NOVEL TECHNOLOGIES FOR IN VIVO IMAGING (R21/R33)

RELEASE DATE:  May 19, 2003

PA NUMBER:  PAR-03-124 (see replacement PA-04-095)

EXPIRATION DATE:  December 1, 2003, unless reissued.

National Cancer Institute (NCI)  
 (http://www.nci.nih.gov/)
National Institute for Biomedical Imaging and Bioengineering (NIBIB) 
 (http://www.nibib.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:  93.394, 93.395, 93.396, 
93.286, 93.287

LETTER OF INTENT RECEIPT DATE:  June 23, 2003 and October 22, 2003

APPLICATION RECEIPT DATE:  July 21, 2003 and November 19, 2003  
 
This Program Announcement (PAR) replaces PAR-01-101, which was published in 
the NIH Guide on May 29, 2001.

THIS PAR CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PAR
o Research Objectives
o Mechanisms of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent 
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PAR  

The National Cancer Institute (NCI) and the National Institute for Biomedical 
Imaging and Bioengineering (NIBIB) invite applications for the development and 
delivery of novel image acquisition or enhancement technology and methods for 
biomedical imaging and image-guided interventions and therapy, and which may 
incorporate limited pilot or clinical feasibility evaluations using either 
pre-clinical models or clinical studies.  This initiative is intended to 
facilitate the proof of feasibility, development and delivery of novel imaging 
technologies for early detection, screening, diagnosis, image-guided 
interventions, and treatment of various diseases, and secondarily to 
facilitate limited evaluation studies to show proof of concept and 
functionality.  

The interests of NCI focus on imaging in vivo for cancer pre-conditions, 
cancer screening, diagnosis, progression, treatment monitoring, recurrence, 
and surrogate endpoints.  NCI interests include the discovery, development and 
delivery of imaging technologies that are cancer specific, and optimization 
and validation of imaging technologies for cancer applications.  The scope 
includes system integration, contrast agents, pre- and post-processing 
algorithms and software for imaging, image understanding, and related 
informatics that are cancer specific.  However, the interests of the National 
Institute of Biomedical Imaging and Bioengineering (NIBIB) focus on the 
discovery, development and delivery of imaging platforms and related component 
technologies, contrast agents, image processing and related informatics that 
can be applied to disease and injury. 

This PAR is directed toward the discovery, development, optimization and 
delivery of innovative image acquisition and enhancement methods, including 
high risk/high gain research on technologies, as follows:
(a) Novel single and multimodality molecular imaging systems, methods, agents, 
and related software and informatics, including the integration of these 
technologies with emerging biomedical imaging methods for more effective 
health care delivery for cancer and other diseases; 
(b) Novel single and multimodality anatomical and functional imaging systems, 
methods, agents, and related software and informatics for more effective 
health care delivery for cancer and other diseases.
(c) Research partnerships among academics and investigators in device and drug 
industries are encouraged to more rapidly translate and deliver completed 
imaging system developments.

This solicitation utilizes the Phased Innovation Award 
(Exploratory/Developmental R21 Phase 1 and R33 Phase 2) Grant mechanisms, and 
runs in parallel with a program announcement of nearly identical scope and 
intent (PAR-03-125) that utilizes the Small business Innovation Research 
(SBIR) and Small Business Technology Transfer Research (STTR) award mechanisms 
based on small business set aside funds.  The SBIR/STTR Fast Track option of 
paired applications uses an expedited review process for transition from Phase 
I to Phase II funding that is the same as the Phase Innovation Award of this 
PAR for exploratory/developmental studies.  Applicants eligible for SBIR/STTR 
funding are encouraged to use that option.

Phased Innovation Awards benefit from expedited evaluation of progress 
following the Phase 1 exploratory/feasibility study for expedited decision on 
transition to Phase 2 funding for expanded developmental work.  

RESEARCH OBJECTIVES

The overarching Research Objectives of this PAR are to stimulate discovery, 
development and delivery of novel imaging technologies and methods to capture, 
process, validate, present, interpret or understand in vivo imaging data that 
support the missions of the NCI and NIBIB. 

Significant advances in medical imaging technologies have been made over the 
past 25 years in such areas as magnetic resonance imaging (MRI), computed 
tomography (CT), nuclear medicine, ultrasound, and optical imaging.  These 
advances largely focused on structural or anatomical imaging at the organ or 
tissue level. Now there is an opportunity to stimulate the development and 
integration of novel imaging technologies that exploit our current knowledge 
of the genetic and molecular bases of various diseases.  Molecular biological 
discoveries have great implications for prevention, detection, and targeted 
therapy. Imaging technologies able to provide similar kinds of cellular and 
molecular information—in vivo molecular imaging—similar to that currently 
available from histological or micro-array techniques in vitro would be very 
useful. 

The advances in molecular methods pose new requirements for the performance of 
conventional biomedical imaging systems. For example, molecular imaging 
systems may need to be optimized for a molecular probe or probes as well as 
anatomical imaging. The integration of molecular imaging methods into multi-
modality systems will affect data acquisition, processing, reduction, display, 
and archiving. Therefore there is a need to support advances in methods for 
both molecular and conventional anatomical and functional imaging. 

The need to encourage and support biomedical imaging and imaging technology 
development by academic and industrial researchers was stressed by 
participants at several NIH- and NCI-supported forums over the past few years 
[Imaging Sciences Working Group (ISWG) July 1997; Lung Imaging Workshop: 
Technology Transfer, Jan 1997; Computer Aided Diagnosis and 3D Image Analysis, 
Oct 1998; Quantitative in-vivo Functional Imaging in Oncology, Jan 1999; Focus 
Group on Magnetic Resonance Spectroscopy (MRS) in Clinical Oncology, April 
1999; NIH BECON Symposium, June 1999; Dynamic Contrast Enhancement Magnetic 
Resonance Imaging Workshop, Rockville, Maryland, November 2000; and NCI/ISMRM 
Workshop on Higher Field MR (1.5 T & Up) in Oncology: Strategic Frontiers in 
Cancer Diagnosis and Treatment, Glasgow, Scotland, April 2001].  The needs 
include promoting (a) the development of novel, high risk, high gain 
technologies, (b) supporting them to maturation, dissemination and full 
exploitation, (c) integration of new technologies into commercially available 
imaging systems for targeted applications, (d) harmonization of imaging 
methods across versions of a single platform or across multiple platforms to 
permit similar image-based surrogate outcome metrics as required for multi-
site pre-clinical and clinical investigations, (e) funding a small number of 
copies of integrated system prototypes for placement, as required, for off-
site research and clinical feasibility studies, and (f) improving technology 
transfer, delivery and dissemination by promoting early-stage partnerships 
between academia and industry to encourage sharing of research resources and 
validation studies necessary to meet Federal regulatory requirements.  Thus 
the aims of this initiative and the support mechanism (Phased Innovation 
Awards R21/R33) are also directed at encouraging the discovery, development 
and delivery of imaging "tools" and related resources to support biomedical 
imaging in general for applications in oncology and other diseases.

Developments of novel imaging technologies usually require multidisciplinary 
approaches and teams with broad expertise in a variety of research areas.  
Such varied expertise might include imaging physics, chemistry, molecular and 
cellular biology, signal and image processing, computer vision, informatics 
and biostatistics, and clinical sciences. The coordination and collaboration 
of investigators with the necessary variety of disciplines to demonstrate the 
utility and applicability of new imaging methods is encouraged.

This initiative is to facilitate the development of novel imaging technologies 
for risk assessment, early detection, screening, diagnosis or image guided 
treatment of cancer and other diseases and to facilitate clinical evaluation 
and optimization studies that are specifically limited to proof of concept and 
pilot data on clinical functionality of the development. Clinical trials for 
clinical validation of emerging imaging technologies are beyond the scope and 
are not responsive to this PAR. 

Studies with pre-clinical models and clinical studies to demonstrate the 
feasibility of developments are encouraged, including multi-site evaluations, 
where appropriate.  Methods that establish "ground truth" are required at 
appropriate levels of resolution to validate these emerging imaging methods, 
e.g., imaging excised tissue using protocols similar to those used in vivo, or 
correlation of molecular imaging results with micro-array library analyses.  
Developments of molecular probes or targeted contrast agents are considered 
important approaches to detection of molecular changes in vivo to take better 
advantage of many technologies with potential for molecular imaging. 

The following topics would make appropriate proposed projects. This list is 
not meant to be all-inclusive. 

o Early Disease Detection:  Developments may address innovative high-
resolution imaging methods, with a particular intent to identify and 
characterize abnormalities or other early changes, including molecular events 
on the path to disease. Novel solutions for in vivo microscopic imaging 
systems, or microscopic implanted devices with high spatial and/or temporal 
resolution, which may use either intrinsic or exogenous contrast agents 
represent possible topics. 

o Disease Screening:  These methods may include, but are not limited to 
development and optimization of efficient imaging systems for screening, with 
the intent of achieving improved sensitivity and specificity for disease 
detection.  Applications could address innovative improvements to current 
imaging methods, including hardware and/or software upgrades, or emerging 
imaging sensors and methods.  Research topics of interest include a means to 
significantly reduce imaging time or effects of motion, use of novel contrast 
agents or imaging probes, and use of technologies that reduce or do not 
involve ionizing radiation, or use of novel contrast agents and imaging 
probes.  System integration and software methods could include a variety of 
image processing and data reduction techniques including temporal analysis of 
serial studies, close to real-time image processing, novel image display 
methods, and related imaging informatics for more cost-effective solutions for 
screening. 

o Imaging for Diagnosis, Staging, or Monitoring the Effects of Therapy:  This 
initiative encourages, but is not limited to the development of novel imaging 
methods such as functional or molecular imaging or spectroscopy methods that 
would significantly improve the specificity of diagnosis of cancer and other 
diseases, allow deterministic methods or patient-specific staging, or measure 
early effects of therapy.  Examples of system integration would include multi-
modality imaging, image fusion or registration of the different modalities 
employed, development of software methods that would estimate the probability 
of malignancy or other specific disease identification, quantitative 
information for monitoring the effects of therapy, and close to real-time 
image analysis.

o Image Guided Biopsy (IGB), Therapy (IGT), and Interventional (IGI) 
Procedures:  This initiative encourages novel approaches using imaging 
technologies needed to significantly improve specificity, to identify lesion 
extent and microscopic involvement, and to minimize tissue damage accompanying 
biopsy and therapy. Of particular interest are innovative approaches to IGB, 
IGT or interventional methods that include novel imaging systems that provide 
molecular target information or information at the cellular or molecular level 
sufficient for image guidance and treatment. Examples of system integration 
that are of interest include, but are not limited to multi-modality imaging, 
navigational systems, registration methods, real-time feedback mechanisms for 
controlling therapy (including radiation therapy) or the use of methods that 
are adaptive or allow patient-specific optimization of treatment and computer-
assisted surgery.

o Copies of Prototype Imaging Systems:  Support may be requested to make one 
or more copies of the prototype for placement in collaborating facilities for 
pre-clinical or clinical feasibility investigations, including harmonization 
across versions of a single platform or across multiple platforms to enable 
multi-center comparison studies.  Collaboration with NCI funded centers may be 
possible, such as the NCI Network for Translational Research in Optical 
Imaging, http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-03-002.html, or 
the Lung Image Database Consortium, http://www3.cancer.gov/bip/steercom.htm.  
Investigators anticipating need for funds to build system copies, 
harmonization of imaging methods or collaboration with NCI funded centers are 
advised to contact program staff.

o Research Resources:  The development of research resources that facilitate a 
consensus process for optimization and validation of emerging imaging 
technologies is encouraged. Examples include the development of open source 
software, image processing software and related informatics that can be ported 
onto different platforms, methods and image databases required for validation 
of software performance, and other hardware or informatics methods that assist 
in more efficient delivery of imaging technologies for screening, diagnosis 
and treatment for cancer and other diseases.  Investigators interested in 
development of research resources and related research are advised to contact 
program staff.

MECHANISMS OF SUPPORT 

This PAR will use the NIH R33, and the combined R21/R33 Phased-Innovation 
Award mechanisms.  Applicants will be solely responsible for planning, 
directing, and executing the proposed project.  

Support for this program will be through the National Institutes of Health 
(NIH) Phase 1 Exploratory/Developmental Research Grant (R21) and the Phase 2 
Exploratory/Developmental Research Grant (R33).  The R33 is a NIH grant 
mechanism to provide a second phase for the support of innovative exploratory 
and development research initiated under the R21 mechanism.  Transition from 
R21 to R33 Phase 2 support will be expedited, and depends upon successful 
completion of Phase 1 aims, including negotiated objective performance targets 
(milestones).

Under this PAR, applicants can submit either a combined R21/R33 application 
(Phased Innovation Award application) or an R33 application alone if 
feasibility can be documented (described in the SPECIFIC INSTRUCTIONS section 
of this program announcement).  Applications for R21 support alone will not be 
accepted.  There are separate program announcements available for them, e.g., 
Exploratory/Developmental Grants for Diagnostic Cancer Imaging, PA-01-030, 
http://grants.nih.gov/grants/guide/pa-files/PA-01-030.html.  The total 
project period for an application submitted in response to this PAR may not 
exceed the following durations: R33, 3 years; combined R21/R33 application, 4 
years.  In the combined application the R21 phase may not exceed 2 years.

For combined R21/R33 applications, the R21 phase may not exceed $125,000 
direct costs per year.  R21 budgets can exceed this cap to accommodate 
indirect costs to subcontracts to the project.  Although the R33 application 
has no official budgetary limit, applications requesting in excess of $500,000 
dollars direct costs in any single year of the grant period require prior 
approval six weeks before submission (see specific instructions below).  It is 
strongly recommended that applicants contact Program staff at an early stage 
of application development to convey critical information, such as potentially 
large budget requests or to discuss programmatic adherence to the guidelines 
of the proposed project.  Early contact with Program staff is particularly 
critical relative to this PAR because it uses the R33 grant mechanism as well 
as an expedited review procedure.  Refer to the INQUIRIES sections of this 
program announcement for Program staff contacts.

The combined R21/R33 Phased Innovation Award application offers two advantages 
over the regular application process:

1.  Single submission and review of both the R21 and R33 Phases as one 
application.

2.  Minimal or no funding gap between R21 and R33 phases.  The award of R33 
funds will be based on program priorities, on the availability of funds and on 
successful completion of Phase 1 aims, including negotiated objective 
performance targets (milestones), as determined by NCI or NIBIB staff in the 
context of peer review recommendations.

To be eligible for the Phased Innovation Award, the R21 phase must include 
well defined objective, preferably quantifiable performance targets 
(milestones) useful for judging the success of the proposed research, as well 
as a credible plan for development of technology in the R33 phase.  The Phased 
Innovation Award must have a section labeled Milestones at the end of the R21 
section of the Research Plan.  This section must include well-defined 
objective performance targets (milestones) for completion of the R21 Phase 
part of the application, a discussion of the suitability of the proposed 
milestones for assessing success of the R21 phase work, and a discussion of 
the implications of successful completion of these milestones for the proposed 
R33 study.

This PAR uses just-in-time concepts.  It also uses the non-modular budgeting 
formats.  Full budget presentations and justifications are required.  Follow 
the instructions for non-modular research grant applications.  This program 
does not require cost sharing as defined in the current NIH Grants Policy 
Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm

ELIGIBLE INSTITUTIONS 

You may submit one or more applications if your institution meets any of the 
following criteria: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

There is a parallel program announcement for USA institutions eligible for 
small business grants, which is being re-issued concurrently with this PAR as 
PAR-03-125 (see http://grants.nih.gov/grants/guide/pa-files/PAR-03-125.html).

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to develop 
an application for support.  Individuals from underrepresented racial and 
ethnic groups as well as individuals with disabilities are always encouraged 
to apply for NIH programs.   

SPECIAL REQUIREMENTS 
 
o  The R21 section of the Research Plan must end with a section on objective 
performance targets (Milestones), quantitative if appropriate, to help 
evaluate the success of Phase I work after its completion.

o  If a copy or copies of a prototype will be needed for placement in one or 
more sites for pre-clinical or clinical testing, include a clear written 
justification for the funds requested in the Budget Justification Section, and 
make written reference to this instruction. 

o  The transition from Phase 1 R21 funding to award of R33 funds will be based 
on program priorities, on the availability of funds and on successful 
completion of Phase 1 R21 aims, including negotiated objective performance 
targets (milestones), as determined by NCI or NIBIB staff in the context of 
peer review recommendations.

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PAR and welcome the opportunity 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:

o Direct your questions about scientific/research issues to the following:

For NCI
Houston Baker, Ph.D., Guoying Liu, Ph.D., or Keyvan Farahani, Ph.D.   
Biomedical Imaging Program
James A. Deye, Ph.D.
Radiation Research Program 
National Cancer Institute 
6130 Executive Plaza, Suite 6000 
Bethesda MD   20892-7412 
Rockville MD  20852 (for express/courier service)  
Telephone:  301-496-9531 for BIP; 301-496-6111 for RRP 
FAX:  301-480-3507 
Email:  bakerhou@mail.nih.gov
guoyingl@mail.nih.gov
farahank@mail.nih.gov
deyej@mail.nih.gov.

For NIBIB
John W. Haller, Ph.D.
Health Scientist Administrator
National Institute of Biomedical Imaging and Biomedical Engineering
6707 Democracy Blvd., Suite 200
Bethesda MD 20892-5469
Telephone:  301-451-4780
Fax:  301-480-4973
Email: hallerj@mail.nih.gov

o Direct your questions about peer review issues to 

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda MD 20892-8329
Telephone:  301-496-3428
FAX:  301-402-0275 
Email:  ncirefof@dea.nci.nih.gov

o Direct your questions about financial or grants management matters to

Brian E. Martin
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, EPS Room 243
Bethesda MD 20892
Rockville MD  20852 (for express/courier service) 
Telephone:  301-496-1014
Fax:  301-846-5720
Email:  martinbr@nih.gov 

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this PAR 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NCI staff to estimate the potential review workload and plan 
the review.
 
The letter of intent is to be sent by the date listed at the beginning of this 
document.  The letter of intent should be sent to

Houston Baker, Ph.D. 
Biomedical Imaging Program 
National Cancer Institute 
6130 Executive Plaza, Room 6060 
Bethesda MD   20892-7412 
Rockville MD  20852 (for express/courier service)  
FAX:  301-480-3507
Email:  bakerhou@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
forms (rev. 5/2001). Follow the PHS 398 instructions and specific instructions 
below.  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone 1 301 435 0714, 
Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted by the receipt dates listed on the first page of 
this program announcement.  

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:  
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying that an appropriate Program staff person 
listed in WHERE TO SEND INQUIRIES (above) has agreed to accept assignment of 
the application.   

Applicants requesting $500,000 or more must perform the following steps:

1)  Contact the appropriate Program staff person listed in WHERE TO SEND 
INQUIRIES (above) at least 6 weeks before submitting the application, i.e., as 
you are developing plans for the study; 

2)  Obtain agreement from the Program staff person that he or she has obtained 
permission to accept your application for consideration for award; and
  
3)  In a cover letter sent with the application, name the program staff person 
and Institute who agreed to accept assignment of the application, and provide 
a copy of the agreement.  

This policy applies to all applications:  investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended or 
revised version of these grant application types. Additional information on 
this policy is available in the NIH Guide for Grants and Contracts, October 
19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SPECIFIC INSTRUCTIONS FOR PREPARING AN R21/R33 or R33 APPLICATION:

Below are two alternative sets of specific instructions.  Use the first set 
for a combined R21/R33 Phased Innovation Award if feasibility testing and 
preliminary and/or pilot data are necessary before progression to Phase 2 
funding.  Follow the second set to apply for an R33 Exploratory-Developmental 
Award if feasibility has already been demonstrated and is supported by 
adequate preliminary and/or pilot data.

I.  SPECIFIC INSTRUCTIONS FOR PREPARING A COMBINED R21/R33 PHASED INNOVATION 
AWARD APPLICATION:

An R21/R33 application must include specific aims that are relevant to each 
phase and include objective performance targets (feasibility milestones) that 
would justify transition to the R33 phase.  Applications must include a 
specific section labeled Milestones following the Research Plan for the R21 
phase.  Milestones should describe objective performance targets--preferably 
quantifiable and scientifically justified, and not simply restate the R21 
specific aims.  Discuss the suitability of the proposed milestones as targets 
against which to measure R21 progress, as well as the implications of their 
successful completion for the R33 phase.  List this section in the Table of 
Contents as "Milestones."  Applications lacking this information, as 
determined by NCI program staff, may be returned to the applicant without 
review.  For funded applications, completion of the R21 objectives as 
presented in a progress report with data on how well the milestones were met 
will elicit an NCI expedited review that will determine whether or not R33 
funding should be awarded.  The release of R33 funds will be based on program 
priorities, availability of funds, and successful completion of Phase I 
objectives and results of the negotiated milestones.  The expedited review may 
result in additional negotiations of award.

The R21/R33 Phased-Innovation Award application must be submitted as one 
application with one Face Page, and with its Research Plan clearly organized 
into two phases of work.  To accomplish a clear distinction between the two 
phases, applicants are directed to complete a two-phase Research Plan.  
Complete Sections a-d of the Research Plan for the R21 Phase 1, including a 
Milestones section, and Sections a-d for the R33 Phase II plan.  It is not 
necessary to repeat information, e.g., there may be little or nothing more to 
add to the R33 Section b. Background and Significance; likewise R33 Section c. 
Preliminary Studies/Progress Report, is prospective.  The Form 398 Table of 
Contents should be modified to show Sections a-d for each phase as well as the 
R21 milestones.  There is a page limit of 25 pages for the composite a-d text, 
i.e., Sections a-d and milestones for the R21 and Sections a-d for the R33 
phase must be contained within the 25 page limit.

The R21/R33 application will be assigned a single priority score.  As 
discussed in the ADDITIONAL REVIEW CRITERIA section, the initial review panel 
has the option of recommending only the R21 phase for support.  A Phased-
Innovation Award application with a poorly prepared R33 Phase II plan that is 
not recommended for support, or presentation of milestones not sufficiently 
rigorous for proper validation of Phase I progress and success may reflect 
upon the judgment of the applicant.  Thus clarity and completeness of the 
R21/R33 application with regard to milestones and specific goals for each 
phase are critical. 

1.  FACE PAGE OF THE APPLICATION:
Item 2.  Check the box marked "YES" and type the NUMBER AND TITLE of this PAR.  
Also, indicate that the application is submitted as an R21/R33.

Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT:
For the R21 phase of the combined R21/R33 application, direct costs may not 
exceed $125,000 per year for up to two years and the award may not be used to 
supplement an ongoing project.  The requested budgets may exceed this 
guideline to accommodate indirect costs of subcontracts to the project.  
Insert the direct costs requested for first year of support in item 7a and 
total first year costs in 7b. 

Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:
For the R21 phase, direct costs requested for the proposed period may not 
exceed $250,000 for two years of support.  The requested budgets may exceed 
this guideline to accommodate indirect costs of subcontracts to the project.  
Insert the sum of all years of requested direct and total support in items 8a 
and 8b.

2.  PAGE 2 - DESCRIPTION:
Concisely state the problem addressed, the technology or methods to be 
developed, its innovative nature, its relationship to presently available 
capabilities, and its expected impact on cancer and other diseases.

3.  BUDGET:
The application should provide a DETAILED BUDGET for Initial Budget Period 
(form page 4) for each of the initial years of both the R21 and R33 phases, 
and on form page 5 present a budget for the entire proposed period of support.  
Form pages should indicate which years are R21 and R33.  All budgets should 
include a justification for each line item and amount requested.

4.  RESEARCH PLAN:
Item a. Specific Aims:  
The application must present specific aims that are scientifically appropriate 
for the relevant phases of the project.  The instructions for the PHS 398 
application suggest that the investigators state hypotheses to be tested under 
Specific Aims. Since the goal of this PAR is to develop technologies or 
methods for in vivo imaging, problem solving (engineering) methods rather than 
hypothesis testing per se may be the driving force in developing such a 
proposal.  Therefore, hypothesis testing may not be applicable.  Preliminary 
data are not required for R21/R33 phased innovation applications.  However, 
scientifically sound preliminary data should be included when available.

Item b. Background and Significance:
The application should describe the importance and innovative nature of the 
proposed research. Clarify how the technology or method development proposed 
in this project would be a significant contribution. Compare it with existing 
approaches.  Explain its potential to impact cancer and other in vivo imaging 
research and/or clinical applications.  Clearly identify how the project, if 
successful, would result in new capabilities, the immediacy of the 
opportunity, and how it would contribute beyond existing approaches.  Item b. 
Background and Significance is an important feature of the R21 Phase 1 
Research Plan.  There may be little additional information to add to the R33 
Phase 2 research plan; do not repeat information already presented for the R21 
component.

Item c. Preliminary studies/Progress report:
The R21 phase should provide current thinking or evidence in the field to 
provide a rationale for feasibility of the R21 Phase aims.  Preliminary data 
are not required for the R21 phase.  However, provide relevant information to 
aid review, if available. The R33 Item c. should not repeat information 
already provided in the R21 Item c.  

Applicants are encouraged to include all information required for adequate 
review evaluation.  If some of the intellectual property is not protected 
sufficiently to disclose key details, the application should present a 
demonstration (results) of the capabilities of the proposed approach.

Item d. Research Design and Methods:
Follow the instructions for the PHS 398 application.  Add a final section 
labeled "Milestones" following the R21 Item d.   The Milestones should provide 
well described objective performance targets, quantifiable if appropriate, 
with scientific justifications.  They should not be simply a restatement of 
the specific aims.  Discuss the milestones relative to judging the success of 
the R21 phase and their implications for R33 Phase 2 work, if successfully 
completed.  List the page number for the Milestones section in the Table of 
Contents.  Applications lacking this information, as determined by Program 
staff, may be returned to the applicant without review.  Completion of the R21 
aims and submission of a non-competing application for transition to R33 
funding will elicit an expedited review by NCI program staff who will 
determine whether or not the R33 should be awarded.  The release of R33 funds 
will depend on successful completion of the R21 Phase 1 project, as determined 
by the aims, reported progress, Milestones, program priorities, and 
availability of funds.  Expedited review may result in additional negotiations 
of award.

II.  SPECIFIC INSTRUCTIONS FOR PREPARATION OF AN R33 APPLICATION WHEN 
SUBMITTED WITHOUT AN R21 PHASE:

1.  FACE PAGE OF THE APPLICATION:  
Item 2.  Check the box marked "YES" and type the TITLE AND NUMBER of this PA.  
Also, indicate that the application is submitted as an R33.

2.  DESCRIPTION:  
Concisely state the problem addressed, the technology or methods to be 
developed, its innovative nature, its relationship to presently available 
capabilities, and its expected impact on cancer and other diseases.

3.  BUDGET:
The application should provide a DETAILED BUDGET for the Initial Budget Period 
(form page 4) as well as a budget for the entire proposed period of support 
(form page 5).  The budget should include a justification for line items and 
amounts requested.  If it will equal or exceed $500,000 direct costs per year, 
SEE SPECIFIC INSTRUCTIONS above FOR APPLICATIONS REQUESTING $500,000 OR MORE 
PER YEAR.

4.  RESEARCH PLAN:  
Item a. Specific Aims:  The application must present specific aims that are 
scientifically appropriate for the project.  The instructions for the PHS 398 
application suggest that the investigators state hypotheses to be tested under 
Specific Aims. Since the goal of this PAR is to develop technologies or 
methods for in vivo imaging, problem solving (engineering) methods rather than 
hypothesis testing per se may be the driving force in developing such a 
proposal.  Therefore, hypothesis testing may not be applicable.  

Item b. Background and Significance:
The application should describe the importance and innovative nature of the 
proposed research. Clarify how the technology or method development proposed 
in this project would be a significant contribution. Compare it with existing 
approaches.  Explain its potential to impact cancer and other in vivo imaging 
research and/or clinical applications.  Clearly identify how the project, if 
successful, would result in new capabilities, the immediacy of the 
opportunity, and how it would contribute beyond existing approaches.  

Item c. Preliminary studies/Progress Report: 
R33 applications should clearly state how feasibility for the project has 
already been demonstrated.  This demonstration should include significant 
data.  This section must document that progress achieved is essentially 
equivalent to that expected from an R21 Phase 1 grant.  The application must 
clearly describe how the project is ready to progress to an expanded 
development stage.

Item d. Research Design and Methods:
Follow the PHS 398 application instructions.

III.  FOR ALL APPLICATIONS:

o Appendix: All instructions in the PHS 398 application apply.

o Copies of Prototype Imaging Systems:  Budget support may be requested to 
make one or more copies of the prototype for placement in a collaborating 
facility or facilities for pre-clinical or clinical feasibility 
investigations, including harmonization across versions of a single platform 
or across multiple platforms to enable multi-center comparison studies.  
Provide justification in the budget justification section, and make written 
reference to this section of the PAR.  

o Technology and know-how transfer:  Budget support may be requested to enable 
exchange of personnel between participating multi-site organizations to 
facilitate transfer of needed technology and know-how.  Provide justification 
in the budget justification section, and make written reference to this 
section of the PAR.  

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed photocopies in one 
package to the

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 the

Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda MD 20892-8329
Rockville MD 20852 (for overnight/courier service)

APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE 
WILL NOT BE ACCEPTED.  This policy does not apply to courier deliveries, e.g., 
USPS, FEDEX, UPS, DHL, etc.  See http://grants.nih.gov/grants/guide/notice-
files/NOT-CA-02-002.html.  This change in practice is effective immediately.  
This policy is similar to and consistent with the policy for applications 
addressed to Centers for Scientific Review (CSR) as published in the NIH Guide 
Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html 

APPLICATION PROCESSING: Applications must be received on or before the receipt 
dates listed on the first page of this program announcement.   If an 
application is received after that date, it will be returned to the applicant 
without review. 

The CSR will not accept an application in response to this PAR that is 
essentially the same as one currently pending initial review unless the 
applicant withdraws the pending application.  The CSR will not accept any 
application that is essentially the same as one already reviewed.  This does 
not preclude submission of a substantive revision of an application already 
reviewed, but such application must include an Introduction addressing the 
previous critiques.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness by the NCI and NIBIB.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration.

Applications that are complete and responsive to the PAR will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the Division of Extramural Activities of the NCI in accordance with the review 
criteria stated below.  As part of the initial merit review, each application 
will

o  Receive a written critique
o  Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score
o  Those that receive a priority score will undergo a second level review by 
the National Cancer Advisory Board and/or National Advisory Council for 
Biomedical Imaging and Bioengineering.

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 
goals of NCI include Discovery, Development, and Delivery of knowledge, 
methods, devices and systems to prevent, screen, diagnose, treat, and monitor 
the health progress of patients.  NIBIB embraces similar goals.  In their 
written comments, reviewers will be asked to discuss the following aspects of 
your application in order to judge the likelihood that the proposed research 
will have a substantive impact on the pursuit of these goals. 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
o Milestones
  
The scientific review group will comment on each of these criteria in 
assigning your application's overall score, weighting them as appropriate for 
each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move a 
field forward.
  
SIGNIFICANCE:  Does the study address an important problem? What may be the 
anticipated benefits of the proposed activity?  If the aims of the application 
are achieved, how will imaging technology, methods or knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?  

APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Does the proposed plan include a sound approach to establishing 
technical feasibility.  Does the applicant acknowledge potential problem areas 
and consider alternative strategies?  Is a time frame described for developing 
and delivering the proposed technology and methods, and is it suitable to 
meeting the needs of the community?  Are plans adequate for the proposed 
development, its integration as a useful, effective solution to the problem, 
and its implementation and dissemination for single or multi-site evaluation, 
if appropriate? 

INNOVATION:  Does the project challenge existing paradigms or employ novel 
concepts, approaches or methods? Are the aims original and innovative?  Does 
the project challenge existing paradigms or develop and deliver new 
methodologies or technologies?  What useful result can be expected from the 
proposed technology or methods development?

INVESTIGATOR:  Is the Principal Investigator capable of coordinating and 
managing the proposed technology or methods development?  Are the researchers 
appropriately experienced, trained and otherwise well suited to perform this 
work?  Is the work proposed appropriate to the backgrounds of the principal 
investigator and other researchers, including consultants and sub-contractors 
(if any)?

ENVIRONMENT:  Does the technical and scientific environment in which the work 
will be performed contribute to the probability of success?  Do the proposed 
developments take advantage of unique features of the intellectual environment 
or employ useful collaborative arrangements?  Is there sufficient access to 
resources to develop and deliver the proposed technology or methods, e.g., 
equipment, facilities, etc?

MILESTONES:  Are there objective performance targets (milestones) and other 
procedures proposed with which to evaluate successful completion of the Phase 
I project, including feasibility of the proposed development, which would be 
adequate to justify transition to funding for the Phase II development and 
delivery phase?  Are there changes, additions or deletions that should be 
recommended to improve the milestones?

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

For the R21/R33 Phased Innovation Award Application, the initial review group 
will evaluate the specific goals for each phase and the objective performance 
targets (Milestones) that would justify transition to R33 phase 2 funding. 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 application's specific 
goals and the Milestones justifying transition to phase 2 R33 funding.  
Deletion of the R33 phase by the review panel or presentation of inadequate 
milestones in the application may affect the merit rating of the application.

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK:  The involvement of human 
subjects and protections from research risk relating to their participation in 
the proposed research will be assessed.  (See additional information and 
Inclusion Criteria in the sections on Federal Citations, below).

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH:  The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups (and 
subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH:
If vertebrate animals are to be used in the project, the five items described 
under Section f of the PHS 398 research grant application instructions (rev 
5/2001) will be assessed.

ADDITIONAL CONSIDERATIONS:  The following items may be considered by reviewers 
but will not be included in the determination of scientific merit.

BUDGET:  
The reasonableness of the proposed budget and the requested period of support 
in relation to the proposed research.  

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Dates:  June 23, 2003 and October 22, 2003.
Application Receipt Dates:  July 21, 2003 and November 19, 2003.
National Advisory Board Review Dates:  February, 2004 and June, 2004.
Earliest Anticipated Award Date:  April, 2004 and July, 2004.

AWARD CRITERIA

Applications submitted in response to a PAR will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o  Scientific merit of the proposed project as determined by peer review
o  Availability of funds 
o  Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

MONITORING PLAN and DATA AND SAFETY MONITORING BOARD:  Research components 
involving Phase I and II clinical trials must include provisions for assessing 
patient eligibility and status, rigorous data management, quality assurance, 
and auditing procedures.  In addition, it is NIH policy that all clinical 
trials require data and safety monitoring, with the method and degree of 
monitoring commensurate with the risks (NIH Policy for Data Safety and 
Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

Clinical trials supported or performed by NCI require special considerations.  
The method and degree of monitoring should be commensurate with the degree of 
risk involved in participation and the size and complexity of the clinical 
trial.  Monitoring exists on a continuum from monitoring by the principal 
investigator/project manager or NCI program staff to a Data and Safety 
Monitoring Board (DSMB).  These monitoring activities are distinct from the 
requirement for study review and approval by an Institutional review Board 
(IRB).  For details about the Policy for the NCI for Data and Safety 
Monitoring of Clinical trials see: 
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm.  

For Phase I and II clinical trials, investigators must submit a general 
description of the data and safety monitoring plan as part of the research 
application.  See NIH Guide Notice on "Further Guidance on a Data and Safety 
Monitoring for Phase I and II Trials" for additional information: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.  
Information concerning essential elements of data and safety monitoring plans 
for clinical trials funded by the NCI is available:  
http://www.cancer.gov/clinical_trials/

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research. This policy results from the NIH Revitalization Act of 1993 (Section 
492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/
NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that a) all 
applications or proposals and/or protocols must provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting analyses, 
as appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy that children, i.e., individuals under the age of 
21 years, must be included in all human subjects research conducted or 
supported by the NIH, unless there are 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.  A 
continuing education program in the protection of human participants in 
research is available online at: http://cme.nci.nih.gov/

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Guidance 
for investigators and institutional review boards regarding research involving 
human embryonic stem cells, germ cells, and stem cell-derived test articles 
can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-044.html. 
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   It is the responsibility of the applicant to provide 
the official NIH identifier(s) for the hESC line(s) to be used in the proposed 
research.  Applications that do not provide this information will be returned 
without review.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law, i.e., a regulation, may be accessed through FOIA.  
It is important for applicants to understand the basic scope of this 
amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public archive, 
which can provide protections for the data and manage the distribution for an 
indefinite period of time.  If so, the application should include a 
description of the archiving plan in the study design and include information 
about this in the budget justification section of the application. In 
addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution.  The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH processes 
involving the review, funding, and progress monitoring of grants, cooperative 
agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving 
the health promotion and disease prevention objectives of "Healthy People 
2010," a PHS-led national activity for setting priority areas. This PA is 
related to one or more of the priority areas. Potential applicants may obtain 
a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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