NOVEL TECHNOLOGIES FOR IN VIVO IMAGING (SBIR/STTR) RELEASE DATE: May 19, 2003 PA NUMBER: PAR-03-125 (see replacement PA-04-094) EXPIRATION DATE: December 1, 2003, unless reissued. National Cancer Institute (NCI) (http://www.nci.nih.gov/) National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov/) National Institute for Biomedical Imaging and Bioengineering (NIBIB) (http://www.nibib.nih.gov/) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.394, 93.395, 93.396, 93.286, 93.287 LETTER OF INTENT RECEIPT DATES: June 23, 2003 and October 22, 2003. APPLICATION RECEIPT DATES: July 21, 2003 and November 19, 2003. This Program Announcement (PAR) replaces PAR-01-102, 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 Project Period and Amount of Award 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 Receipt and Review Schedule o Award Criteria o Required Federal Citations NOTICE: This program announcement (PAR) must be read in conjunction with the current OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH, CENTERS FOR DISEASE CONTROL AND PREVENTION, AND FOOD AND DRUG ADMINISTRATION FOR SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS. The solicitation (see http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf) contains information about the SBIR and STTR programs, regulations governing the programs, and instructional information for submission. All of the instructions within the current SBIR/STTR Omnibus Solicitation apply, with exceptions: o Special Receipt Dates o Initial review convened by the NCI Division of Extramural Activities o Special time and budget limitations o Additional review considerations PURPOSE OF THE PAR The National Cancer Institute (NCI), the National Institute of Environmental Health Sciences (NIEHS), the National Institute for Biomedical Imaging and Bioengineering (NIBIB) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 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. The interests of NIEHS focus on detection, screening or diagnosis of tissue and organ toxicity related to exposures to environmental agents. These include initiation of toxicity or exacerbation of disease or dysfunction resulting from toxic exposure, treatment and recovery. NIDDK interests focus on diabetes, digestive, and kidney diseases. 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 multi-modality 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 investigators in device and drug industries are encouraged to more rapidly translate and deliver completed imaging system developments. This solicitation utilizes the Small Business Innovation Research (SBIR R43 and R44) and Small Business Technology Transfer (STTR R41 and R42) mechanisms, and runs in parallel with a program announcement of identical scope (PAR-03- 124) that utilizes the Phased Innovation Award (R21/33) mechanism for exploratory/developmental studies and which is open to a broad range of organizations. Fast Track applications are strongly encouraged in this solicitation because they benefit from expedited evaluation of progress following the Phase I exploratory/feasibility study for immediate decision on transition to Phase II funding for expanded developmental work. Applications are subject to cost and duration guidelines that are expanded over those stated in the OMNIBUS SOLICITATION of the National Institutes of Health, Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Grant Applications (PHS 2003-2). RESEARCH OBJECTIVES The overarching Research Objectives of this PAR are to stimulate discovery, 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 missions of the NCI, NIEHS, NIBIB, and NIDDK. 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 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 the image-based surrogate outcome metrics of the kind 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, including data sharing and validation studies necessary to meet Federal regulatory requirements. Thus the aims of this initiative and the support mechanism (SBIR/STTR, especially Fast Track applications) are also directed at encouraging the discovery, development and delivery of imaging "tools" 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 not responsive to this PAR. Studies with pre-clinical models and clinical studies to demonstrate the feasibility of developments are encouraged, including multi-site evaluations, where appropriate. Methods that establish "ground truth" are required at appropriate levels of resolution to validate these emerging imaging methods, e.g., imaging excised tissue using protocols similar to those used in vivo, or correlation of molecular imaging results with micro-array library analyses. Developments of molecular probes or targeted contrast agents are considered important approaches to detection of molecular changes in vivo to take better advantage of many technologies with potential for molecular imaging. The following topics would make appropriate proposed projects. This list is not meant to be all-inclusive. o Early Disease Detection: Developments may address innovative high- resolution imaging methods, with a particular intent to identify and characterize abnormalities or other early changes, including molecular events on the path to disease. Novel solutions for in vivo microscopic imaging systems, or microscopic implanted devices with high spatial and/or temporal resolution, which may use either intrinsic or exogenous contrast agents represent possible topics. o Disease Screening: These methods may include, but are not limited to development and optimization of efficient imaging systems for screening, with the intent of achieving improved sensitivity and specificity for disease detection. Applications could address innovative improvements to current imaging methods, including hardware and/or software upgrades, or emerging imaging sensors and methods. Research topics of interest include a means to significantly reduce imaging time or effects of motion, use of novel contrast agents or imaging probes, and use of technologies that reduce or do not involve ionizing radiation, or use of novel contrast agents and imaging probes. System integration and software methods could include a variety of image processing and data reduction techniques including temporal analysis of serial studies, close to real-time image processing, novel image display methods, and related imaging informatics for more cost-effective solutions for screening. o Imaging for Diagnosis, Staging, or Monitoring the Effects of Therapy: This initiative encourages, but is not limited to the development of novel imaging methods such as functional or molecular imaging or spectroscopy methods that would significantly improve the specificity of diagnosis of cancer and other diseases, allow deterministic methods or patient-specific staging, or measure early effects of therapy. Examples of system integration would include multi- modality imaging, image fusion or registration of the different modalities employed, development of software methods that would estimate the probability of malignancy or other specific disease identification, quantitative information for monitoring the effects of therapy, and close to real-time image analysis. o Image Guided Biopsy (IGB), Therapy (IGT), and Interventional (IGI) Procedures: This initiative encourages novel approaches using imaging technologies needed to significantly improve specificity, to identify lesion extent and microscopic involvement, and to minimize tissue damage accompanying biopsy and therapy. Of particular interest are innovative approaches to IGB, IGT or interventional methods that include novel imaging systems that provide molecular target information or information at the cellular or molecular level sufficient for image guidance and treatment. Examples of system integration that are of interest include, but are not limited to multi-modality imaging, navigational systems, registration methods, real-time feedback mechanisms for controlling therapy (including radiation therapy) or the use of methods that are adaptive or allow patient-specific optimization of treatment and computer- assisted surgery. o Copies of Prototype Imaging Systems: Support may be requested to make one or more copies of the prototype for placement in collaborating facilities for pre-clinical or clinical feasibility investigations, including harmonization across versions of a single platform or across multiple platforms to enable multi-center comparison studies. Collaboration with NCI funded centers may be possible, such as the NCI Network for Translational Research in Optical Imaging, http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-03-002.html, or the Lung Image Database Consortium, http://www3.cancer.gov/bip/steercom.htm. Investigators anticipating need for funds to build system copies, harmonization of imaging methods or collaboration with NCI funded centers are advised to contact program staff. o Research Resources: The development of research resources that facilitate a consensus process for optimization and validation of emerging imaging technologies is encouraged. Examples include the development of open source software, image processing software and related informatics that can be ported onto different platforms, methods and image databases required for validation of software performance, and other hardware or informatics methods that assist in more efficient delivery of imaging technologies for screening, diagnosis and treatment for cancer and other diseases. Investigators interested in development of research resources and related research are advised to contact program staff. MECHANISMS OF SUPPORT This PAR uses the R43 and R44 SBIR and R41 and R42 STTR mechanisms funded by Small Business set-aside funds. Applicants are solely responsible for planning, directing, and executing the proposed project. Current and future unsolicited, competing-continuation applications based on this project will compete with all SBIR/STTR applications for funds, and if not submitted to a re-issuance of this (or similar) PAR, will be reviewed according to established peer review procedures. This PAR uses just-in-time concepts described in the current SBIR/STTR Omnibus Solicitation. It does not use the modular budgeting format. Full budget presentations and justifications are required. Follow the instructions for non-modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_I_1.htm. Except as otherwise stated in this PAR, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, March 2001, available at: http://grants.nih.gov/grants/policy/nihgps_2001/part_I_1.htm. Applications may be submitted for Phase I STTR (R41) or Phase I SBIR (R43) grant support; Phase II STTR (R42) or Phase II SBIR (R44) grant support; or as a pair of Phase I and II applications under the SBIR/STTR FAST TRACK option described in the Omnibus Solicitation. Phase II applications in response to this PAR will be accepted only as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The Phase II application must be a logical extension of the Phase I research, but the Phase I project does not need to have been supported in response to this PAR. Fast track applications will benefit from expedited evaluation of progress following Phase I feasibility work for faster transition to Phase II funding for development work, with minimal or no funding gap between the Phase I and Phase II work. This PAR has features intended to enhance success rates for Fast Track applications. PROJECT PERIOD AND AMOUNT OF AWARD: The SBIR/STTR Omnibus Solicitation describes statutory guidelines on levels of funding support and periods of project duration for SBIR and STTR Phase I and Phase II awards. Guidelines for this PAR are up to $100,000 total costs per Phase I year and time periods up to two years. Phase II applications submitted to this PAR have no budget limitations and may request up to four years of support. For a Phase I-Phase II pair of Fast Track applications the total duration of support cannot exceed five years. NCI grantees who have successfully completed their Phase II aims may submit a competitive renewal of their Phase II project requesting support up to an additional three years for research activities that must include steps necessary to meet Federal regulatory requirements, e.g., good practice requirements, validation, early stage clinical safety, efficacy and feasibility studies, pre-marketing approval (PMA), investigational device exception (IDE), etc. All Phase II provisions stated in this PAR apply to a competing continuation application. ELIGIBLE INSTITUTIONS Eligibility requirements are described in the SBIR/STTR Omnibus Solicitation. Only small businesses are eligible to submit applications. A small business is one that meets ALL of the criteria described in the SBIR/STTR Omnibus Solicitation on the date of award for both Phase I and Phase II grants. There is a parallel NCI program announcement for institutions ineligible for small business grants that is being reissued concurrently as PAR-03-124 (see http://grants.nih.gov/grants/guide/pa-files/PAR-03-124.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 his or her 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. The SBIR Principal Investigator must have primary employment (more than 50%) with the small business at the time of award and for the duration of the project. The STTR Principal Investigator may be employed with the small business or the participating non-profit research institute so long as she or he has a formal appointment with or commitment to the applicant small business and which is characterized by an official relationship between the small business and the Principal Investigator. SPECIAL REQUIREMENTS o The Research Plan of R41 and R43 FAST-TRACK applications must conclude with a section on Objective Performance Targets (Milestones), quantitative if appropriate, to serve as one approach to judging the success of Phase I work after completion. Milestones are recommended for other Phase I applications, but not required. 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. WHERE TO SEND INQUIRIES We encourage inquiries concerning this PAR and welcome the opportunity to 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 NIEHS Jerrold (Jerry) J. Heindel, Ph.D. Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 (for express/courier service: 79 T.W. Alexander Drive, 4401 Research Commons, 3rd Floor) Research Triangle Park, NC 27709 Telephone: 919-541-0781 FAX: 919-541-5064 Email: heindelj@niehs.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 For NIDDK Judith Podskalny, Ph.D. Program Director for Training and Career Development, Digestive Diseases Centers, and SBIR/STTR National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/DDDN) 6707 Democracy Blvd, Suite 667 Bethesda MD 20892-5450 Telephone: 301-594-8876 Fax: 301-480-8300 E-mail: jp53s@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, email 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 provides allows NCI staff to estimate the potential review workload and plan the review. Send the letter of intent 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 All SBIR/STTR Phase I, Phase II, and Fast-Track applications must be prepared using the PHS 398 research grant application instructions and forms, available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Prepare your application in accordance with instructions in the PHS 398, instructions in the SBIR/STTR Omnibus Solicitation, and instructions in this PAR for a new or revised SBIR or STTR Phase I or Phase II application, or pair of Fast-Track applications. Helpful information for advice and preparation of the application is available at: http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf. The NIH will return applications that are not submitted using the 5/2001 version of PHS 398 grant application forms. For further assistance contact GrantsInfo, Telephone 301 435 0714, email GrantsInfo@nih.gov. The title and number of this PAR must be typed on line 2 of the face page of the application and the YES box must be marked. 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 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 applications to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda MD 20892-8329 Rockville MD 20852 (for express/courier service) APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e., FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice- files/NOT-CA-02-002.html). This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. RECEIPT OF APPLICATIONS: Applications must be received on or before the receipt dates listed at the top of the first page of this PAR. If an application is received after that date, it will be retuned to applicant without review. The Center for Scientific Review (CSR) will not accept any 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 the submission of a substantive revision of an application already reviewed, but such application must include an Introduction that addresses the previous critiques. Although there is no immediate acknowledgement of the receipt of an application, applicants are usually notified of the review and funding assignments within 8 weeks. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by CSR staff and responsiveness by NCI or another participating Institute. Incomplete applications and applications not adhering to instructions described above may be returned to the applicant without further consideration. If a complete application is not responsive to the PAR, NCI staff may contact the applicant to determine if the application should be returned un-reviewed or submitted for review in competition with unsolicited applications at the earliest appropriate NIH review cycle. Applications that are complete and responsive to this 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 peer review criteria listed below. As part of the initial merit review, all applications will o Receive a written critique; o Undergo a process in which 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 Receive second level review by appropriate National Advisory Boards or Councils of the NCI, NIEHS, NIBIB, and/or NIDDK. 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. NIEHS, NIBIB and NIDDK embrace similar goals. In their written comments, reviewers will be asked to discuss the following criteria in evaluating the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. o Significance o Approach o Innovation o Investigators o Environment The scientific review group will consider 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 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? Does the proposed project have commercial potential to lead to a marketable product or process? What may be the anticipated commercial and/or societal benefits of the proposed activity? If the aims of the application are achieved, how will imaging technology, methods or knowledge be advanced? Does the proposal lead to enabling technologies (instrumentation, software, etc.) for further discoveries? Will the technology have a competitive advantage over existing alternative technologies that can meet market needs? APPROACH: Are the conceptual framework, design, methods, and scientific and engineering analyses adequately developed, well-integrated, and appropriate to the aims of the project? Is the proposed plan a sound approach to establishing technical and commercial 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 multi- site evaluation? INNOVATION: Does the project challenge existing paradigms or employ novel technologies, approaches or methodologies? Are the aims original and innovative? What useful purpose can be expected of the proposed technology or methods developments? INVESTIGATORS: Is the Principal Investigator capable of coordinating and managing the proposed SBIR/STTR technology development? Are the researchers appropriately experienced, trained, or 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)? Are the relationships of the key personnel to the small business and to other institutions appropriate for the work proposed? 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, e.g., equipment, facilities, etc? 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: 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). Human Subjects: 1. Protection of Human Subjects from Research Risks-for all studies involving human subjects. See instructions and "Guidance for Preparing the Human Subjects Research Section." If an exemption is claimed, is it appropriate for the work proposed? If no exemption is claimed, does the application provide appropriate responses to the six required points? Are human subjects placed at risk by the proposed study? Are the risks reasonable in relation to the anticipated benefits to the subjects and others? Are the risks reasonable in relation to the importance of the knowledge that reasonably may be expected to be gained? Are adequate plans proposed for the protection of human subjects? 2. Inclusion of Women Plan-for clinical research only. Does the application include a plan for inclusion of both genders that will provide appropriate representation? Does it include appropriate justification when representation is limited or absent? Does the application include appropriate and acceptable plans for recruitment, outreach and retention of study participants? 3. Inclusion of Minorities Plan-for clinical research only. Does the application include a plan for inclusion of minorities that will provide their appropriate representation? Does it include appropriate justification when representation is limited or absent? Does the application include appropriate and acceptable plans for recruitment, outreach and retention of study participants? 4. Inclusion of Children Plan-for all studies involving human subjects. Does the application include a plan in which the representation of children of all ages (under the age of 21) is scientifically appropriate and which realistically addresses recruitment and retention? If not, does the applicant provide an appropriate justification for their exclusion? 5. Data and Safety Monitoring Plan-for clinical trials only. Does the application describe a Data and Safety Monitoring Plan that defines the general structure of the monitoring entity and mechanisms for reporting Adverse Events to the NIH and the IRB? CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the required five items described under Vertebrate Animals (section f. of the Research Plan instructions) will be assessed. If vertebrate animals are involved, are adequate plans proposed for their care and use? Are the application's responses to the five required points appropriate? Will the procedures be limited to those that are unavoidable in the conduct of scientifically sound research? BIOHAZARDS: Is the use of materials or procedures that are potentially hazardous to research personnel and/or the environment proposed? Is the proposed protection adequate? 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 may be considered. For all applications, is the percent effort listed for the PI appropriate for the work proposed? On applications requesting up to $100,000 total costs, is the overall budget realistic and justified in terms of the aims and methods proposed? On applications requesting over $100,000 in total costs, is each budget category realistic and justified in terms of the aims and methods? Is the requested period of support appropriate in relation to the proposed research? PHASE II APPLICATION REVIEW CRITERIA: In addition to the above criteria, apply the following: 1. How well does the application demonstrate progress toward meeting the Phase I objectives, demonstrate feasibility and provide a solid foundation for the proposed Phase II work? Is there a detailed plan to validate the development? 2. Does the application provide a concise Commercialization Plan [formerly Product Development Plan] that adequately addresses the seven areas described in the Research Plan item J? 3. Does the project have appropriate commercial potential, as described in the Commercialization Plan? 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? AMENDED APPLICATIONS In addition to the above criteria, the following apply to revised applications: 1. Are adequate responses provided to points raised in the Summary Statement of the prior review? 2. Are amendments in the revised applications appropriate? PHASE I/PHASE II FAST TRACK REVIEW CRITERIA For Phase I/Phase II Fast Track applications, the following additional criteria will be applied: 1. Does the Phase I application specify appropriate, clear, objective performance targets (milestones)--quantitative if appropriate, that are suitable for judging investigator performance and success in meeting Phase I objectives? If the milestones were to be met, would Phase I work have demonstrated feasibility and provided a solid foundation for the proposed Phase II work? Are there changes, additions or deletions that should be recommended to improve the milestones? Does the Phase II application provide a detailed plan to validate the development? 2. Does the Phase II application provide a concise Commercialization Plan [formerly Product Development Plan] that adequately addresses the seven areas described in the Research Plan item J? 3. Does the Phase II application include letters of interest, additional funding commitments and/or resources from private sector or non-SBIR/STTR funding sources that would enhance the likelihood for commercialization? 4. Does the project have appropriate commercial potential, as described in the Commercialization Plan? TYPE 2 PHASE II COMPETING CONTINUATION APPLICATION REVIEW CRITERIA In addition to the above criteria, the following items will be applied to ALL Type 2 Competing Continuation Phase II Applications in the determination of scientific merit and the priority score: o Does the proposed activity address issues related to Federal regulatory approval processes? o How well does the application demonstrate progress toward meeting the Phase II objectives and provide a solid foundation for the proposed Phase II competitive continuation work? o What will be the effect of these studies on the concepts, systems or methods that drive this field? The initial review group will evaluate the specific goals for both Phase I and II Fast Track applications, and the objective Phase I performance targets (milestones) that would help justify continuing work into Phase II. A single priority score will be assigned to the pair of Fast Track applications. The initial review group has the option of recommending changes in milestones, requested support and time, and base the final merit rating on the recommended portion of the application. This may result in a recommendation that only Phase I (R41 or R43) of a Fast Track application be supported. 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 this PAR will compete with all other recommended SBIR and STTR applications for available Small Business set aside funds. 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 Phase II Fast Track 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), and the availability of funds. 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 that involve 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 and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the Principal Investigator/Project Manager or Institute Program staff to a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional Review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the Data and Safety Monitoring Plan as part of the research application. See NIH Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I and II Trials" for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data and safety monitoring plans for clinical trials funded by the NCI is available at http://www.cancer.gov/clinical_trials/. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children, i.e., individuals under the age of 21, must be included in all human subjects research conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research is available online at: http://cme.nci.nih.gov/. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/guide/notice- files//NOT-OD-02-005.html. Guidance for investigators and institutional review boards regarding research involving human embryonic stem cells, germ cells, and stem cell-derived test articles can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-044.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law, i.e., a regulation, may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PAR in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PAR 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 under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. 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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