and Human Services (HHS)
EXPIRED
NON-INVASIVE IMAGING FOR DIABETIC RETINOPATHY RELEASE DATE: July 12, 2004 (see addendum NOT-EB-04-004) RFA Number: RFA-EY-04-001 EXPIRATION DATE: February 15, 2005 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Eye Institute (NEI) (http://www.nei.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.867 APPLICATION RECEIPT DATE: February 14, 2005 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria PURPOSE OF THIS RFA Diabetes is a prototypical chronic disease that imposes a large public health burden. One of its many complications is diabetic retinopathy (DR). Early detection of DR is an important problem because many Americans with diabetes do not get regular eye exams due mainly to distance, geography, and economic status. Studies conducted in the 1980’s and 1990’s demonstrated that vision loss from DR could be prevented if treatment with laser photocoagulation therapy was initiated based upon regular screening and subsequent diagnosis of retinal disease. In this Request for Applications (RFA) the NEI seeks to develop, apply, and evaluate noninvasive technology that is practical, affordable, and accessible so that patients with diabetes can benefit from remote site disease screening. RESEARCH OBJECTIVES Nature of the Research Problem Early detection is critical for the prevention and treatment of the blinding complications of retinopathy in persons with diabetes. Evidence suggests that the retina begins to malfunction very early in diabetes, and that the sooner treatment is initiated the greater the chance for medical benefit. Ophthalmologists started treating diabetic retinopathy with lasers in the 1960s in an attempt to seal leaking blood vessels and limit neovascular growth. While laser treatment is effective, unfortunately about half of diabetic patients do not receive this treatment because they do not have the recommended regular dilated eye examination. Currently, new retinal imaging technologies are being developed which have potential utility in remote-site clinics. If interfaced with the internet, these technologies could allow primary health care providers to identify patients with retinopathy. There are at least two barriers however to effective screening: the cost of the noninvasive instrument and the ease and simplicity of its use. Noninvasive technologies coupled with internet-based telemedicine communication platforms might facilitate remote expert clinical diagnosis and subsequent treatment recommendations, thus increasing access to medical care. Background Information Noninvasive assessment of retinal function in patents with diabetes has traditionally been done using fluorescein angiography, which is especially valuable in assessing advanced stages of retinal neovascularization. This procedure allows an ophthalmologist to determine the course of further treatment. Retinal fundus photography is another technique to assess retinal status so that the clinician can visualize the microvasculature features of DR. However, complete examination with fluorescein angiography and/or fundus photography requires the patient, the photographer, and the retinal specialist to be physically present in the clinic. Although this may be the best way to examine an individual, it may not be the best approach for mass screening for early detection of DR in diabetics. Newer noninvasive technologies are currently being developed. These include functional magnetic resonance imaging (fMRI), laser Doppler ultrasound, electron spin resonance spectroscopy (ESR), and fluorescence spectrometry. These technologies are expensive, and diagnostic improvements are only one aspect of the problem of how to deliver the benefits of early detection to the widest possible range of Americans with diabetes. The screening data needs to be interpreted, and treatment recommendations made. With the increased ability to digitize images and transfer data over the internet it is possible for a retinal specialist at a major medical center to diagnose disease with the patient at a remote location. This could allow screening of persons with diabetes by a qualified specialist, thus bringing the benefits of advanced surface feature and tissue imaging and high bandwidth Internet platforms to remote clinical settings. Scientific Knowledge to be Achieved Proliferative DR involves the formation of new blood vessels that develop from the retinal blood supply. Much recent research points to the involvement of several factors in the etiology of DR, and several biological therapies are either in or close to entering clinical trials. But no drug treatment for DR is currently available. While laser photocoagulation and vitrectomy for proliferative retinal disease have been shown to be effective by large-scale, randomized, controlled clinical trials, these treatments require clinical observation of overt retinopathy. Noninvasive techniques to enhance eye health care delivery at remote sites could add to the current knowledge base of clinical diagnosis and treatment and help increase our understanding of pathogenic mechanisms. As therapies are developed, these could be made available to a larger number of patients if individuals with the disease were effectively screened and then diagnosed by an expert eye care professional. Objectives The need to develop human biomedical imaging techniques has been identified at several recent workshops and conferences on diabetic complications. For example, a March 30-31, 1999, workshop entitled "Biomedical Imaging Symposium: Visualizing the Future of Biology and Medicine" which was coordinated by the NIH Bioengineering Consortium (BECON), and addressed three scientific areas: (1) imaging at the cellular and molecular levels for early detection of disease; (2) imaging for the clinical diagnosis, staging and recurrence of disease; and (3) imaging applied to therapeutic applications and monitoring for various disease processes. This symposium also emphasized the need to support fundamental methodological development of imaging techniques before disease-oriented and organ-specific applications are determined. A conference entitled JDRF-NASA Diabetic Retinopathy Research Workshop in 1999, sponsored in part by the NEI; the National Institute of Diabetes and Digestive and Kidney Diseases; and the National Institute of Neurological Disorders and Stroke, reviewed current technologies for assessing retinal function as well as new approaches to therapy. A 2001 workshop on Screening and Eye Exams for Diabetic Retinopathy addressed the need for screening and eye exams for retinopathy and the way new technologies and telemedicine could enhance patient access to eye exams. This RFA is designed to encourage submission of research grant applications that create, utilize, and evaluate noninvasive retinal imaging technologies that when joined with telemedicine provide retinopathy screening and eye exams at remote locations. At present only about 50% of all diabetic patients are involved in an appropriate eye care program. Telemedicine would allow eye imaging at the point of care, eliminating the need for a separate screening appointment. Images can be captured and transmitted to a central resource for accurate medical assessment with diagnostic information and recommendations transferred back to the provider at the point of contact. Telemedicine technology makes it possible to remove the barriers of distance, time, geography, and economics and bring services to the patients rather than the patients to the services. Telemedicine is currently being tested and utilized in a number of state programs, including the California Indian health program. Most current noninvasive technologies fall into several broad categories: retinal imaging, neurological function, and vascular function. For retinal imaging, current technologies include the Retinal Thickness Analyzer (RTA) which produces three-dimensional maps of the retina. A similar approach is used in optical coherence tomography (OCT) to obtain a high-resolution cross sectional map of the retina. Spectral imaging of the retina can reveal tissue composition using chemical and spectroscopic signatures. Spectroscopy can potentially map and/or classify clinical features such as perfusion, capillary dropout, hemorrhage, and retinal metabolism (by mapping cytochrome oxidative state). Although potentially limited by spatial resolution, fMRI has the potential to be clinically powerful in measuring blood flow and oxygen content. Sensitivity to inner retinal neuronal dysfunction is important for detection and study of early local changes in the retinas of diabetics and retinal neural circuitry can be assessed with the multifocal electroretinogram that tests the retina’s adaptive properties based on multifocal and geographically precise flashes. Certain aspects of vascular structure and function can be studied noninvasively by fundus photography but the currently available cameras are bulky and require pharmacological dilation of the pupil for optimal image quality. New advances in optical technology that could theoretically produce a sharper image include adaptive optics, ballistic imaging, and scanning laser ophthalmoscope. These advancements can benefit diabetic patients by improving the technology needed to assess the functional status of the retina. But they are currently expensive and have not been adapted for low cost use as screening technologies. To be useful the application of the technology needs clinical and technological validation before it can be adopted for clinic application. Project Organization The NEI anticipates that applications will likely require the involvement of engineers, physicists, computer specialists, and bio-scientists knowledgeable in interfacing technology with disease applications. MECHANISM OF SUPPORT This RFA will use the NIH Research Project (R01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is December 1, 2005. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE NEI intends to commit approximately $2M in FY 05 to fund 1 to 3 new grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs up to $500K per year. Although the financial plans of the NEI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: 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 Foreign institutions are not eligible to apply INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA 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: Peter A. Dudley, Ph.D. Director, Retinal Diseases Program Division of Extramural Research National Eye Institute Suite 1300 5635 Fishers Lane, MSC 9300 Bethesda, MD 20892 Telephone: (301) 451-2020 Email: [email protected] o Direct your questions about peer review issues to: Sam Rawlings, Ph.D. Chief, Scientific Review Branch Division of Extramural Research National Eye Institute Suite 1300 5635 Fishers Lane Bethesda, MD 20892 Telephone: (301) 451-2020 Email: [email protected] o Direct your questions about financial or grants management matters to: William Darby Grants Management Officer Division of Extramural Research National Eye Institute Suite 1300 5635 Fishers Lane Bethesda, MD 20892 Telephone: (301) 451-2020 Email: [email protected] SUBMITTING AN APPLICATION Applications must be prepared using the Public Health Service (PHS) 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected]. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf. 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) At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to: Sam Rawlings, Ph.D. Chief, Scientific Review Branch Division of Extramural Research National Eye Institute Suite 1300 5635 Fishers Lane Bethesda, MD 20892 Telephone: (301) 451-2020 Email: [email protected] APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NEI. Incomplete and/or nonresponsive applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NEI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: 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 Receive a written critique o Receive a second level review by the National Advisory Eye Council REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: 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 criteria included in the section 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. 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 REVIEW CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Application Receipt Date: February 14, 2005 Peer Review Date: June/July, 2005 Council Review: September, 2005 Earliest Anticipated Start Date: December 1, 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic 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 gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 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 Office of Management and Budget (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 (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. 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 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 RFA 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 DHHS issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants1.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 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. 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 the authorization of Sections 301 and 405 of the PHS 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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