APPLICATIONS OF INNOVATIVE TECHNOLOGIES FOR THE MOLECULAR ANALYSIS OF CANCER:
PHASED TECHNOLOGY APPLICATION AWARD (R21/33)

Release Date:  May 14, 1999

PA NUMBER:  PAR-99-102

P.T.

National Cancer Institute

Letter of Intent Receipt Dates: June 18, October 18, 1999; February 18, June 19,
October 19, 2000 and February 20, 2001
Application Receipt Dates: July 21, November 21, 1999; March 21, July 21,
November 21, 2000 and March 21, 2001

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, 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
and tissue repositories.

This solicitation, (The Application of Innovative Technologies to the Molecular
Analysis of Cancer) will utilize the newly created Phased Technology Application
Award (PTAA) mechanism (R21/R33).  Specific features of this mechanism include:

Single submission and evaluation of both the R21 and R33 as one application.
Expedited transition of evaluation phase to application phase.
Flexible budgets.
Flexible staging of evaluation and application phases.

Small businesses are encouraged to consider a parallel program announcement (PAR-
99-103) of identical scope that utilizes the SBIR and STTR mechanism with
accelerated review and transition, as well as cost and duration requirements
comparable to the Phased Technology Application Awards.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, Application 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 2000"
(Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-
00473-1) through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800) or at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

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

MECHANISM OF SUPPORT

This PA will expire two years from the initial receipt date as indicated by the
dates on the front of this solicitation.  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 PHS grants policy as stated in the NIH Grants Policy
Statement, NIH Publication No 99-8, October 1998.

Support for this program will be through the National Institutes of Health (NIH)
Exploratory/Developmental Research Grant (R21) and the Exploratory/Developmental
Research Grant Phase 2 (R33).  The R33 is a newly established NIH grant mechanism
to provide a second phase for the support of innovative exploratory and
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 (PTAA)
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 only exceed this cap to accommodate indirect
costs to subcontracts to the project.  Although the R33 application has no
official budgetary limit, applications requesting in excess of $500,000 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 responsiveness of
the proposed project.  Early contact with NCI staff is particularly critical
relative to this PA because it uses a new grant mechanism R33 as well as 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 PTAA, 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 to apply the selected technology in a study of biological
interest to cancer research for the R33 phase. The PTAA must have a section
labeled Milestones at the end of the Research Plan of the R21 phase. 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 phase.

Through a separate program announcement (PAR-99-103) the NCI is inviting
applications for SBIR and STTR support, focusing on the identical research areas
as described in the RESEARCH OBJECTIVES section of this solicitation.  For
SBIR/STTR solicitation, the expedited NCI review and cost allowance policies and
procedures will be identical to this PA.  Qualified applicants are strongly
encouraged to consider responding to the SBIR/STTR program announcement.  SBIR
and STTR application information is available on the web at:
http://www.nih.gov/grants/funding/sbir.htm

Potential applicants who believe that they may be eligible for the SBIR/STTR
award should consult the PHS Omnibus Solicitation) prior to discussions of their
eligibility with NCI staff listed under INQUIRIES.

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.  To this end, the NCI has established the Cancer Genome
Anatomy Project (CGAP), which will put in place the research infrastructure that
will allow deciphering of the molecular anatomy of a cancer cell at the DNA, RNA,
and protein levels.  Within the CGAP program, the NCI has established the Tumor
Gene Index, an index identifying the genes that are expressed in normal,
precancerous, and cancerous cells. This project is well under way and further
information about the Index can be found at http://www.ncbi.nlm.nih.gov//ncicgap.
The NCI has also begun a project to identify cancer chromosome aberrations
(Cancer Chromosome Aberration Project, CCAP).  The NCI has started the generation
of a public repository of a standardized set of bacterial artificial chromosome
(BAC) clones anchored across the whole human genome at 1 megabase intervals, for
the identification of cancer chromosomal aberrations and reference
points/landmarks clones for the integration of cancer chromosome aberrations and
genomic data.  Information on the repository and regent access will be released
on CCAP homepage (http://www.ncbi.nlm.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 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.

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
subpopulations 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 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

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.

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:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

As part of the scientific and technical merit evaluation of the research plan,
reviewers will be instructed to address the adequacy of plans for including
children as appropriate for the scientific goals of the research.

LETTER OF INTENT

Prospective applicants are asked to submit, by the dates listed at the beginning
of this program announcement, 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 avoid conflict of interest in the review.  The letter of intent is
to be sent to Dr. Jay George at the address listed under INQUIRIES.

APPLICATION PROCEDURES

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

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

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
description of the Research Plan for the R21 phase.  Milestones should be well
described, quantifiable and scientifically justified. A discussion of the
suitability of the milestones relative to assessing the success 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 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 PTAA 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 sections and
a-d again for the R33 phase.  The Form 398 Table of Contents should be modified
to show sections a-d for each phase.  There is a page limit of 25 pages for the
composite a-d text (i.e., sections a-d and milestones for the R21 and 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 PTAA 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, and 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.

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
page 5 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 application of novel molecular analysis
technologies to the study of cancer, 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.  Furthermore for R21 grant
applications, preliminary data are not required, although they should be included
when available.

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 demonstrate new capabilities for research, and how these
technologies to be applied would differ from existing technologies.  Describe
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 R12 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 Plan of the R21 phase.  Milestones should be well described,
quantifiable, scientifically justified, and not be simply a restatements of the
specific aims. 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, with the page number cited.  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
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 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 (rev. 4/98) and prepared according to the instructions provided unless
specified otherwise within items 1-5 below.  Application kits are available at
most institutional offices of sponsored research and may be obtained from the
Division of Extramural Outreach and Information Resources, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email:
grantsinfo@nih.gov.

1.  Face Page of the application:

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

2.  Page 2 Description:

As part of the description, identify concisely the technology or methodology to
be applied and, 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.

Budget: The application should provide a detailed budget for Initial Budget
Period (form page 4).  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 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 support the pilot application
of novel molecular analysis technologies to the study of cancer, 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 including the evaluation of the utility of the technology to be used on
samples similar to those that will be used in the proposed study.  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.

The completed original application and three legible copies must be sent or
delivered 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
6130 Executive Boulevard, Room 636a, MSC 7405
Bethesda, MD 20892-7405
Rockville, MD 20852 (for overnight/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275

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

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the CSR for completeness and by
NCI program staff for responsiveness. Applications not adhering to application
instructions described above and those applications that are incomplete or non-
responsive as determined by CSR or by NCI program staff will be returned to the
applicant without review.  Applications that are complete and responsive to the
PA will be evaluated for scientific and technical merit by an appropriate peer
review group convened by the 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 field forward.

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

Approach.  Are the conceptual frameworks, 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?

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

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 or expanded capabilities of the proposed technology?

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

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

Additional Considerations

For the R21/R33 PTAA, the initial review group will evaluate the specific goals
for each phase and the feasibility milestones that would  justify expansion to
the R33 phase. A single priority score will be assigned to each scored
application.  As with any grant application, the initial review group has the
option of recommending support for a shorter duration than that requested by the
applicant, and basing the final merit rating on the recommended portion of the
application.  For the R21/R33 application, this may result in a recommendation
that only the R21 phase be supported, based on concerns related to the
applicant's specific goals and the feasibility milestones justifying expansion
to the R33 phase.  Deletion of the R33 phase by the review panel or inadequate
scientific 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 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 as well as  the adequacy of plans for including children as
appropriate for the scientific goals of the research, or justification for
exclusion. (See section on NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN
AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS).

AWARD CRITERIA

Applications will compete for available funds with all other recommended
applications.  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.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Jay George, Ph.D.
Office of Technology and Industrial Relations
National Cancer Institute
Building 31, Room 11A03
31 Center Drive, MSC 2590
Bethesda, MD  20892-2590
Telephone:  (301) 496-1550
FAX:  (301) 496-7807
Email: jgeorge@mail.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Ms. Kathleen J.Shino
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800 ext. 248
FAX:  (301) 496-8601
Email:  shinok@gab.nci.nih.gov

Direct inquiries regarding review matters to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892-7150
Telephone:  (301) 496-3428
FAX:  (301) 402-0275

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.394, Cancer Detection and Diagnosis. Research Awards are made under
authorization of the Sections 301 and 405 of the Public Health Service Act, as
amended (42 USC 241 and 284) and administered under PHS grants policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74 and part 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 and contract 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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