatic 
cells, or host derived samples, from model cancer systems, preclinical 
or clinical research, or from population based research.

Technologies suited for this solicitation, include those that enable 
the detection of alterations and instabilities of genomic DNA; 
measurement of expression of genes and gene products; analysis and 
detection of gene and or cellular products including differential 
expression, quantitation, post translational modification, and function 
of proteins; identification of exogenous infectious agents in cancer; 
and assaying the function or major signal transduction networks 
involved in cancer.  Additionally, technologies that will support 
molecular analysis in vitro, in situ, or in vivo (by imaging or other 
methods) are suitable for this PA.  Technologies are defined as 
instrumentation, techniques, devices and analytical tools (e.g., 
computer software) but are distinct from resources such as databases, 
reagents, and tissue repositories. 

This PA will expire on July 22, 2003, unless reissued.

BACKGROUND

Rapid molecular analysis tools will expedite the molecular 
characterization of normal cells, precancerous, cancerous, and 
metastatic cells, as well as, expand our understanding of the 
biological basis of cancers.  Comprehensive analysis of cancers at the 
molecular level will facilitate cancer detection and diagnosis, as well 
as identify new targets for therapeutic and preventative agents.  

The definition of the molecular alterations in cancer will require the 
continued development and dissemination of comprehensive molecular 
analysis technologies as well as identification of all of the molecular 
species encoded in genomes of cancer and normal cells. The National 
Cancer Institute implemented the Cancer Genome Anatomy Project (CGAP) 
to create an information infrastructure of the molecular changes 
associated with cancer development, and to develop technological tools 
to support the analysis of molecular profiles of cancer cells and their 
normal counterparts. The current CGAP program comprises Tumor Gene 
Indices for the human and mouse (hTGI and mTGI), a Genetic Annotation 
Initiative (GAI) and the Cancer Chromosome Aberration Project (cCAP). 
The TGI and GAI, are focused toward building a catalog of annotated 
genes associated with cancer. The third component, cCAP, is developing 
resources to catalog and facilitate the molecular characterization of 
cancer-related chromosomal aberrations. Complete information about CGAP 
can be found at http://cgap.nci.nih.gov.  The NCI is also targeting 
support for the development and dissemination to basic, preclinical, 
and clinical researchers of novel technologies that will allow high-
throughput analysis of genetic alterations, expression of genome 
products, and monitoring of signal transduction pathways in cancers.  A 
complimentary program on "Innovative Technologies for the Analysis of 
Cancer" to support technology development was announced in May 1998 and 
has recently been reissued for the next two years. 
   
This initiative, "Applications of Innovative Technologies for the 
Molecular Analysis of Cancer" is intended to support the demonstration 
that newly developed and emerging technologies have matured and are 
suitable for use in cancer research, followed by the initial 
application of these technologies in well-defined studies of biological 
interest to cancer research using model cancer systems, preclinical or 
clinical samples, or in population research. The routine use of 
improved molecular analysis tools will lead to a better understanding 
of the molecular basis of cancer, and will facilitate the 
identification of molecular characteristics of individuals, that 
influence cancer development and prognosis.

Molecular analysis technologies of interest include those that will 
support:

--A more complete understanding of the biological basis of cancer.

--The identification of molecular variations between normal, 
precancerous, cancerous, and metastatic cells that can serve as targets 
for the detection, diagnosis, therapy, and prevention.

--An examination of genetic factors that influence an individual's 
likelihood to develop cancer or their ability to respond to external 
damaging agents, such as radiation and carcinogens. 

--The molecular correlation between individuals with therapeutic or 
toxic responses to treatment and prevention measures and genetic 
factors that influence the efficacy and safety of these strategies and 
agents (pharmacogenomics). 

--Identification of molecular markers in the individual that correlate 
with the body's response to the onset or clearance of disease and the 
development of biomarkers to track and even image the efficacy of 
therapy (therametrics) and prevention, as well as the onset of 
secondary cancers. 

--Tracking of the damage to the genome from exogenous agents such as 
carcinogens, radiation and existence of exogenous infectious agents 
resident in cancer cells.
     
The comprehensive molecular analysis of cancer will require:

--High through put analysis strategies to elucidate the processing and 
expression of genetic material in the cell.

--Detection of molecular changes in the cell without preconceived ideas 
about which information will be most valuable to monitor.

--Adequate adaptations to accommodate technical issues specific to the 
study of cancer in vitro and in vivo, such as limited cell number, 
sample heterogeneity, and heterogeneity of specimen types (i.e., bodily 
fluids and waste, tissues, cells).

--Adaptation of novel technologies for use in cancer research, 
including use on tumor specimens, in patient imaging, and in population 
research.

--Integration of sample preparation components that maintain the 
efficiencies of the assay system and effectively accommodate human 
tumor specimens.

--Data analysis tools for interpreting the information from highly 
multiplexed molecular analyses.
   
Novel technologies for comprehensive molecular analysis are being 
developed.  Many of these technologies have not yet been demonstrated 
to have utility or cost effectiveness in application to cancer model 
systems, cancer specimens, or in population-based research. It will be 
necessary to demonstrate that relevant technologies have adequate 
sensitivity to discriminate differences between tumors and normal 
tissues, and tumors of different stages. Therefore, the need exists to 
demonstrate the ability of emerging molecular analysis technologies to 
provide routine assay performance, adequate sensitivity and 
discrimination, and associated robust data analysis tools, that can be 
adapted to basic, pre-clinical, and clinical research settings for the 
purpose of cancer research.

Translation of new in vitro technologies for the multiplexed analysis 
of molecular species in clinical specimens will require a 
multidisciplinary team approach with broad expertise in a variety of 
research areas.  Such varied expertise, potentially including but not 
limited to, expertise in pathology, specimen acquisition and 
preparation, informatics and biostatistics exists in ongoing cancer 
centers and clinical trials cooperative groups. The coordination and 
collaboration of investigators from these various disciplines to 
demonstrate the utility and applicability of new analytical tools in 
clinical and population based studies is considered to be a high 
priority.

Existing technologies for molecular analysis are also largely 
restricted to in vitro analysis.  While these systems are suitable for 
discovery and many basic and clinical research questions, they are 
limited in their ability to offer information relative to molecular 
changes in real time and in the appropriate context of the intact cell 
or body.  Imaging in situ or in vivo is becoming increasingly important 
for extending molecular analysis of early cancer formation.  The 
application of high-resolution imaging at the cellular or molecular 
levels to, tissue samples, pre-clinical models, or human investigations 
is therefore considered to be an important extension of molecular 
analysis methods.  Similarly, the application of molecular probes for 
imaging molecular events is also of interest for pre-clinical and human 
investigations.  Finally, the use of molecular contrast enhancement 
techniques, such as contrast modifications of gene expression are 
considered critical to improve the sensitivity of detection of 
molecular changes in vivo. The molecular imaging methodologies 
proposed, including hardware and software, are specifically understood 
as being within the context of molecular analysis tools.  They include 
specialized high resolution or microscopic imaging methods dedicated to 
detection and analysis of molecular events related to cancer formation 
or as applied to pre-clinical drug discovery.  Improvements in these 
areas will bring capabilities for real time molecular analysis at whole 
body levels.  Investigations of tumor models that do not target 
molecular species are not responsive to this application.  
Investigators are encouraged to contact NCI program staff for further 
information.

RESEARCH OBJECTIVE

The National Cancer Institute (NCI) invites applications for research 
projects to evaluate the utility and pilot the application of newly 
developed molecular analysis technologies in studies relevant to cancer 
research.  The Program Announcement (PA) provides support for a first 
phase for technology evaluation and a second phase for pilot 
application of the technology in a study of biological interest to 
cancer research. The first (evaluation) phase should include proof of 
principle experiments that will demonstrate the utility of the 
technology on samples comparable to those that will be used in the 
second phase study.  Applicants will be expected to demonstrate the 
utility of all components of the process required for a fully 
integrated system, including sample preparation, molecular analysis 
assay, and data capture and analysis.  The second (application) phase 
supports the transition of the technology optimized in the first 
(evaluation) phase to pilot application in a study of biological 
interest to cancer research.  The design of the second phase study 
should allow the demonstration that the technology can reproducibly 
obtain molecular data from the selected sample type and produce 
information of biological interest to cancer research.  Studies might 
appropriately target analysis of precancerous, cancerous, or metastatic 
cells, or host derived samples, from model cancer systems, preclinical 
or clinical research, or from population based research.

The application of new tools that support the comprehensive molecular 
characterization of normal, precancerous, cancerous, and metastatic 
cells, as well as the identification of new targets for detection, 
diagnosis, preventative, and therapeutic strategies, is needed to 
support the basic discovery process and the translation of basic 
discoveries to pre-clinical and clinical research. Application of 
improved molecular analysis technologies will also allow a more 
thorough examination of the variations that influence predisposition to 
cancer, and individual variability in response to therapeutic and 
prevention agents as well as the identification of exogenous infectious 
agents that may be associated with the development of cancer.  Examples 
given below are not intended to be all-inclusive, but are illustrative 
of the types of molecular analysis capabilities that are of interest 
for evaluation and pilot application in response to this solicitation.

--In vitro identification and characterization of sites of chromosomal 
aberrations, which arise from inherited or somatic alterations 
resulting from aging or oxidation, or exposure to radiation or 
carcinogens, including those that are suitable for scaling for use 
across whole genomes, detecting DNA adducts, detecting rare variants in 
mixed populations, or identifying infrequently represented mutations in 
mixed populations of DNA molecules.

--Detection and characterization of nucleic acid sequences of novel 
exogenous infectious agents including viruses, bacteria or other 
microscopic forms of life that may be etiologic factors or co-factors 
in the initiation and/or progression of human cancers.  New 
technologies are demonstrating that microorganisms may play a more 
important role in the initiation of malignancies than was previously 
appreciated. 

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

-- Highly specific and sensitive detection of specific mutations in 
multiplexed high through put analysis.

-- Detection of mismatch and recombinational DNA repair anomalies 
related to cancer susceptibility, cancer progression, and drug 
sensitivity.

-- In vitro multiplexed analysis of the expression of genes.

-- Computer assisted quantitation of gene expression. 

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

--Assaying the function of proteins and genetic pathways, including 
measurement of ligand-protein complexes and technologies for monitoring 
protein function of all members of a class of proteins or members of a 
complete genetic pathway.
 
Translation of the utility of the technologies described above and 
basic research findings into tools for pre-clinical and clinical 
applications requires additional technological innovation with regard 
to sample preparation, enhanced sensitivity, and expanded data analysis 
tools.  Of interest is the application of technologies suitable for:

-- Detection, quantification and analysis of DNA mutations and 
polymorphisms and functional proteins in clinical specimens  (e.g. 
tissue, serum, plasma, nipple aspirates, bronchioalveolar lavage, 
sputum, urine, pancreatic juice, colonic wash, and bladder wash).

--Imaging in situ or in vivo in order to extend molecular analysis to 
early cancer formation.  The application of high-resolution imaging at 
the cellular or molecular levels to, tissue samples, pre-clinical 
models, or clinical investigations are therefore considered to be an 
important extension of molecular analysis methods.  Similarly, the 
application of molecular probes for imaging molecular events is also of 
interest for pre-clinical and human investigations.  Finally, the use 
of molecular contrast enhancement techniques, such as contrast 
modifications of gene expression are considered critical to improve the 
sensitivity of detection of molecular changes in vivo. The molecular 
imaging methodologies proposed, include hardware and software, are 
specifically understood as being within the context of molecular 
analysis tools.  They include specialized high resolution or 
microscopic imaging methods dedicated to detection and analysis of 
molecular events related to cancer formation or as applied to pre-
clinical drug discovery.  Improvements in these areas will bring 
capabilities for real time molecular analysis at whole body levels.

The R21 proposal supports a first phase for technology evaluation.  
Applicants should describe proof of principle experiments that will 
demonstrate the utility of the technology. The applicant should: 

--Demonstrate performance of the selected technology on samples 
comparable to those to be used in the proposed study in the R33 phase.

--Have a detailed plan to optimize and troubleshoot the technology for 
complete adaptation of the technology for the R33 pilot application.

--Discuss how they will evaluate cost effectiveness of the technology 
relative to existing and competing technologies.

--Specifically address approaches to sample preparation, molecular 
analysis assays, data collection, and data management.
   
Applicants must include in a separate section the milestones to be 
accomplished in the first phase of the application.  Milestones are 
separate from specific aims.  They provide a clear measure of the 
success of the R21 application which is necessary to proceed to the 
second phase, therefore they should be clearly stated and presented in 
a manner that is easily quantifiable.

The R33 study is intended to support the pilot application of 
technology evaluated and refined in the R21 proposal, to a study of 
biological interest to cancer research.  Technology developers are 
strongly encouraged to seek collaborations with qualified cancer 
researchers. In the R33 phase the applicants should:

--Describe how they will assess the performance of the technology in 
providing useful molecular data relative to existing technologies.

--Address plans to refine study design parameters based on R21 results.

--Provide a more refined plan detailing the biological questions to be 
asked by the study and how the forthcoming data will be translated, 
either directly or indirectly, into information relevant to the study 
of cancer.

--Comment in detail on the suitability of the study design (i.e. 
numbers, types of samples) for asking the biological questions posed by 
the study. This should be discussed in the context of information and 
data to be obtained from R21 studies. The study design parameters (i.e. 
number of samples, data analysis, etc.)  should be of a scale to 
reflect that this is a pilot application of the technologies.

--Clearly define what is considered to be a high quality sample for the 
technology to be used.

--Document a strategy for obtaining access to high-quality samples that 
will be needed to carry out the study.

--Discuss the ease of transition of the technology from R21 to R33 
application with respect to scaling up the technology and implications 
related to sample cost, availability, and sample through-put.
   
Effective data management and analysis will be critical to the 
successful and productive application of the proposed technology. 
Therefore applications must:

--Address the ability to acquire, store, analyze, and extract 
information from data collected through the course of the study.

--Demonstrate capabilities to capture the data and to perform the 
complex multiplex analysis on data a acquired through the course of the 
study.

--Describe bioinformatics, other analytical systems, and approaches 
that will be used to interpret data obtained from the study.

Applicants are encouraged to discuss potential strategies for making 
resulting molecular data sets available to the cancer research 
community in both peer reviewed-publications as well as in complete 
electronically accessible data sets.

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 program announcement, awards will be 
administered under NIH grants policy as stated in the NIH Grants Policy 
Statement, March 2001, available at: 
http://grants.nih.gov/grants/policy/nihgps_2001/.  Hard copies are not 
available.

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

Under this PA, applicants can submit either a combined R21/R33 
application (Phased Innovation Award application) or the R33 
application alone, if feasibility can be documented, as described in 
the APPLICATION PROCEDURES section of this program announcement.  
Applications for R21 support alone will not be accepted.  The total 
project period for an application submitted in response to this PA may 
not exceed the following duration: R33, 3 years; combined R21/R33 
application, 4 years.  In the combined application the R21 phase cannot 
extend beyond 2 years.

For combined R21/R33 applications, the R21 phase may not exceed 
$100,000 direct costs per year.  R21 budgets can exceed this cap to 
accommodate indirect costs to subcontracts to the project.  R33 
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 NCI 
staff at an early stage of application development to convey critical 
information, such as potentially large budget requests or to discuss 
programmatic adherence to the guidelines of the proposed project.  
Early contact with NCI staff is particularly critical relative to this 
PA because it uses an expedited review procedure.  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 as one 
application.

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

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 pilot application 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.

This program will run in parallel with a program of identical 
scientific scope 
(http://grants.nih.gov/grants/guide/pa-files/PAR-01-107.html) that will utilize 
the Small Business Innovation Research (SBIR) and Small Business Technology 
Transfer (STTR) mechanisms.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and 
not-for-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:

Carol A. Dahl, Ph.D. 
Office of Technology and Industrial Relations
National Cancer Institute
31 Center Drive, Room 11A03
Bethesda, MD  20892-2590
Telephone:  (301) 496-1550
FAX: (301) 496-7807
Email: carol_dahl@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Kathleen J. Shino
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd. Room 243
Bethesda, MD  20892-7150
Telephone:  (301) 846-1016
FAX:  (301) 846-5720
Email:  shinok@gab.nci.nih.gov

Direct inquiries regarding review matters to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8326
Bethesda, MD  20892-8326
Rockville, MD  20852 (for express/courier service)
Telephone (301) 496-3428
Fax: (301) 402-0275
Email:  tf12w@nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit, by the dates listed on the 
first page of this PA, 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 PA in 
response to which the application may be 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. Carol Dahl, listed under 
INQUIRIES, by the Letter of Intent receipt date. 

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 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 on the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html.

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 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 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 each phase are 
critical.  The presentation of milestones that are not sufficiently 
scientifically rigorous to be valid for assessing progress in the R21 
phase will reflect upon the scientific judgement of the applicant in 
this proposal.

1.  Face Page of the application:

Item 2.  Check the box marked YES and type the number and title of this 
program announcement.  Also indicate if the application is a R21/33 or 
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 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 in item 8a

2.  Page 2 - Description:
As part of the description, identify concisely 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 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. 

An annual meeting of all investigators funded through this program will 
be held to share progress and research insights that may 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.

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 PA is to support the pilot 
application of innovative technologies, hypothesis testing per se may 
not be the driving force in developing such a proposal 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 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 within this section are essential.  
Studies pursuing comprehensive analysis in particular may result in 
hypothesis generation, rather than hypothesis testing.  

Item b: Background and Significance

Elaborate on the innovative nature of the proposed research.  Clarify 
how the technology proposed for evaluation 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.  Describe the significance of the second phase 
pilot biological study in terms of relevance to cancer research.

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 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 
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 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 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 on the Internet at: 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

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.  Page 2 Description:

As part of the description, identify concisely 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 pilot biological study in 
which the technology will be applied.

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 program announcement is to pilot 
the application of innovative technologies, hypothesis testing per se 
may not be the driving force in developing such a proposal and, 
therefore, may not be applicable.  Studies pursuing comprehensive 
analysis in particular may result in hypothesis generation rather than 
hypothesis testing.

Item b: Background and Significance

Elaborate on the innovative nature of the proposed research.  Clarify 
how the technology proposed for evaluation 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, and how these proposed 
technologies would differ from existing technologies.  Discuss the 
significance of the pilot biological application to be undertaken in 
terms of relevance for cancer research.

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 application 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.  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.

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 8326
Bethesda, MD 20892-8326
Rockville, MD 20852 (for overnight/courier service)

Applications must be received by the receipt dates listed at the 
beginning of this PA.

The Center for Scientific Review (CSR) will not accept any application 
in response to this PA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application. The CSR will not accept any application that is 
essentially the same as one already reviewed. This does not preclude 
the submission of substantial revisions of applications already 
reviewed, but such applications must include an introduction addressing 
the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the CSR for completeness 
and by NCI program staff for adherence to the guidelines.  Applications 
not adhering to application instructions described above and those 
applications that are incomplete as determined by CSR or by NCI program 
staff will be returned to the applicant without review.

Applications that are complete and adhere to the guidelines of this PA 
will be evaluated for scientific and technical merit by an appropriate 
peer review group convened by the Division of Extramural Activities, 
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 
(NCAB).

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
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? 

3.  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? What is the throughput and cost effectiveness of the 
proposed technology?  What additional uses can be projected for the 
proposed technology?

4.  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)?

5.  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

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

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 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 assigned to the NCI.  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.

SCHEDULE

Letter of Intent Receipt Dates:   June 15, 2001; October 17, 2001; 
                                  February 14, 2002; June 10, 2002; 
                                  October 18, 2002; February 14, 2003; 
                                  and June 16, 2003
Application Receipt Dates:        July 20, 2001; November 21, 2001; 
                                  March 21, 2002; July 22, 2002; 
                                  November 22, 2002; March 21, 2003; 
                                  and July 21, 2003
NCAB Review Dates:                February 2002; May 2002; September 2002; 
                                  February 2003;  May 2003; September 2003; 
                                  February 2004
Earliest Anticipated Award Date:  April 1, 2002; July 1, 2002; November 1, 2002; 
                                  April 1 2003; July 1, 2003; November 1, 2003; 
                                  April 1, 2004

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 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 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 is 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.

REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS

All investigators proposing research involving human subjects should 
read the NIH policy on education in the protection of human research 
participants now required for all investigators, which is published in 
the NIH Guide for Grants and Contracts, June 5, 2000 (Revised August 
25, 2000), available at the following URL address 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.  A 
continuing education program on the protection of human participants in 
research is now available online at http://cme.nci.nih.gov/.

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 PA, 
Applications of Innovative Technologies for the Molecular Analysis of 
Cancer, 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.  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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