NOVEL TECHNOLOGIES FOR IN VIVO IMAGING (R21/R33) RELEASE DATE: May 19, 2003 PA NUMBER: PAR-03-124 (see replacement PA-04-095) EXPIRATION DATE: December 1, 2003, unless reissued. National Cancer Institute (NCI) (http://www.nci.nih.gov/) National Institute for Biomedical Imaging and Bioengineering (NIBIB) (http://www.nibib.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.394, 93.395, 93.396, 93.286, 93.287 LETTER OF INTENT RECEIPT DATE: June 23, 2003 and October 22, 2003 APPLICATION RECEIPT DATE: July 21, 2003 and November 19, 2003 This Program Announcement (PAR) replaces PAR-01-101, which was published in the NIH Guide on May 29, 2001. THIS PAR CONTAINS THE FOLLOWING INFORMATION o Purpose of the PAR o Research Objectives o Mechanisms of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PAR The National Cancer Institute (NCI) and the National Institute for Biomedical Imaging and Bioengineering (NIBIB) invite applications for the development and delivery of novel image acquisition or enhancement technology and methods for biomedical imaging and image-guided interventions and therapy, and which may incorporate limited pilot or clinical feasibility evaluations using either pre-clinical models or clinical studies. This initiative is intended to facilitate the proof of feasibility, development and delivery of novel imaging technologies for early detection, screening, diagnosis, image-guided interventions, and treatment of various diseases, and secondarily to facilitate limited evaluation studies to show proof of concept and functionality. The interests of NCI focus on imaging in vivo for cancer pre-conditions, cancer screening, diagnosis, progression, treatment monitoring, recurrence, and surrogate endpoints. NCI interests include the discovery, development and delivery of imaging technologies that are cancer specific, and optimization and validation of imaging technologies for cancer applications. The scope includes system integration, contrast agents, pre- and post-processing algorithms and software for imaging, image understanding, and related informatics that are cancer specific. However, the interests of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) focus on the discovery, development and delivery of imaging platforms and related component technologies, contrast agents, image processing and related informatics that can be applied to disease and injury. This PAR is directed toward the discovery, development, optimization and delivery of innovative image acquisition and enhancement methods, including high risk/high gain research on technologies, as follows: (a) Novel single and multimodality molecular imaging systems, methods, agents, and related software and informatics, including the integration of these technologies with emerging biomedical imaging methods for more effective health care delivery for cancer and other diseases; (b) Novel single and multimodality anatomical and functional imaging systems, methods, agents, and related software and informatics for more effective health care delivery for cancer and other diseases. (c) Research partnerships among academics and investigators in device and drug industries are encouraged to more rapidly translate and deliver completed imaging system developments. This solicitation utilizes the Phased Innovation Award (Exploratory/Developmental R21 Phase 1 and R33 Phase 2) Grant mechanisms, and runs in parallel with a program announcement of nearly identical scope and intent (PAR-03-125) that utilizes the Small business Innovation Research (SBIR) and Small Business Technology Transfer Research (STTR) award mechanisms based on small business set aside funds. The SBIR/STTR Fast Track option of paired applications uses an expedited review process for transition from Phase I to Phase II funding that is the same as the Phase Innovation Award of this PAR for exploratory/developmental studies. Applicants eligible for SBIR/STTR funding are encouraged to use that option. Phased Innovation Awards benefit from expedited evaluation of progress following the Phase 1 exploratory/feasibility study for expedited decision on transition to Phase 2 funding for expanded developmental work. RESEARCH OBJECTIVES The overarching Research Objectives of this PAR are to stimulate discovery, development and delivery of novel imaging technologies and methods to capture, process, validate, present, interpret or understand in vivo imaging data that support the missions of the NCI and NIBIB. Significant advances in medical imaging technologies have been made over the past 25 years in such areas as magnetic resonance imaging (MRI), computed tomography (CT), nuclear medicine, ultrasound, and optical imaging. These advances largely focused on structural or anatomical imaging at the organ or tissue level. Now there is an opportunity to stimulate the development and integration of novel imaging technologies that exploit our current knowledge of the genetic and molecular bases of various diseases. Molecular biological discoveries have great implications for prevention, detection, and targeted therapy. Imaging technologies able to provide similar kinds of cellular and molecular information—in vivo molecular imaging—similar to that currently available from histological or micro-array techniques in vitro would be very useful. The advances in molecular methods pose new requirements for the performance of conventional biomedical imaging systems. For example, molecular imaging systems may need to be optimized for a molecular probe or probes as well as anatomical imaging. The integration of molecular imaging methods into multi- modality systems will affect data acquisition, processing, reduction, display, and archiving. Therefore there is a need to support advances in methods for both molecular and conventional anatomical and functional imaging. The need to encourage and support biomedical imaging and imaging technology development by academic and industrial researchers was stressed by participants at several NIH- and NCI-supported forums over the past few years [Imaging Sciences Working Group (ISWG) July 1997; Lung Imaging Workshop: Technology Transfer, Jan 1997; Computer Aided Diagnosis and 3D Image Analysis, Oct 1998; Quantitative in-vivo Functional Imaging in Oncology, Jan 1999; Focus Group on Magnetic Resonance Spectroscopy (MRS) in Clinical Oncology, April 1999; NIH BECON Symposium, June 1999; Dynamic Contrast Enhancement Magnetic Resonance Imaging Workshop, Rockville, Maryland, November 2000; and NCI/ISMRM Workshop on Higher Field MR (1.5 T & Up) in Oncology: Strategic Frontiers in Cancer Diagnosis and Treatment, Glasgow, Scotland, April 2001]. The needs include promoting (a) the development of novel, high risk, high gain technologies, (b) supporting them to maturation, dissemination and full exploitation, (c) integration of new technologies into commercially available imaging systems for targeted applications, (d) harmonization of imaging methods across versions of a single platform or across multiple platforms to permit similar image-based surrogate outcome metrics as required for multi- site pre-clinical and clinical investigations, (e) funding a small number of copies of integrated system prototypes for placement, as required, for off- site research and clinical feasibility studies, and (f) improving technology transfer, delivery and dissemination by promoting early-stage partnerships between academia and industry to encourage sharing of research resources and validation studies necessary to meet Federal regulatory requirements. Thus the aims of this initiative and the support mechanism (Phased Innovation Awards R21/R33) are also directed at encouraging the discovery, development and delivery of imaging "tools" and related resources to support biomedical imaging in general for applications in oncology and other diseases. Developments of novel imaging technologies usually require multidisciplinary approaches and teams with broad expertise in a variety of research areas. Such varied expertise might include imaging physics, chemistry, molecular and cellular biology, signal and image processing, computer vision, informatics and biostatistics, and clinical sciences. The coordination and collaboration of investigators with the necessary variety of disciplines to demonstrate the utility and applicability of new imaging methods is encouraged. This initiative is to facilitate the development of novel imaging technologies for risk assessment, early detection, screening, diagnosis or image guided treatment of cancer and other diseases and to facilitate clinical evaluation and optimization studies that are specifically limited to proof of concept and pilot data on clinical functionality of the development. Clinical trials for clinical validation of emerging imaging technologies are beyond the scope and are not responsive to this PAR. Studies with pre-clinical models and clinical studies to demonstrate the feasibility of developments are encouraged, including multi-site evaluations, where appropriate. Methods that establish "ground truth" are required at appropriate levels of resolution to validate these emerging imaging methods, e.g., imaging excised tissue using protocols similar to those used in vivo, or correlation of molecular imaging results with micro-array library analyses. Developments of molecular probes or targeted contrast agents are considered important approaches to detection of molecular changes in vivo to take better advantage of many technologies with potential for molecular imaging. The following topics would make appropriate proposed projects. This list is not meant to be all-inclusive. o Early Disease Detection: Developments may address innovative high- resolution imaging methods, with a particular intent to identify and characterize abnormalities or other early changes, including molecular events on the path to disease. Novel solutions for in vivo microscopic imaging systems, or microscopic implanted devices with high spatial and/or temporal resolution, which may use either intrinsic or exogenous contrast agents represent possible topics. o Disease Screening: These methods may include, but are not limited to development and optimization of efficient imaging systems for screening, with the intent of achieving improved sensitivity and specificity for disease detection. Applications could address innovative improvements to current imaging methods, including hardware and/or software upgrades, or emerging imaging sensors and methods. Research topics of interest include a means to significantly reduce imaging time or effects of motion, use of novel contrast agents or imaging probes, and use of technologies that reduce or do not involve ionizing radiation, or use of novel contrast agents and imaging probes. System integration and software methods could include a variety of image processing and data reduction techniques including temporal analysis of serial studies, close to real-time image processing, novel image display methods, and related imaging informatics for more cost-effective solutions for screening. o Imaging for Diagnosis, Staging, or Monitoring the Effects of Therapy: This initiative encourages, but is not limited to the development of novel imaging methods such as functional or molecular imaging or spectroscopy methods that would significantly improve the specificity of diagnosis of cancer and other diseases, allow deterministic methods or patient-specific staging, or measure early effects of therapy. Examples of system integration would include multi- modality imaging, image fusion or registration of the different modalities employed, development of software methods that would estimate the probability of malignancy or other specific disease identification, quantitative information for monitoring the effects of therapy, and close to real-time image analysis. o Image Guided Biopsy (IGB), Therapy (IGT), and Interventional (IGI) Procedures: This initiative encourages novel approaches using imaging technologies needed to significantly improve specificity, to identify lesion extent and microscopic involvement, and to minimize tissue damage accompanying biopsy and therapy. Of particular interest are innovative approaches to IGB, IGT or interventional methods that include novel imaging systems that provide molecular target information or information at the cellular or molecular level sufficient for image guidance and treatment. Examples of system integration that are of interest include, but are not limited to multi-modality imaging, navigational systems, registration methods, real-time feedback mechanisms for controlling therapy (including radiation therapy) or the use of methods that are adaptive or allow patient-specific optimization of treatment and computer- assisted surgery. o Copies of Prototype Imaging Systems: Support may be requested to make one or more copies of the prototype for placement in collaborating facilities for pre-clinical or clinical feasibility investigations, including harmonization across versions of a single platform or across multiple platforms to enable multi-center comparison studies. Collaboration with NCI funded centers may be possible, such as the NCI Network for Translational Research in Optical Imaging, https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-03-002.html, or the Lung Image Database Consortium, http://www3.cancer.gov/bip/steercom.htm. Investigators anticipating need for funds to build system copies, harmonization of imaging methods or collaboration with NCI funded centers are advised to contact program staff. o Research Resources: The development of research resources that facilitate a consensus process for optimization and validation of emerging imaging technologies is encouraged. Examples include the development of open source software, image processing software and related informatics that can be ported onto different platforms, methods and image databases required for validation of software performance, and other hardware or informatics methods that assist in more efficient delivery of imaging technologies for screening, diagnosis and treatment for cancer and other diseases. Investigators interested in development of research resources and related research are advised to contact program staff. MECHANISMS OF SUPPORT This PAR will use the NIH R33, and the combined R21/R33 Phased-Innovation Award mechanisms. Applicants will be solely responsible for planning, directing, and executing the proposed project. Support for this program will be through the National Institutes of Health (NIH) Phase 1 Exploratory/Developmental Research Grant (R21) and the Phase 2 Exploratory/Developmental Research Grant (R33). The R33 is a NIH grant mechanism to provide a second phase for the support of innovative exploratory and development research initiated under the R21 mechanism. Transition from R21 to R33 Phase 2 support will be expedited, and depends upon successful completion of Phase 1 aims, including negotiated objective performance targets (milestones). Under this PAR, applicants can submit either a combined R21/R33 application (Phased Innovation Award application) or an R33 application alone if feasibility can be documented (described in the SPECIFIC INSTRUCTIONS section of this program announcement). Applications for R21 support alone will not be accepted. There are separate program announcements available for them, e.g., Exploratory/Developmental Grants for Diagnostic Cancer Imaging, PA-01-030, https://grants.nih.gov/grants/guide/pa-files/PA-01-030.html. The total project period for an application submitted in response to this PAR may not exceed the following durations: R33, 3 years; combined R21/R33 application, 4 years. In the combined application the R21 phase may not exceed 2 years. For combined R21/R33 applications, the R21 phase may not exceed $125,000 direct costs per year. R21 budgets can exceed this cap to accommodate indirect costs to subcontracts to the project. Although the R33 application has no official budgetary limit, applications requesting in excess of $500,000 dollars direct costs in any single year of the grant period require prior approval six weeks before submission (see specific instructions below). It is strongly recommended that applicants contact Program staff at an early stage of application development to convey critical information, such as potentially large budget requests or to discuss programmatic adherence to the guidelines of the proposed project. Early contact with Program staff is particularly critical relative to this PAR because it uses the R33 grant mechanism as well as an expedited review procedure. Refer to the INQUIRIES sections of this program announcement for Program staff contacts. The combined R21/R33 Phased Innovation Award application offers two advantages over the regular application process: 1. Single submission and review of both the R21 and R33 Phases as one application. 2. Minimal or no funding gap between R21 and R33 phases. The award of R33 funds will be based on program priorities, on the availability of funds and on successful completion of Phase 1 aims, including negotiated objective performance targets (milestones), as determined by NCI or NIBIB staff in the context of peer review recommendations. To be eligible for the Phased Innovation Award, the R21 phase must include well defined objective, preferably quantifiable performance targets (milestones) useful for judging the success of the proposed research, as well as a credible plan for development of technology in the R33 phase. The Phased Innovation Award must have a section labeled Milestones at the end of the R21 section of the Research Plan. This section must include well-defined objective performance targets (milestones) for completion of the R21 Phase part of the application, a discussion of the suitability of the proposed milestones for assessing success of the R21 phase work, and a discussion of the implications of successful completion of these milestones for the proposed R33 study. This PAR uses just-in-time concepts. It also uses the non-modular budgeting formats. Full budget presentations and justifications are required. Follow the instructions for non-modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm ELIGIBLE INSTITUTIONS You may submit one or more applications if your institution meets any of the following criteria: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign There is a parallel program announcement for USA institutions eligible for small business grants, which is being re-issued concurrently with this PAR as PAR-03-125 (see https://grants.nih.gov/grants/guide/pa-files/PAR-03-125.html). INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS o The R21 section of the Research Plan must end with a section on objective performance targets (Milestones), quantitative if appropriate, to help evaluate the success of Phase I work after its completion. o If a copy or copies of a prototype will be needed for placement in one or more sites for pre-clinical or clinical testing, include a clear written justification for the funds requested in the Budget Justification Section, and make written reference to this instruction. o The transition from Phase 1 R21 funding to award of R33 funds will be based on program priorities, on the availability of funds and on successful completion of Phase 1 R21 aims, including negotiated objective performance targets (milestones), as determined by NCI or NIBIB staff in the context of peer review recommendations. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PAR and welcome the opportunity answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to the following: For NCI Houston Baker, Ph.D., Guoying Liu, Ph.D., or Keyvan Farahani, Ph.D. Biomedical Imaging Program James A. Deye, Ph.D. Radiation Research Program National Cancer Institute 6130 Executive Plaza, Suite 6000 Bethesda MD 20892-7412 Rockville MD 20852 (for express/courier service) Telephone: 301-496-9531 for BIP; 301-496-6111 for RRP FAX: 301-480-3507 Email: bakerhou@mail.nih.gov guoyingl@mail.nih.gov farahank@mail.nih.gov deyej@mail.nih.gov. For NIBIB John W. Haller, Ph.D. Health Scientist Administrator National Institute of Biomedical Imaging and Biomedical Engineering 6707 Democracy Blvd., Suite 200 Bethesda MD 20892-5469 Telephone: 301-451-4780 Fax: 301-480-4973 Email: hallerj@mail.nih.gov o Direct your questions about peer review issues to Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda MD 20892-8329 Telephone: 301-496-3428 FAX: 301-402-0275 Email: ncirefof@dea.nci.nih.gov o Direct your questions about financial or grants management matters to Brian E. Martin Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, EPS Room 243 Bethesda MD 20892 Rockville MD 20852 (for express/courier service) Telephone: 301-496-1014 Fax: 301-846-5720 Email: martinbr@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this PAR Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to Houston Baker, Ph.D. Biomedical Imaging Program National Cancer Institute 6130 Executive Plaza, Room 6060 Bethesda MD 20892-7412 Rockville MD 20852 (for express/courier service) FAX: 301-480-3507 Email: bakerhou@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application forms (rev. 5/2001). Follow the PHS 398 instructions and specific instructions below. The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone 1 301 710-0267, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted by the receipt dates listed on the first page of this program announcement. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying that an appropriate Program staff person listed in WHERE TO SEND INQUIRIES (above) has agreed to accept assignment of the application. Applicants requesting $500,000 or more must perform the following steps: 1) Contact the appropriate Program staff person listed in WHERE TO SEND INQUIRIES (above) at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the Program staff person that he or she has obtained permission to accept your application for consideration for award; and 3) In a cover letter sent with the application, name the program staff person and Institute who agreed to accept assignment of the application, and provide a copy of the agreement. This policy applies to all applications: investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SPECIFIC INSTRUCTIONS FOR PREPARING AN R21/R33 or R33 APPLICATION: Below are two alternative sets of specific instructions. Use the first set for a combined R21/R33 Phased Innovation Award if feasibility testing and preliminary and/or pilot data are necessary before progression to Phase 2 funding. Follow the second set to apply for an R33 Exploratory-Developmental Award if feasibility has already been demonstrated and is supported by adequate preliminary and/or pilot data. I. SPECIFIC INSTRUCTIONS FOR PREPARING A COMBINED R21/R33 PHASED INNOVATION AWARD APPLICATION: An R21/R33 application must include specific aims that are relevant to each phase and include objective performance targets (feasibility milestones) that would justify transition to the R33 phase. Applications must include a specific section labeled Milestones following the Research Plan for the R21 phase. Milestones should describe objective performance targets--preferably quantifiable and scientifically justified, and not simply restate the R21 specific aims. Discuss the suitability of the proposed milestones as targets against which to measure R21 progress, as well as the implications of their successful completion for the R33 phase. List this section in the Table of Contents as "Milestones." Applications lacking this information, as determined by NCI program staff, may be returned to the applicant without review. For funded applications, completion of the R21 objectives as presented in a progress report with data on how well the milestones were met will elicit an NCI expedited review that will determine whether or not R33 funding should be awarded. The release of R33 funds will be based on program priorities, availability of funds, and successful completion of Phase I objectives and results of the negotiated milestones. The expedited review may result in additional negotiations of award. The R21/R33 Phased-Innovation Award application must be submitted as one application with one Face Page, and with its Research Plan clearly organized into two phases of work. To accomplish a clear distinction between the two phases, applicants are directed to complete a two-phase Research Plan. Complete Sections a-d of the Research Plan for the R21 Phase 1, including a Milestones section, and Sections a-d for the R33 Phase II plan. It is not necessary to repeat information, e.g., there may be little or nothing more to add to the R33 Section b. Background and Significance; likewise R33 Section c. Preliminary Studies/Progress Report, is prospective. The Form 398 Table of Contents should be modified to show Sections a-d for each phase as well as the R21 milestones. There is a page limit of 25 pages for the composite a-d text, i.e., Sections a-d and milestones for the R21 and Sections a-d for the R33 phase must be contained within the 25 page limit. The R21/R33 application will be assigned a single priority score. As discussed in the ADDITIONAL REVIEW CRITERIA section, the initial review panel has the option of recommending only the R21 phase for support. A Phased- Innovation Award application with a poorly prepared R33 Phase II plan that is not recommended for support, or presentation of milestones not sufficiently rigorous for proper validation of Phase I progress and success may reflect upon the judgment of the applicant. Thus clarity and completeness of the R21/R33 application with regard to milestones and specific goals for each phase are critical. 1. FACE PAGE OF THE APPLICATION: Item 2. Check the box marked "YES" and type the NUMBER AND TITLE of this PAR. Also, indicate that the application is submitted as an R21/R33. Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT: For the R21 phase of the combined R21/R33 application, direct costs may not exceed $125,000 per year for up to two years and the award may not be used to supplement an ongoing project. The requested budgets may exceed this guideline to accommodate indirect costs of subcontracts to the project. Insert the direct costs requested for first year of support in item 7a and total first year costs in 7b. Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT: For the R21 phase, direct costs requested for the proposed period may not exceed $250,000 for two years of support. The requested budgets may exceed this guideline to accommodate indirect costs of subcontracts to the project. Insert the sum of all years of requested direct and total support in items 8a and 8b. 2. PAGE 2 - DESCRIPTION: Concisely state the problem addressed, the technology or methods to be developed, its innovative nature, its relationship to presently available capabilities, and its expected impact on cancer and other diseases. 3. BUDGET: The application should provide a DETAILED BUDGET for Initial Budget Period (form page 4) for each of the initial years of both the R21 and R33 phases, and on form page 5 present a budget for the entire proposed period of support. Form pages should indicate which years are R21 and R33. All budgets should include a justification for each line item and amount requested. 4. RESEARCH PLAN: Item a. Specific Aims: The application must present specific aims that are scientifically appropriate for the relevant phases of the project. The instructions for the PHS 398 application suggest that the investigators state hypotheses to be tested under Specific Aims. Since the goal of this PAR is to develop technologies or methods for in vivo imaging, problem solving (engineering) methods rather than hypothesis testing per se may be the driving force in developing such a proposal. Therefore, hypothesis testing may not be applicable. Preliminary data are not required for R21/R33 phased innovation applications. However, scientifically sound preliminary data should be included when available. Item b. Background and Significance: The application should describe the importance and innovative nature of the proposed research. Clarify how the technology or method development proposed in this project would be a significant contribution. Compare it with existing approaches. Explain its potential to impact cancer and other in vivo imaging research and/or clinical applications. Clearly identify how the project, if successful, would result in new capabilities, the immediacy of the opportunity, and how it would contribute beyond existing approaches. Item b. Background and Significance is an important feature of the R21 Phase 1 Research Plan. There may be little additional information to add to the R33 Phase 2 research plan; do not repeat information already presented for the R21 component. Item c. Preliminary studies/Progress report: The R21 phase should provide current thinking or evidence in the field to provide a rationale for feasibility of the R21 Phase aims. Preliminary data are not required for the R21 phase. However, provide relevant information to aid review, if available. The R33 Item c. should not repeat information already provided in the R21 Item c. Applicants are encouraged to include all information required for adequate review evaluation. If some of the intellectual property is not protected sufficiently to disclose key details, the application should present a demonstration (results) of the capabilities of the proposed approach. Item d. Research Design and Methods: Follow the instructions for the PHS 398 application. Add a final section labeled "Milestones" following the R21 Item d. The Milestones should provide well described objective performance targets, quantifiable if appropriate, with scientific justifications. They should not be simply a restatement of the specific aims. Discuss the milestones relative to judging the success of the R21 phase and their implications for R33 Phase 2 work, if successfully completed. List the page number for the Milestones section in the Table of Contents. Applications lacking this information, as determined by Program staff, may be returned to the applicant without review. Completion of the R21 aims and submission of a non-competing application for transition to R33 funding will elicit an expedited review by NCI program staff who will determine whether or not the R33 should be awarded. The release of R33 funds will depend on successful completion of the R21 Phase 1 project, as determined by the aims, reported progress, Milestones, program priorities, and availability of funds. Expedited review may result in additional negotiations of award. II. SPECIFIC INSTRUCTIONS FOR PREPARATION OF AN R33 APPLICATION WHEN SUBMITTED WITHOUT AN R21 PHASE: 1. FACE PAGE OF THE APPLICATION: Item 2. Check the box marked "YES" and type the TITLE AND NUMBER of this PA. Also, indicate that the application is submitted as an R33. 2. DESCRIPTION: Concisely state the problem addressed, the technology or methods to be developed, its innovative nature, its relationship to presently available capabilities, and its expected impact on cancer and other diseases. 3. BUDGET: The application should provide a DETAILED BUDGET for the Initial Budget Period (form page 4) as well as a budget for the entire proposed period of support (form page 5). The budget should include a justification for line items and amounts requested. If it will equal or exceed $500,000 direct costs per year, SEE SPECIFIC INSTRUCTIONS above FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR. 4. RESEARCH PLAN: Item a. Specific Aims: The application must present specific aims that are scientifically appropriate for the project. The instructions for the PHS 398 application suggest that the investigators state hypotheses to be tested under Specific Aims. Since the goal of this PAR is to develop technologies or methods for in vivo imaging, problem solving (engineering) methods rather than hypothesis testing per se may be the driving force in developing such a proposal. Therefore, hypothesis testing may not be applicable. Item b. Background and Significance: The application should describe the importance and innovative nature of the proposed research. Clarify how the technology or method development proposed in this project would be a significant contribution. Compare it with existing approaches. Explain its potential to impact cancer and other in vivo imaging research and/or clinical applications. Clearly identify how the project, if successful, would result in new capabilities, the immediacy of the opportunity, and how it would contribute beyond existing approaches. Item c. Preliminary studies/Progress Report: R33 applications should clearly state how feasibility for the project has already been demonstrated. This demonstration should include significant data. This section must document that progress achieved is essentially equivalent to that expected from an R21 Phase 1 grant. The application must clearly describe how the project is ready to progress to an expanded development stage. Item d. Research Design and Methods: Follow the PHS 398 application instructions. III. FOR ALL APPLICATIONS: o Appendix: All instructions in the PHS 398 application apply. o Copies of Prototype Imaging Systems: Budget support may be requested to make one or more copies of the prototype for placement in a collaborating facility or facilities for pre-clinical or clinical feasibility investigations, including harmonization across versions of a single platform or across multiple platforms to enable multi-center comparison studies. Provide justification in the budget justification section, and make written reference to this section of the PAR. o Technology and know-how transfer: Budget support may be requested to enable exchange of personnel between participating multi-site organizations to facilitate transfer of needed technology and know-how. Provide justification in the budget justification section, and make written reference to this section of the PAR. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to the Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 Bethesda MD 20892-7710 Bethesda MD 20817 (for express/courier service) To expedite the review process, at the time of submission send two additional copies of the application to the Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda MD 20892-8329 Rockville MD 20852 (for overnight/courier service) APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NOT BE ACCEPTED. This policy does not apply to courier deliveries, e.g., USPS, FEDEX, UPS, DHL, etc. See https://grants.nih.gov/grants/guide/notice- files/NOT-CA-02-002.html. This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review (CSR) as published in the NIH Guide Notice https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html APPLICATION PROCESSING: Applications must be received on or before the receipt dates listed on the first page of this program announcement. If an application is received after that date, it will be returned to the applicant without review. The CSR will not accept an application in response to this PAR that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude submission of a substantive revision of an application already reviewed, but such application must include an Introduction addressing the previous critiques. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NCI and NIBIB. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the PAR will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the NCI in accordance with the review criteria stated below. As part of the initial merit review, each application will o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Those that receive a priority score will undergo a second level review by the National Cancer Advisory Board and/or National Advisory Council for Biomedical Imaging and Bioengineering. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The goals of NCI include Discovery, Development, and Delivery of knowledge, methods, devices and systems to prevent, screen, diagnose, treat, and monitor the health progress of patients. NIBIB embraces similar goals. In their written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantive impact on the pursuit of these goals. o Significance o Approach o Innovation o Investigator o Environment o Milestones The scientific review group will comment on each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does the study address an important problem? What may be the anticipated benefits of the proposed activity? If the aims of the application are achieved, how will imaging technology, methods or knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the proposed plan include a sound approach to establishing technical feasibility. Does the applicant acknowledge potential problem areas and consider alternative strategies? Is a time frame described for developing and delivering the proposed technology and methods, and is it suitable to meeting the needs of the community? Are plans adequate for the proposed development, its integration as a useful, effective solution to the problem, and its implementation and dissemination for single or multi-site evaluation, if appropriate? INNOVATION: Does the project challenge existing paradigms or employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop and deliver new methodologies or technologies? What useful result can be expected from the proposed technology or methods development? INVESTIGATOR: Is the Principal Investigator capable of coordinating and managing the proposed technology or methods development? Are the researchers appropriately experienced, trained and otherwise well suited to perform this work? Is the work proposed appropriate to the backgrounds of the principal investigator and other researchers, including consultants and sub-contractors (if any)? ENVIRONMENT: Does the technical and scientific environment in which the work will be performed contribute to the probability of success? Do the proposed developments take advantage of unique features of the intellectual environment or employ useful collaborative arrangements? Is there sufficient access to resources to develop and deliver the proposed technology or methods, e.g., equipment, facilities, etc? MILESTONES: Are there objective performance targets (milestones) and other procedures proposed with which to evaluate successful completion of the Phase I project, including feasibility of the proposed development, which would be adequate to justify transition to funding for the Phase II development and delivery phase? Are there changes, additions or deletions that should be recommended to improve the milestones? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: For the R21/R33 Phased Innovation Award Application, the initial review group will evaluate the specific goals for each phase and the objective performance targets (Milestones) that would justify transition to R33 phase 2 funding. A single priority score will be assigned to each scored application. As with any grant application, the initial review group has the option of recommending support for a shorter duration than that requested by the applicant and basing the final merit rating on the recommended portion of the application. For the R21/R33 application, this may result in a recommendation that only the R21 phase be supported, based on concerns related to the application's specific goals and the Milestones justifying transition to phase 2 R33 funding. Deletion of the R33 phase by the review panel or presentation of inadequate milestones in the application may affect the merit rating of the application. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See additional information and Inclusion Criteria in the sections on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS: The following items may be considered by reviewers but will not be included in the determination of scientific merit. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Dates: June 23, 2003 and October 22, 2003. Application Receipt Dates: July 21, 2003 and November 19, 2003. National Advisory Board Review Dates: February, 2004 and June, 2004. Earliest Anticipated Award Date: April, 2004 and July, 2004. AWARD CRITERIA Applications submitted in response to a PAR will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. MONITORING PLAN and DATA AND SAFETY MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessing patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff to a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I and II Trials" for additional information: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data and safety monitoring plans for clinical trials funded by the NCI is available: http://www.cancer.gov/clinical_trials/ INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/ NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children, i.e., individuals under the age of 21 years, must be included in all human subjects research conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://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 https://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 https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Guidance for investigators and institutional review boards regarding research involving human embryonic stem cells, germ cells, and stem cell-derived test articles can be found at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-044.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law, i.e., a regulation, may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at https://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 https://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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