DIAGNOSTIC IMAGING AND GUIDED THERAPY IN PROSTATE CANCER (PHASED INNOVATION
AWARD)

Release Date:  August 19, 1999
RFA:  CA-99-015

National Cancer Institute
National Institute on Aging

Letter of Intent Receipt Date:  October 20, 1999
Application Receipt Date:  November 17, 1999

PURPOSE

The National Cancer Institute (NCI) and the National Institute on Aging (NIA)
invite applications on the development, risk assessment, and application of
improved imaging methods for the localization, biopsy and image guided biopsy
or therapy of prostate cancer.  Relevant investigations could include
technology development, in vitro laboratory work, pre-clinical animal studies,
or early feasibility testing in humans depending on the maturity of the
methods proposed, or evaluation of the effects of age-associated changes and
co-morbid conditions as they affect imaging diagnosis and treatment
techniques.  The development of several methodologies and their optimization
for this particular organ system is required.  The specific goals include the
development and application of one or more of the following inter-related
components:  (a) means for measuring local extent of disease using anatomic,
metabolic or alternative novel imaging methods, (b) means for improved image
guided biopsy, staging or identification of aggressive cancers by metabolic or
alternative novel imaging methods, and (c) means for navigation, control of
image guided therapy or measurement of early biological effects of therapy. 
Research is also encouraged on how age-associated differences in tumor
characteristics and age-related changes in the prostate and adjacent tissues
may affect the sensitivity, specificity, prognostic value, or the efficacy of
imaging techniques in guiding therapy.  The development of methods to increase
sensitivity, specificity, prognostic value, and therapeutic applicability of
these techniques across the full range of ages in which prostate cancer most
frequently occurs, and in the presence of age-related co-morbid conditions in
the prostate, other organs, and systems, is of particular interest.

This solicitation (Diagnostic Imaging And Guided Therapy in Prostate Cancer)
will utilize the Phased Innovation Award Mechanism which is designed to
encourage technology development.  Specific features of this mechanism
include:

o  Single submission and evaluation of both the R21 and R33 phases as one
application.  An R33 application alone may be submitted.
o  Initial review convened by the NCI Division of Extramural Activities.
o  Expedited transition of feasibility phase (R21) to development phase (R33),
based on completion of negotiated Milestones.
o  Flexible staging of feasibility (R21) and development (R33) phases.
o  Industry applications or industry partnerships with other groups are
encouraged.

Small businesses are encouraged to consider a parallel program announcement
PAR-99-149 (see https://grants.nih.gov/grants/guide/pa-files/PAR-99-149.html) 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 RFA, Diagnostic Imaging And Guided
Therapy in Prostate 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, industries, 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

The following are points to note about the mechanism of support and its
implementation:
o  This RFA is a one-time 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 Number 99-8, October 1998.
o  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
relatively new NIH grant mechanism that provides a second phase to support
innovative exploratory and developmental research initiated under the R21
mechanism.  Transition of the R21 to the R33 phase will be expedited and is
dependent on completion of negotiated Milestones.
o  Under this RFA, applicants can submit either a combined R21/R33 application
(Phased Innovation Award application) or an R33 application alone, if
feasibility can be documented, as described in the APPLICATION PROCEDURES
section of this RFA.
o  Applications for R21 support alone will not be accepted, but may be
eligible to apply under PA-98-008 (see
https://grants.nih.gov/grants/guide/pa-files/PA-98-008.html.)
o  The total project period for an application submitted in response to this
RFA may not exceed the following duration: R21, 2 years; R33, 3 years;
combined R21/R33 application, 4 years.  In the combined application the R21
phase cannot extend beyond 2 years.
o  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
Facilities and Administrative 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 by NCI program staff before submission.
o  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 RFA because it uses a relatively new grant mechanism (R33) as
well as an expedited review procedure.  Refer to the INQUIRIES sections of
this RFA for NCI staff contacts.
o  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.

o  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 separate
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-99-149
(https://grants.nih.gov/grants/guide/pa-files/PAR-99-149.html), the NCI is
inviting applications for SBIR and STTR support, focusing on the same 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 RFA.  Qualified applicants
are strongly encouraged to consider responding to the SBIR/STTR program
announcement.  SBIR and STTR application information is available at the
following website:
https://grants.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.

FUNDS AVAILABLE

The NCI proposes to fund six to eight R21/R33 grants.  For the entire RFA, a
total of $13.6 million has been set aside. The NIA will commit up to $500,000
per year in total costs for the support of research on aging-relevant issues
within funded projects.  Examples of such issues are provided in "Research
Objectives," Section E.  Funding in response to this RFA is dependent upon the
receipt of a sufficient number of applications of high scientific merit.
Although this program is provided for in the financial plans of NCI, the award
of grants pursuant to this RFA is contingent upon the anticipated availability
of funds for this purpose.

BACKGROUND

The ability to diagnose early prostate cancer has outpaced imaging methods for
accurate localization and staging of the disease, and for delivering the most
appropriate form of therapy.  This is reflected in the specific research needs
identified by the Prostate Cancer Clinical Guidelines Panel of the AUA as
early as 1995.  Needs include improved methods for: (a) identification of the
boundary of the prostate and localization of the extent of the disease, (b)
staging and determination of biologic aggressiveness, and (c) minimally
invasive treatment of localized prostate cancer.  Within the past year, the
NCI Prostate Portfolio Review Group (PRG) and the NCI Imaging Sciences Working
Group (ISWG) made similar recommendations.

Accurate determination of the extent of local disease in the prostate is
difficult.  Current imaging techniques include transrectal ultrasound (TRUS),
endorectal coil magnetic resonance imaging (MRI), and proton magnetic
resonance spectroscopic imaging (MRSI).  The reported accuracy of TRUS for
determining if prostate cancer is confined within the capsule varies widely
from 58% to 90%.  However, preliminary data from recent studies of endorectal
MRI show higher accuracy (75-90%) than TRUS, and better consistency.  Further
technical advances in high-resolution ultrasound and MRI are feasible and
would result in localization and staging of local prostate cancer that is more
accurate than current methods.

In addition to morphologic extent, directed biopsy and assessment of tumor
aggressiveness are important for accurate staging and treatment for prostate
cancer when there is an elevated PSA.  Current biopsy techniques are based on
random spatial sampling and have a lower than desired sensitivity (60-70%) for
identification of carcinoma of the prostate.  Early preliminary studies of
combined MRI/MRSI demonstrated localization of cancer to a sextant of the
prostate with sensitivity up to 95% and specificity up to 91%.  However,
localization more specific than to a sextant would be desirable.  New contrast
agents or metabolic markers measurable by MRI, MRS, TRUS, nuclear medicine or
other imaging sensors (e.g., optical technologies) may contribute to improved
image guidance and tumor staging.

Early metabolic studies of prostate cancer by 3D proton MRSI show an ability
to predict tumor aggressiveness equal to or better than other markers such as
tumor grade or peak serum PSA.  Preliminary results for spectral analysis of
ultrasound images suggest a similar role for this modality; spectral
differences have been found to correlate with histopathology of certain tumors
located in other organ systems.  Optical spectra and chemical diagnostic
imaging probes need to be investigated as indicators of biologic
aggressiveness as well.

The clinical management of localized prostate cancer remains controversial. 
The two generally accepted methods of treatment for clinically localized
prostate cancer, namely radical prostatectomy and external beam radiation
therapy, have significant, but different, morbidity.

A variety of local therapies are being developed that can potentially treat
prostate cancer without major surgery.  They include brachytherapy,
hyperthermia, cryosurgery, interstitial laser therapy, focused ultrasound,
focused microwaves, or local delivery of therapeutic agents such as gene
therapy vectors.  Treatment of localized prostate cancer with one of these
alternative methods has several potential advantages.  Image-guidance systems
are essential to the successful application of these and other local
therapies.  Image guided therapy is the use of images obtained either during
or prior to treatment, coupled with the use of computers, sensors, graphics,
or other technologies to assist or guide the administration of treatment.

As image guidance of therapy improves, wider dissemination of the techniques
will be possible because they will become less operator-dependent.  For
technologies where great skill is required, practitioners outside of centers
with large numbers of patients may not be able to attain the level of skill
necessary to achieve successful intervention and cure.

The opportunity to make significant advances in image guided therapy now is
great because of technological breakthroughs in several areas.  "Open" MRI
magnets, developed to reduce patient discomfort, make it possible for
radiologists, surgeons and others to perform interventional procedures while
the patient is being imaged.  The digital architecture of current ultrasound
machines, and advances in ultrasound transducer manufacture have opened new
possibilities for ultrasound guidance.  Translation of discoveries in
fiberoptic and laser technologies to medical applications make optical
techniques an exciting new area for image guided procedures.  Increasing
computer power at lower cost makes image-processing techniques possible in
real-time.

RESEARCH OBJECTIVES

The purpose of this RFA is to stimulate research into the development and
application of improved imaging methods for the localization, risk assessment,
and minimally invasive biopsy or delivery of therapy for prostate cancer. 
Prostate cancer incidence increases as a function of age to a magnitude
unparalleled by all other tumors.  Aging men are diverse in overall health and
physiologic and physical functioning.  These factors may impact on diagnosis
and therapy.  Research is particularly encouraged on how age-associated
changes in the prostate and adjacent tissues and co-morbid conditions may
affect imaging techniques' sensitivity, prognostic value, or their utility in
guiding therapy.  Relevant investigations could include technology
development, in vitro laboratory work, pre-clinical animal studies, or early
feasibility testing in humans depending on the maturity of the methods
proposed, and the evaluation of age-associated changes or co-morbid conditions
on imaging techniques for prostate diagnosis and treatment.  Image guided
therapy requires the development of several methodologies and their
optimization for this particular organ system.  The specific goals therefore
include the following inter-related components:  (a) means for measuring local
extent of disease using anatomic, metabolic or alternative novel imaging
methods, (b) means for improved image guided biopsy or other image guided
tissue sampling methods and staging or identification of aggressive cancers by
metabolic or alternative novel imaging methods, and (c) means for navigation,
control of image guided therapy or measurement of early biological effects of
therapy.

One key issue is that the navigational device requires the virtual object to
be accurately registered to the therapeutic object, ideally during the full
course of therapy, with improved navigational accuracy for the small scale of
the prostate gland.  Considerable bioengineering expertise must be combined
with basic science and clinical input in designing and developing image guided
therapy systems. The response to the RFA should therefore address one or more
of the following four broad areas and development phases.

A.  Improved localization, image guided biopsy or tissue sampling, or staging
methods for early prostate cancer.

Important areas for investigation should be specific to the prostate gland,
and may include, but are not limited to:

o  Improvements in MRI and MRSI methods, such as: (a) specialized radio
frequency (RF) transmit and receive coils, RF pulse sequencing and 3D imaging
methods to improve signal to noise (S/N) and image contrast, and (b)
development and application of novel MR contrast materials for identification
of prostate cancer.
o  Improvements in ultrasound, such as novel probe design, RF pulse
sequencing, contrast materials, 3D imaging methods, and multi-spectral imaging
to improve S/N and image contrast.
o  Advances in PET or SPECT imaging, such as using novel radio-ligands
specific for prostate cancer to improve tumor localization and staging.
o  Other novel imaging methods, such as optical imaging, spectroscopy, and
contrast enhancement methods, to improve image-guided biopsy or tissue
sampling and staging of cancer.
o  Image processing methods for improved image registration, image fusion,
image contrast and resolution.
o  Innovative tissue sampling methods to improve localization and the adequacy
of tissue samples for diagnosis of prostate cancer.
o  Improved and, ideally, automatic image segmentation techniques for the
prostate gland and surrounding tissues for determining the boundary of the
prostate gland, connective tissues and proposed treatment area.
o  Multi-spectral analysis or computer classification methods as applied to
MRI, MRS, ultrasound, radio frequency (RF) or other sensor images/spectra are
important to explore for classification of tissues as normal or cancer, or to
determine the level of cancer aggressiveness.
o  Combination of the above methods with PSA or other markers for improved
staging of prostate cancer and patient selection for image guided therapy.

B.  Image Guided Therapy Methods.

All the minimally invasive locally ablative therapies are still under
development and should not be pre-judged as to their effectiveness relative to
each other or to existing standard therapies.  Thus, new approaches to image
guided local therapy will be responsive to this RFA.

Therapy methods specific for the prostate may include, but are not limited to:

o  Heating the tissue directly, to coagulate cellular proteins, with
controlled temperature probes or lasers, or killing cellular proteins by
freezing with small probes (cryosurgery).
o  Administration of chemotherapeutic agents, such as gene therapy vectors, or
toxic chemicals, either delivered directly into tumors by small catheter-based
tools, or administered systemically and deposited locally by the addition of
externally applied energy such as focused ultrasound.
o  Focused ultrasound waves, radiowaves, or microwaves used to heat tissue and
cause protein coagulation.  Externally focused energy methods are particularly
attractive in that no needle or probe has to be inserted into the tissue, of
more control over the distribution and amount of heat generated throughout the
treatment volume.

C.  Image Guidance and Control of Therapy

All the above therapeutic methods require image guidance, both to steer the
focal point of the therapy and to provide a means to control degree of local
therapy.

Technical problems that need to be addressed, specifically for the prostate
include, but are not limited to:

o  Design of the navigational system.  Image guided therapy systems need to be
developed for specific application to the prostate, and to address the
navigational and control scales required for this small gland and associated
surrounding critical tissue structures. Similarly, for instances where
physical probe insertions are required, the integration of models for
incorporating soft tissue deformation characteristics into the image guided
therapy system needs to be investigated. The image guided therapy system also
needs to address all registration issues that influence the accuracy of
navigation. The use of robotics for improved navigation and reproducible
controlled probe insertion is also an area of interest.
o  Means for controlling therapy delivery.  Control of the various forms of
therapy may require modeling of the therapy response (which may be non-linear)
to ensure patient-specific local spatial control and control of the total
therapy dose delivered.  There is a need to explore physical methods to
control localized therapy.  For example, MRI can provide both high spatial
resolution and tissue temperature measurement. There is a need to further
develop and model such temperature measurement methods and feed back
mechanisms and integrate these components into the image guided therapy
system, to assure accurate spatial delivery of thermal exposure throughout the
gland.
o  Monitoring of early biological effects and feedback mechanisms for the
image guided therapy system.  Novel methods for measurement of early
biological effects, such as for non-thermal therapies, are considered
important; feed back mechanisms may provide a basis for therapy control.  For
example, photo-dynamic therapy (PDT) is one local therapy that has been
proposed and an early biologic marker of successful response to PDT would be
useful.
o  Imaging as a follow up to therapy treatment.  There is a need to understand
and quantitate the changes in the images following therapy and to relate the
image differences to tissue changes.  Imaging can be used to follow treated
patients, especially if the changes expected to be caused by therapy are
known.
o  Optimization and validation of all the engineering components of the
navigational system. There is a need to develop metrics to determine the
performance of the image guided therapy system components and overall
integrated system performance.

D.  Image Guided Therapy Systems: Development Phases for Fully Integrated
Systems.

Development and optimization of the image guided therapy for the prostate may
require several phases of technology development and pre-clinical evaluation
as outlined above.  For example, we anticipate that applications may be
received for two levels of effort.  First, investigators who have image guided
therapy experience with totally integrated systems for another organ system
may seek support for the translation of research and development for an fully
integrated image guided therapy system specifically for the prostate.  Such
applications may propose development of the integrated system within 2-3
years, with performance specifications and pre-clinical or preliminary
clinical testing to be completed by the end of the grant period.  It is
anticipated that clinical trials would be performed after this grant period. 
Second, requests are anticipated for the development and integration of
several key components, but not necessarily all, outlined above, and for
limited evaluation of performance specifications or pre-clinical evaluation,
where the image guided therapy components are optimized for the scale of
measurement and application to the prostate gland.

E.  Effects of age-related changes on sensitivity, specificity, prognostic
value, or therapeutic applicability of new imaging techniques.

Age-associated differences in tumor characteristics, and age-related changes
in the prostate and adjacent tissues, may affect imaging techniques'
sensitivity, specificity, prognostic value, or therapeutic applicability. 
Applicants are encouraged to examine these aspects of new imaging techniques
across the full range of ages in which prostate cancer most frequently occurs,
including advanced ages in which incidence and mortality rates are the very
highest.  Applicants are asked to consider how non-malignant age-related
changes in the prostate (e.g., benign prostatic hypertrophy), and other age-
related changes and co-morbid conditions may affect the sensitivity,
specificity, prognostic value, or therapeutic applicability of imaging
techniques.  Applicants are encouraged to develop and test methods to optimize
these aspects of imaging techniques in the presence of age-related changes or
co-morbid conditions.

Partnerships of appropriate medical institutions with medical device
manufacturers will facilitate the integration of system components for image
guided diagnosis and therapy of the prostate.

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, available on the web at the following URL address:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html

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

Applications received in response to this RFA are expected to focus on
scientific issues related to prostate cancer.  In describing the plan to
recruit human subjects, investigators may cite a focus on prostate cancer as
the justification for why women will be excluded.  In this regard applicants
may use Justification 1 from the policy announcement.

LETTER OF INTENT

Prospective applicants are asked to submit, by the date listed at the
beginning of this RFA, a letter of intent that includes a descriptive title of
the proposed research, the name, address, and telephone number of the
Principal Investigator, the identities of other key personnel and
participating institutions, and the number and title of the RFA in response to
which the application 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. Barbara Croft 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
301/710-0267, email: [email protected].  See also the website for PHS 398:
https://grants.nih.gov/grants/funding/phs398/phs398.html

The R21/R33 application must include the specific aims for each phase and the
Milestones that would justify transition to the R33 phase.  See below, Item
d., "Research Design and Methods" for directions for including Milestones in
the application.  For applications that are funded through this solicitation,
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 all 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.

1.  Face Page of the application:

Item 2.  Check the box marked "YES" and type the number and title of this RFA. 
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 Facilities and Administrative costs to
subcontracts to the project.  Insert the first year of R21 support in item 7a. 
Modular Grant Application instructions in PHS 398 do NOT apply to this RFA.

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

For the R21 phase, direct costs requested for the proposed period may not
exceed $100,000 per year 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 diagnosis and treatment
of prostate 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 RFA is specifically directed at the development of
innovative technologies, hypothesis testing per se may not be the driving
force in developing such a proposal and, therefore, may not be applicable. For
the R21 portion of the grant application, 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 from fields such as engineering, biomedical
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, based on a literature review of this topic.  Explain
the potential of the proposed technology for having a broad impact on cancer
research, diagnosis and treatment of the prostate. Clearly identify how the
project, if successful, would result in new capabilities for diagnosis and
treatment, 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 separate section should be indicated
in the Table of Contents.  Applications lacking Milestone information as
determined by the NCI program staff, will be returned to the applicant without
review.

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 301/710-0267, email:
[email protected].  See also the website for PHS 398:
https://grants.nih.gov/grants/funding/phs398/phs398.html

1.  Face Page of the application:

Item 2.  Check the box marked "YES" and type the number and title of this RFA
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 diagnosis and treatment
of prostate 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 RFA 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, diagnosis and treatment. Clearly
identify how the project, if successful, would result in new capabilities for
diagnosis and treatment, 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 RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application.  Failure to use
this label could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition, the RFA
title and number must be typed on line 2 of the face page of the application
form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:

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

At the time of submission, two additional copies of the application must be
sent to:

Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Blvd., MSC-7407
Rockville, MD 20852 (express courier)
Bethesda MD 20892-7407

Applications must be received by November 17, 1999.  If an application is
received after that date, it will be returned to the applicant without review. 
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR will not accept any application that is essentially the same as one
already reviewed.

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 RFA 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 for the
targeted disease?

2.  Approach.  Are the conceptual framework, design, and methods 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 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
minorities and their subgroups, and children as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects;
the provisions for the protection of human and animal subjects; and the safety
of the research environment.

AWARD CRITERIA

Applications recommended by the appropriate national advisory board/council
will be considered for award based upon (a) quality of the proposed project as
determined by peer review; (b) availability of fund; and (c) program priority.

SCHEDULE

Letter of Intent Receipt Date:    October 20, 1999
Application Receipt Date:         November 17, 1999
Review by NCAB Advisory Board:    May 2000
Earliest Anticipated Start Date:  July 2000

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Barbara Y. Croft, Ph.D.
Diagnostic Imaging Program
National Cancer Institute
6130 Executive Plaza, Suite 800
Bethesda, MD  20892-2590
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-9531
FAX:  (301) 480-5785
Email: [email protected]

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) 496-8635
FAX:  (301) 496-8601
Email: [email protected]

Direct inquiries regarding review matters to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892-7399
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.395, Cancer Treatment 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 NIH grants policies and Federal Regulations 42
CFR 52 and 45 CFR Parts 74 and 92.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.

The PHS strongly encourages all grant 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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)