NOVEL TECHNOLOGIES FOR IN VIVO IMAGING (R21/R33)

RELEASE DATE:  April 19, 2004 

PA NUMBER:  PA-04-095  

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date. The 
non-AIDS portion of this funding opportunity expires on the date indicated below. 
Replacement R21/R33 (PA-06-398) and R33 (PA-06-399) funding opportunity announcement 
has been issued for the submission date of June 1, 2006 and submission dates for 
AIDS and non-AIDS applications thereafter.

August 12, 2005 - Expiration date extended, see NOT-CA-05-026

EXPIRATION DATE for Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for AIDS and AIDS-Related Applications: May 2, 2006 
Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATION: 
National Institutes of Health (NIH) 
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION:  
National Cancer Institute (NCI)
 (http://www.nci.nih.gov/)

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

This Program Announcement (PA) replaces PAR-03-124, which was published in the 
NIH Guide on May 19, 2003.

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanisms of Support
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA

The National Cancer Institute (NCI) invites applications for the development and 
delivery of novel image acquisition or enhancement technologies 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 primarily 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 image-
based surrogate end points.  NCI’s interests include 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.  

This PA is directed toward the development, optimization, and delivery of 
innovative image acquisition and enhancement methods, including high-risk/high-
gain research on technologies, such as: (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 and (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. In addition, research partnerships among investigators in both 
academia and device and drug industries are encouraged to more rapidly translate 
and deliver completed imaging system developments.

This solicitation utilizes the Exploratory/Developmental Phased Innovation Award 
(R21 Phase 1 and R33 Phase 2) grant mechanisms, and runs in parallel with a 
program announcement of nearly identical scope and intent PA-04-094 
(http://grants.nih.gov/grants/guide/pa-files/PA-04-094.html) that utilizes the Small 
business Innovation Research (SBIR) and Small Business Technology Transfer 
Research (STTR) award mechanisms based on small business set aside funds.  

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 PA are to stimulate development, 
optimization, and delivery of novel imaging technologies and methods to capture, 
process, validate, present, interpret, or understand in vivo imaging data that 
support the mission of the NCI.

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 (i.e., in vivo molecular imaging) similar to that 
currently available from histological or micro-array techniques used for in 
vitro studies 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 (a) 
promoting the development of novel, high-risk, high-gain technologies, (b) 
supporting those technologies to maturation, dissemination, and full 
exploitation; (c) integrating new technologies into commercially available 
imaging systems for targeted applications; (d) harmonizing 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.  Therefore, the aims 
of this initiative and the support mechanism (Phased Innovation Awards R21/R33) 
are also directed at encouraging the 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.

The purpose of 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 PA.

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, that may use 
either intrinsic or exogenous contrast agents represent possible topics.

o Disease Screening:  These methods may include, but are not limited to, the 
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 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 
the use of ionizing radiation or 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), Image-Guided Therapy (IGT), and Image-Guided 
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 
research purposes, namely 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, harmonize imaging methods or collaborate with NCI 
funded centers are advised to contact the NIH program staff listed in the 
section of this document that is entitled “Where to Send Inquiries.”

o Research Resources:  Developments of publicly accessible research resources 
that facilitate a consensus process for optimization and validation of emerging 
imaging technologies are 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 
NIH program staff.

MECHANISMS OF SUPPORT

This PA will use the NIH R33 Exploratory Developmental Phase II Award, and the 
combined R21/R33 Phased-Innovation Award mechanisms.  Transition from R21 to R33 
Phase 2 support will be expedited, and will depend upon successful completion of 
Phase 1 aims, including negotiated Objective Performance Targets (Milestones).  
Applicants will be solely responsible for planning, directing, and executing the 
proposed project. 

Under this PA, 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 SUPPLEMENTARY INSTRUCTIONS section of this 
program announcement).  Applications for R21 support alone will not be accepted.  
There are separate program announcements available for R21 support alone, e.g., 
In Vivo Cancer Imaging Exploratory/Developmental Grants, PA-04-045, 
http://grants.nih.gov/grants/guide/pa-files/PA-04-045.html.  For combined 
R21/R33 applications, the applicant may request an R21 budget period of up to 2 
years with a combined budget guideline for direct costs of up to $275,000 for 
the 2-year period.  The amount of funds requested and their distribution between 
years should be tailored to the needs of the project, usually no more than 
$200,000 in any one year.  Although the R33 application has no official 
budgetary limit, applications requesting $500,000 or more in direct costs in any 
single year of the grant period require prior approval 6 weeks before submission 
(see specific instructions below).  The total project period for an application 
submitted in response to this PA 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.

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

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

2.  Minimal or no funding gap between, the 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 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 
(quantitative if possible) 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 PA 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 budget 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_2003/NIHGPS_Part2.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 institutions/organizations

There is a parallel program announcement for USA institutions eligible for small 
business grants, which is being re-issued concurrently with this PA as PA-04-094 
(http://grants.nih.gov/grants/guide/pa-files/PA-04-094.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.

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Guoying Liu, Ph.D., Keyvan Farahani, Ph.D., James A. Deye, Ph.D., or Houston 
Baker, Ph.D.
National Cancer Institute
6130 Executive Plaza, EPN Room 6000
Bethesda, MD   20892-7412
Rockville, MD  20852 (for express/courier service)
Telephone:  301-496-9531 for GL, KF, HB; 301-496-6111 for JAD
FAX:  301-480-3507
E-mails:  
guoyingl@mail.nih.gov
farahank@mail.nih.gov
deyej@mail.nih.gov.
bakerhou@mail.nih.gov

o Direct your questions about financial or grants management matters to:

Shane Woodward 
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, EPS Room 243
Bethesda MD 20892
Rockville MD 20852 (for express/courier service)
Telephone:  301-846-1017 
Fax:  301-846-5720
E-mail:  woodwars@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal 
Identifier when applying for Federal grants or cooperative agreements. The DUNS 
number can be obtained by calling (866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 
of the face page of the PHS 398 form. 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: (301) 435-0714; 
Email: GrantsInfo@nih.gov.

The title and number of this program announcement must be typed on line 2 of the 
face page of the application form and the YES box must be checked.

SUPPLEMENTARY INSTRUCTIONS 

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, 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.  Therefore 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 PA. 
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, the applicant may request an R21 budget period of up to 2 
years with a combined budget guideline for direct costs of up to $275,000 for 
the 2-year period.  The amount of funds requested and their distribution between 
years should be tailored to the needs of the project, usually no more than 
$200,000 in any one year.  If special circumstances require a larger Phase I 
budget, provide a clear justification in the Budget Justification section.  The 
award may not be used to supplement an ongoing project.  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:
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 phase 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 PA 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; and 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 PA 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 PA.

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 PA.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which are 
available at http://grants.nih.gov/grants/dates.htm.  Application deadlines are 
also indicated in the PHS 398 application kit.

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. 

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.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the 
application, including the Checklist, and five 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
Bethesda MD 20817 (for express/courier service)

APPLICATION PROCESSING:  Applications must be mailed on or before the receipt 
dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm.  
The CSR will not accept any application in response to this PA that is 
essentially the same as one currently pending initial review unless the 
applicant withdraws the pending application.  The CSR will not accept any 
application that is essentially the same as one already reviewed.  This does not 
preclude the submission of a substantial revision of an unfunded version an 
application already reviewed, but such application must include an Introduction 
addressing the previous critique.

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

Applications submitted for this PA will be assigned on the basis of established 
PHS referral guidelines.  Appropriate scientific review groups convened in 
accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by an appropriate national advisory council or 
board.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In the 
written comments, reviewers will be asked to evaluate application in order to 
judge the likelihood that the proposed research will have a substantial impact 
on the pursuit of these goals.  The scientific review group will address and 
consider each of the following criteria in assigning the application’s overall 
score, weighting them as appropriate for each application.

o Significance
o Approach
o Innovation
o Investigator
o Environment

The 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, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

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

APPROACH: Are the conceptual framework, design, methods, and analyses adequately 
developed, well-integrated, and appropriate to the aims of the project? Does the 
applicant acknowledge potential problem areas and consider alternative tactics?

INNOVATION: Does the project employ novel concepts, approaches or methods? Are 
the aims original and innovative? Does the project challenge existing paradigms 
or develop new methodologies or technologies?

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

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

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

OBJECTIVE PERFORMANCE TARGETS (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? 

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, and updated 09/09/2003) will be assessed.

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

Sharing Research Data 

Applicants requesting $500,000 or more in direct costs in any year of the 
proposed research are expected to include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the rationale for 
not sharing research data will be assessed by the reviewers. However, reviewers 
will not factor the proposed data sharing plan into the determination of 
scientific merit or priority score.

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

AWARD CRITERIA

Applications submitted in response to a PA 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; and
o  Relevance to program priorities.

Phase II non-competing applications may be funded following submission and 
program staff evaluation and approval of the Phase I Progress Report and other 
documents necessary for continuation.  Continuation funding will depend on a 
determination of successful completion of goals set for Phase I work (assessed 
in part on meeting performance targets negotiated as Phase I Milestones), 
program priorities, and the availability of funds.

REQUIRED FEDERAL CITATIONS

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities involving 
live, vertebrate animals must comply with PHS Policy on Humane Care and Use of 
Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal 
Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as 
applicable.

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. See 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all 
types of clinical trials, including physiologic, toxicity, and dose-finding 
studies (phase I); efficacy studies (phase II); and efficacy, effectiveness and 
comparative trials (phase III). The establishment of data and safety monitoring 
boards (DSMBs) is required for multi-site clinical trials involving 
interventions that entail potential risk to the participants.  (See the NIH 
Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 
12, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-084.html.)  

SHARING RESEARCH DATA:  Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing (http://grants.nih.gov/grants/policy/data_sharing) or 
state why this is not possible. Investigators should seek guidance from their 
institutions, on issues related to institutional policies, local IRB rules, as 
well as local, State, and Federal laws and regulations, including the Privacy 
Rule. Reviewers will consider the data sharing plan but will not factor the plan 
into the determination of the scientific merit or the priority score.

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. 

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://stemcells.nih.gov/index.asp and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.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, in the project description 
and elsewhere in the application as appropriate, 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). 
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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

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