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) 710-0267; 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.

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