INNOVATIVE TECHNOLOGIES FOR THE MOLECULAR ANALYSIS OF CANCER: PHASED INNOVATION 
AWARD (R21/R33)

Release Date:  May 14, 1999

PA NUMBER:  PAR-99-100

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

This PA is a reissuance of PAR-98-067, which was published in the NIH Guide on
May 8, 1998.

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 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 solicitation, (Innovative Technologies for the Molecular Analysis of Cancer)
will utilize the newly created Phased Innovation Award Mechanism (R21/R33). 
Specific Features of this mechanism will include:

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

Small businesses are encouraged to consider a parallel program announcement (PAR-
99-101) of identical scientific scope that utilizes the SBIR and STTR mechanisms
with accelerated review and transition, as well as cost and duration requirements
comparable to the Phased Innovation 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, 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.  Awards will be administered under NIH grants policy as stated in the
NIH Grants Policy Statement, NIH Publication No 99-8, October 1998

Support for this program will be through the National Institutes of Health (NIH)
Exploratory/Developmental Research Grant (R21) and the Exploratory/Developmental
Research Grant Phase 2 (R33).  The R33 is a newly established NIH grant mechanism
to provide a second phase for the support of innovative exploratory and
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 F&A costs to
subcontracts to the project.  Although the R33 application has no official
budgetary limit, applications requesting in excess of $500,000 dollars direct
costs in any single year of the grant period require prior approval before
submission.  It is strongly recommended that applicants contact 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 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.

Through a separate program announcement (PAR-99-101), 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 SBIR; and STTR Omnibus Solicitation prior to
discussions of their eligibility with NCI staff listed under INQUIRIES.

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 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. To this end, the NCI has established the Cancer Genome Anatomy
Project (CGAP), which will put in place the tools that will allow deciphering of
the molecular anatomy of a cancer cell at the DNA, RNA and protein levels.  The
NCI has established the Tumor Gene Index, an index identifying 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
chromosomes aberrations and reference points/landmarks clones for the integration
of cancer chromosome aberrations and genomic data.  Information on the repository
will be released on CCAP homepage (http://www.ncbi.nlm.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
are 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 epidemiologic 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 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 PA 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 Applications of Innovative
Technologies for the Molecular Analysis of Cancer (PAR-99-101).

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

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
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
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 F&A costs to subcontracts to the project.  Insert the
first year of R21 support in item 7a

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

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

2.  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 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 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.

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 technology forward.

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

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics? What is the time frame for developing the proposed
technologies and suitability of this time frame for meeting the scientific
community's needs?  How easy will it be to use the proposed technology?  Are the
plans for proposed technology dissemination adequate?

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

4.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies? What is the throughput
and cost effectiveness of the proposed technology?  What additional uses can be
projected for the proposed technology?

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

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

Additional Considerations

For the R21/R33 Phased Innovation Award Application, the initial review group
will evaluate the specific goals for each phase and the feasibility milestones
that would justify expansion to the R33 phase. A single priority score will be
assigned to each scored application.  As with any grant application, the initial
review group has the option of recommending support for a shorter duration than
that requested by the applicant, and basing the final merit rating on the
recommended portion of the application.  For the R21/R33 application, this may
result in a recommendation that only the R21 phase be supported, based on
concerns related to the applicant 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 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 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, MSC 2590
Bethesda, MD  20892-2590
Telephone:  (301) 496-1550
FAX:  (301) 496-7807
Email:  jgeorge@mail.nih.gov

Direct inquiries regarding fiscal 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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