INNOVATIVE TECHNOLOGIES FOR THE MOLECULAR ANALYSIS OF CANCER:  PHASED 
INNOVATION AWARD
 
Release Date:  May 31, 2001 (see addendum NOT-CA-03-007)

PA NUMBER:  PAR-01-104

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-99-100, 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 develop novel technologies that will support the molecular 
analysis of cancers and their host environment in support of basic, 
clinical, and epidemiological research.  Technology encompasses methods 
and tools that enable research including, but not limited to, 
instrumentation, techniques, devices, and analysis tools (e.g., 
computer software). Technology is distinct from resources such as 
databases, reagents, and tissue repositories.  Applications for support 
of such resources will not be considered to be responsive to this 
Program Announcement (PA).  Technologies solicited include those that 
are suitable for the detection of alterations and instabilities of 
genomic DNA; measurement of the expression of genes and gene products; 
analysis and detection of gene and or cellular products including post 
translational modification, and function of proteins; identification 
and characterization of exogenous infectious agents in cancer; and 
assaying the function of major signal transduction networks involved in 
cancer. This PA is intended to support the development of all required 
components of fully integrated systems for analysis including front end 
preparation of sample materials from cells, bodily fluids, and tumor 
specimens; novel chemistries or contrast agents; molecular detection 
systems; data acquisition methods; and data analysis tools.  
Technologies under consideration include those that will support 
molecular analysis either in vitro, in situ, or in vivo (by imaging or 
other methods) in the discovery process, as well as in pre-clinical 
models and clinical research.  

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

BACKGROUND

In the past several decades it has become clear that cancer is not one 
disease but many, and that cancers arise as the result of the gradual 
accumulation of genetic changes in single cells. Identifying which 
subset of the genes encoded within the human genome can contribute to 
the development of cancer remains a challenge.  The identification of 
these cancer genes and their associated gene products remains a high 
priority in cancer research.  Identifying the molecular alterations 
that distinguish any particular cancer cell from a normal cell will 
ultimately help to define the nature and predict the pathologic 
behavior of that cancer cell, as well as the responsiveness to 
treatment of that particular tumor.  By understanding the profile of 
molecular changes in any particular cancer it will become possible to 
correlate the resulting phenotype of that cancer with molecular events.  
Resulting knowledge will offer the potential for a better understanding 
of cancer biology; the discovery of new tools and biomarkers for 
detection, diagnosis, and prevention studies; and new targets for 
therapeutic development.

The definition of the molecular profiles of cancer will require the 
development and dissemination of enhanced molecular analysis 
technologies, as well as elucidation 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 the 
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. 
Products of this PA are intended to contribute to this goal.

This solicitation is intended to support the development of molecular 
analysis tools that will allow for the more careful examination of the 
molecular basis and profiles of cancer, and also provide the ability to 
identify the molecular characteristics of individuals that influence 
cancer development and prognosis.  These tools will allow for an 
examination of genetic factors that influence an individual’s 
likelihood to develop cancer or their ability to respond to damaging 
external agents, such as radiation, carcinogens, and therapeutic 
regimes.  Correlating the molecular variations between individuals with 
therapeutic or toxic responses to treatment and prevention measures 
should define genetic factors that influence the efficacy and safety of 
these strategies and agents (pharmacogenomics).  Identification of 
molecular markers in the individual that characterize the body’s 
response to the onset or clearance of disease will allow for the 
development of biomarkers to track and even image the efficacy of 
therapy (therametrics) and prevention, as well as the onset of 
secondary cancers.  The ability to completely screen the genome for 
variations should enable tracking of the damage to the genome from 
exogenous agents such as carcinogens, infectious agents, radiation, and 
therapeutic regimes.  Products of this PA such as molecular imaging in 
situ are intended to contribute to this goal.

Modern molecular technology can contribute to 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.  New 
molecular analysis tools resulting from this initiative are intended to 
contribute to this goal.

In order to fully understand cancer and define the molecular response 
of the host to cancer, it will be critical to not only have knowledge 
at the DNA level, but to have a complete understanding of the 
processing of genetic information in cellular function. Current 
discoveries indicate that alterations in many of the cellular 
processes, pathways, or networks may contribute to the genesis of 
cancer and could be exploited for therapeutic or prevention 
intervention.  Therefore, it is important to put in place technologies 
that can detect molecular changes in the cell without preconceived 
ideas about which information will be most valuable to monitor or which 
technologies will have the greatest impact. It is currently possible to 
monitor very specific changes in the expression and function of genes 
and gene products at the DNA, RNA, or protein level.  However, many 
existing technologies do not adequately address technical issues 
specific to the study of cancer in vitro and in vivo, such as limited 
cell number, sample heterogeneity, heterogeneity of specimen types 
(i.e. bodily fluids and waste, tissues, cells), and cost effectiveness.  
Adaptation of novel technologies to support use in cancer research, 
including use on tumor specimens, and in patient imaging, is 
encouraged.

In the discovery phase, it will be of great utility to have 
technologies that can effectively scan variations or function, in many 
or all members of the populations of DNA, RNA or protein molecules 
present in cells through highly multiplexed analysis.  Current 
technologies for the multiplexed analysis of molecular species are at a 
stage where the greatest utility exists for the analysis of large 
numbers of relatively homogeneous cell populations that can be assayed 
in vitro. While many of the existing technologies have relatively 
sophisticated multiplexing capability in the assay format of the 
system, none of the existing systems is comprehensive for any 
particular molecular species (DNA, RNA or protein).  In addition, none 
of the existing systems for in vitro analysis have well integrated 
sample preparation components that maintain the cost efficiencies of 
the assay system and effectively accommodate human tumor specimens. 
Similarly, data analysis tools for interpreting the information from 
highly multiplexed molecular analyses have not been sufficiently 
developed and tested for use in the context of basic, preclinical, and 
clinical cancer research questions. Therefore, the opportunity exists 
for further development to insure that resulting technologies provide 
enhanced assay potential, adequate sensitivity and discrimination, 
robust data analysis tools, and are easily adapted to the basic, 
preclinical, and clinical research settings.

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 including but not limited to 
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 preclinical, clinical and in 
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, preclinical, 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 development of high-resolution imaging at the cellular 
or molecular scales in tissue samples, pre-clinical models, or human 
investigations is considered to be an important extension of molecular 
analysis methods.  Similarly, the development 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 modification 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.

RESEARCH OBJECTIVES

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

New tools that allow development of a more complete molecular profile 
of normal, precancerous, and cancerous cells, as well as the process of 
carcinogenesis, are needed to support the basic discovery process. 
These tools 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. Of 
interest are technologies and data analysis tools for:

--In vitro scanning of or identification of the sites of chromosomal 
aberrations which reflect inherited aberrations 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, or detecting rare variants 
in mixed populations.

--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, or identifying 
infrequently represented mutations in mixed populations of DNA 
molecules.

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

--Highly specific and sensitive detection of specific mutations.  

--Detecting mismatch and recombinational DNA repair related to cancer 
susceptibility 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 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.

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

Translation of the utility of the technologies described above and 
basic research findings into tools for preclinical, and clinical 
research; requires additional technological innovation with regard to 
sample preparation, enhanced sensitivity, and expanded data analysis 
tools.  Of interest are technologies for:

--In vitro sample and specimen preparation that is suitable for human 
tissues and tumor (including solid tumor) specimens that interface with 
molecular analysis tools of the type listed above.

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

During the basic discovery process enhanced capability is critically 
needed for the following:

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

Applications may request support for the development of individual 
components of the final system, for example, front-end sample 
preparation components for in vitro systems, molecular detection 
systems, data acquisition systems, and data analysis tools. Issues 
related to the integration of the entire analysis process should be 
discussed particularly in the context of the R33 application.

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

The focus of this Program Announcement is technology development. 
Support for mechanistic studies of basic questions will not be 
provided, although testing on biological samples or in whole organisms 
in the course of enhancing the utility of the technology is 
appropriate.  Support for the pilot applications of new technologies to 
questions of interest to cancer research is outside the scope of this 
PA, but is the subject of another solicitation entitled Application of 
Innovative Technologies for the Molecular Analysis 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 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 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.

This program will run in parallel with a program of identical 
scientific scope 
(http://grants.nih.gov/grants/guide/pa-files/PAR-01-105.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 developed, its innovative nature, its relationship to 
presently available capabilities, and its expected impact on the 
molecular analysis of cancer.

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 develop innovative 
technologies, hypothesis testing per se may not be the driving force in 
developing such a proposal and, therefore, may not be applicable.  
Furthermore 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 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 developed, its innovative nature, its relationship to 
presently available capabilities and its expected impact on the 
molecular analysis of cancer.

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 develop 
innovative technologies, 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 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? 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.  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, 
Innovative Technologies for the Molecular Analysis of Cancer: Phased 
Innovation Award, 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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