PROTEOMIC AND METABOLOMIC APPROACHES TO DIAGNOSE DIABETES AND PRE-DIABETES RELEASE DATE: March 18, 2004 PA NUMBER: PAR-04-076 (see addendum NOT-DK-04-008) Department of Health and Human Services (DHHS) EXPIRATION DATE: July 21, 2004 PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.847 LETTER OF INTENT RECEIPT DATE: June 18, 2004 APPLICATION RECEIPT DATE: July 20, 2004 THIS PAR CONTAINS THE FOLLOWING INFORMATION o Purpose of this PAR o Research Objectives o Mechanism(s) of Support o Funds Available 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 Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS PAR Over 5 million adults in the U.S. have undiagnosed type 2 diabetes, and another 38 million with pre-diabetes are at increased risk for developing diabetes. The lack of a simple and reliable way to detect diabetes and pre- diabetes has hindered identification of these individuals and provision of effective therapies. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) encourages the application of proteomic and other novel technology to develop new diagnostic tests and/or to identify new biomarkers for the diagnosis of pre-diabetes and/or diabetes that do not require fasting or glucose administration. RESEARCH BACKGROUND AND OBJECTIVES Diabetes is a metabolic disease characterized by hyperglycemia that in 2002 affected nearly 9% of U.S. adults. Over 90% of the people with diabetes have type 2 diabetes. The symptoms of type 2 diabetes develop gradually. Some people have no symptoms until after they develop complications, which could have been prevented or delayed with early diagnosis and effective treatment. Additionally, 38 million U.S. adults aged 40-74 have pre-diabetes. Pre- diabetes is defined as impaired fasting glucose or impaired glucose tolerance (http://www.diabetes.org/diabetes-prevention/pre-diabetes.jsp). These individuals have glucose levels above normal but below the level needed for diagnosis of diabetes. They are at increased risk of cardiovascular disease compared to those with normal glucose tolerance and at substantial risk for developing diabetes. Clinical trials have demonstrated effective interventions for preventing or delaying complications in those with diabetes and for preventing or delaying onset of diabetes in those with pre-diabetes. However, millions of Americans are not receiving effective therapy, in part due to the limitations of current methods of diagnosing diabetes and pre-diabetes. The oral glucose tolerance test (OGTT), the gold standard for diagnosis of diabetes and pre- diabetes is inconvenient requires fasting and is not highly reproducible. The fasting blood glucose (FBG) is less burdensome but much less sensitive, particularly in older Americans who have the highest prevalence of diabetes and pre-diabetes. The quantitation of Hemoglobin A1c (a glycated form of hemoglobin) from blood has been widely used as test for assessing the adequacy of glycemic control and risk of complications in diabetic patients, but this test is not sufficiently sensitive to detect the range of glucose values typically seen in pre-diabetes or new onset type 2 diabetes. Furthermore, there are many variants of hemoglobin present in blood, particularly in minority populations disproportionately affected by diabetes, and this adds additional uncertainty to the use of this test. A simplified, less burdensome approach to the diagnosis of diabetes and pre- diabetes would facilitate increased recognition and improved care of these conditions. Many proteins and other blood components may be modified in individuals with elevated blood glucose. Identification of these molecules or of identifiable correlates of hyperglycemia would facilitate development of potential new laboratory tests for diagnosis of diabetes and pre-diabetes. With this initiative we are encouraging scientists with expertise in proteomics and metabolomics to develop new tests to detect pre-diabetes and diabetes that correlate with the results of the OGTT but do not require fasting or administration of glucose. Proteomic and metabolomic approaches have been successfully used for studying complex biological problems and for the identification of disease markers. Recent developments indicate that these technologies could be used or appropriately modified for developing new methods to diagnose diabetes and pre-diabetes. For example mass spectrometry has been successfully used for the identification and quantitation of large number of proteins from plasma. Similar studies were performed for quantifying large number of metabolites. In some cases fractionation prior to the mass spectrometric analysis was shown to be very effective for increasing the number of proteins and metabolites that could be identified and perhaps further development in fractionation methodologies could be the key for the identification of novel biomarkers. The use of isotopically labeled reagents recently made many proteomic methodologies usable for quantitative studies and further development of these reagents might also lead to a more comprehensive analysis of the sera proteome and possible identification of novel biomarkers. This initiative solicits the application of proteomic and metabolomic technologies for the development of novel methodologies and/or identification of new biomarkers for the diagnosis of pre-diabetes and of type 2 diabetes that do not require fasting or glucose administration. To facilitate this effort, plasma from well-characterized individuals of diverse racial and ethnic backgrounds with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes will be made available to investigators for validation of potential new diagnostic tests. The novel diagnostic test could ultimately be used in place of the OGTT, if adequately validated, or for the identification of high-risk individuals who should undergo testing for diabetes and pre-diabetes using a more functional assay such as the OGTT. Focused deployment of the OGTT in appropriately selected individuals would reduce costs, limit burden, and improve the yield of diagnostic testing for diabetes and pre-diabetes. The NIDDK will make available citrated plasma and blood cell samples from individuals with normal glucose tolerance, impaired glucose tolerance and newly diagnosed type 2 diabetes for use in the R21 and for the R33 phases to all awardees. Applicants should specify how these samples will be used to identify and validate new biomarkers that can distinguish among these conditions. The NIDDK will provide the following samples to all awardees of the R21 phase: o 1ml (4X250 l) of sera from 10 patients with normal glucose tolerance (NGT) o 1ml (4X250 l) of sera from 10 patients with impaired glucose tolerance (IGT) o 1ml (4X250 l) of sera from 10 patients with newly diagnosed type 2 diabetes o The corresponding blood cell pellet from each NGT, IGT and diabetic patient will also be provided. The cell pellet for each patient will not be divided in four aliquots as for the plasma but will be provided in a single vial. The above conditions are diagnosed using the oral glucose tolerance test (OGTT). Briefly, after a fast of 8 to 12 hours, a person’s blood glucose is measured before and 2 hours after drinking a glucose-containing solution. Determination of NGT is made when glucose rises to no higher than 140 mg/dl 2 hours after the drink. IGT is diagnosed when the glucose level is between 140 and 199 mg/dl 2 hours after the drink. Diabetes is diagnosed if blood glucose rises to 200 mg/dl or above. For clinical diagnosis of diabetes this measurement must be confirmed on a subsequent measurement. A similar set of samples but from a larger population will be provided for the R33 phase at the time of the award for this phase. We expect to be able to provide plasma and blood cell samples from approximately 200 patients with IGT, 200 patients with NGT and 50 diabetic patients. To be considered for the transition to the R33 phase the applicant must show that he/she has identified differences between the pre-diabetes, diabetes, and normal patient samples provided by NIDDK for the R21 phase (i.e. have identified at least one potential biomarker for pre-diabetes and/or diabetes). These differences should be determined in a reproducible (analysis in triplicate) and quantitative way and with a throughput that shows promise for translation to a clinical setting. In addition the investigator can include in the proposal the use of samples from other clinical studies for optimizing or further validating the methodology. For the purpose of assessing research progresses and facilitating interaction between the 4-5 funded principal investigators a workshop will be held in May/June 2006 in Bethesda, MD. All funded principal investigators are required to attend and collaborators are encouraged to participate. Funds for attending this meeting should be included in the budget proposal. MECHANISMS OF SUPPORT This special emphasis PAR will use the NIH Exploratory/Development Research Grant (R21) combined with the Exploratory/Development Research Grant Phase 2 (R33). The R33 is an NIH grant mechanism that provides a second phase for the support of innovative exploratory and development research initiated under the R21 mechanism. The transition of the R21 to the R33 phase will be expedited and is dependent on completion of negotiated milestones. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This PAR is a one-time solicitation. Future unsolicited, competing- continuation applications based on this project will have to be submitted using a standard RO1 or R21 mechanism, will compete with all investigator- initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is April 1, 2005. Applications that are not funded in the competition described in this PAR may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This PAR uses just-in-time concepts. It also uses the modular 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 format. Otherwise 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://odoerdb2.od.nih.gov/gmac/nihgps_2003/index.htm. Specific features of this Phased Innovation Award (R21/33) Program Announcement include: o The total project period for an application in response to this PAR may not exceed 2 years for the R21 phase and 3 years for the R33 phase. o Single submission and evaluation of both a feasibility/pilot phase (R21) and an expanded development phase (R33) as one application. o Expedited transition of the R21 feasibility phase to an R33 development phase. However, the award of the R33 funds will be based on program priorities, the availability of funds and the successful completion of negotiated scientific milestones as determined by program staff in the context of peer review recommendations o Responsibility for the planning, direction and execution of the proposed research project will be solely that of the applicant. Except as otherwise stated in this PAR, awards will be administered under the NIH grants policy as stated in the NIH Grants Policy Statement, December 2003, available from the internet only at http://odoerdb2.od.nih.gov/gmac/nihgps_2003/index.htm. o The Phased Innovation Award must have a section labeled Milestones at the end of the Research Plan of the R21 application. This section must include well-defined quantifiable milestones for the completion of the R21 portion of the application, a discussion of the suitability of the proposed milestones for assessing the success in the R21 phase, and a discussion of the implications of successful completion of the milestones for the proposed R33 study. FUNDS AVAILABLE The NIDDK intends to commit approximately $1 million in direct cost for FY 2005 to fund 4 to 5 new grants in response to this PAR. An applicant may request a project period of 2 years for the R21 phase and 3 years for the R33 phase. The R21 phase may not exceed $250,000 direct costs per year. The R21 budgets can exceed this cap to accommodate F&A costs to subcontracts to the project, in which case a non-modular budget format must be used. The R33 application has a budgetary limit of $500,000 direct costs for each year. This limit cannot be exceeded to accommodate F&A to subcontracts. Awards pursuant to this PAR 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 Domestic or foreign institutions/organizations 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 Applicants from institutions, which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources, may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. 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: Salvatore Sechi, Ph.D. Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd. Rm. 611 Bethesda, MD 20892-5460 Telephone: (301) 594-8814 FAX: (301) 480-2688 E-mail: ss24q@nih.gov o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 752 Bethesda, MD 20892-5452 Telephone: (301) 594-8897 FAX: (301) 480-3505 E-mail: fc15y@nih.gov o Direct your questions about financial or grants management matters to: Ms. Kathleen Shino Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Rm.708 Bethesda, MD 20892-5460 Telephone: (301) 594-8869 FAX: (301) 594-9523 E-mail: ks48e@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 IC 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: Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 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: GrantsInfo@nih.gov. The title and number of this program announcement must be typed on line 2 of the face page of the application form and the YES box must be checked. SUPPLEMENTARY INSTRUCTIONS: I. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD APPLICATION: The R21/R33 application must include the specific aims for each phase and clear measurable goals (milestones) that would demonstrate feasibility and justify transition to the R33 phase. Applications must include a specific section labeled Milestones following the Research Plan of the R21 phase. Milestones should be well described, quantifiable and scientifically justified and not simply a restatement of the specific aims. A discussion of the milestones relative to the progress of the R21 phase, as well as, the implications of successful completion of the milestones for the R33 phase should be included. The Milestones section should be indicated in the Table of Contents. Applications lacking this information, as determined by the NIH program staff, will be returned to the applicant without review. For funded applications, completion of the R21 milestones will elicit an NIH expedited review that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on successful completion of negotiated scientific milestones, program priorities, and on the availability of funds. The expedited review may result in additional negotiations of award. The R21/R33 combined applications must be submitted as a single application, with one face page. Although it is submitted as a single application, it should be clearly organized into two phases. To accomplish a clear distinction between the two phases, applicants are directed to complete Sections a-d of the Research Plan twice. One write-up of Sections a-d and milestones for the R21 phase and sections a-d again for the R33 phase. The Form 398 Table of Contents should be modified to show sections a-d for each phase as well as the milestones. There is a page limit of 25 pages for the composite a-d text of all applications (i.e., section a-d and milestones for the R21 phase plus sections a-d for the R33 phase must be contained within the 25 page limit for R21/R33 applications.) In preparing the R21/R33 application, investigators should consider the fact that applications will be assigned a single priority score. For this reason, the clarity and completeness of the application with regard to specific goals and feasibility milestones for each phase are critical. The presentation of milestones that are not sufficiently scientifically rigorous to be valid for assessing progress in the R21 phase will reflect upon the scientific judgment of the applicant in this application. Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT. For the R21 phase of the combined R21/R33 application, direct costs are limited to a maximum of $250,000 per year for a maximum of two years and the award may not be used to supplement an ongoing project. The non-modular budget format must be used for the combined R21/R33 application. The requested budgets can exceed this cap to accommodate for F&A costs to subcontracts to the project only for the R21 phase. Insert the first year of R21 support in item 7a. Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT. Insert sum of all years of requested support in item 8a.The statement in item 7a above pertaining to subcontract costs also applies here. 2. Page 2 - Description: As part of the description, identify concisely the research team, the fundamental research to be performed or the technology/tool to be developed, its innovative nature, its relationship to presently available knowledge or capabilities, and its expected impact on the diagnosis, treatment or prevention of type 2 diabetes or its complications. 3. Budget: The application should provide a DETAILED BUDGET for Initial Budget Period (form page 4), for each of the initial years of the R21 and R33 phases as well as a budget for the entire proposed period of support (form page 5). Form pages should indicate which years are R21 and R33. All budgets should include a justification for each item requested. Funds for attending a meeting in May/June 2006 in Bethesda, MD should be included in the budget proposal. 4. Research Plan: Item a, Specific Aims: The applicants must present specific aims that the applicant considers to be scientifically appropriate for the relevant phases of the project. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Furthermore for the R21 phase, preliminary data are not required, although they should be included when available. The applicant must include a plan for analyzing the samples provided by NIDDK for the R21 and for the R33 phase (see research background and objectives section at the beginning of this PAR). The applicant might also include a plan for the analysis of additional samples from other patients but a plan for analyzing the samples provided by NIDDK is the minimum requirement. Similarly, one of the milestones must be the identification of a potential biomarker for pre-diabetes and/or diabetes using the samples provided by NIDDK. The investigator can include additional milestones. For examples, additional milestones could be related to methodology developments or to the analysis of samples from other patients. Item b, Background and Significance: Elaborate on the innovative nature of the proposed research. Clarify how the fundamental research or tools/technologies to be developed as proposed in this project will result in a significant improvement over existing approaches. Explain the potential of the proposed studies for having a broad impact on a compelling area of type 2 diabetes research. Clearly identify how the project, if successful, would result in new capabilities for the treatment and prevention of type 2 diabetes and its complications. Item c, Preliminary Studies/Progress Report: While preliminary data are not required for the submission of the R21 phase, this section should provide current thinking or evidence in the field to substantiate the feasibility of the R33 phase. While preliminary data are not required for submission of the R21 phase, easily understandable data that provide relevant information to aid the review should be included when available. The R33 phase need not repeat information already provided in the R21 phase. Item d, Research Design and Methods: Follow the instructions in the PHS 398 booklet. In addition a specific section labeled Milestones must follow the Research Design and Methods section of the R21 phase. Milestones should be well described, quantifiable, and scientifically justified and not be simply a restatement of the specific aims. The milestones should not be a reiteration of the Specific Aims of the research project, but should be tangible accomplishments. A discussion of the milestones relative to the success of the R21 phase, as well as the implications of successful completion of the milestones for the R33 phase and the page number of the milestones section should be listed. This section should be indicated in the Table of Contents. For funded applications, completion of the R21 milestones will elicit an Institute expedited review that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on successful completion of milestones, program priorities and on the availability of funds. The expedited review may result in additional negotiations of award. 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 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: Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this PAR. 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 8 weeks. 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 substantial revision of an unfunded version of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Applications lacking the milestones section and description, as indicated in the Supplementary instruction section of this PAR, will not be reviewed. Incomplete and/or non-responsive applications will not be reviewed. 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 NIDDK 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 Diabetes and Digestive and Kidney Advisory 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: Are 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: The initial review group will evaluate the specific goals for each phase and the feasibility of the milestones that would justify expansion to the R33 phase. The initial review group will evaluate how appropriate, realistic and quantifiable the proposed research milestones are, and whether the milestones are adequate for the demonstration and feasibility for transition to the R33 development phase. The initial review group will also assess the timeframe for achieving the milestones and whether they are appropriate. 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. 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 CONSIDERATIONS 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 Date: June 18, 2004 Application Receipt Date: July 20, 2004 Peer Review Date: October/November 2004 Council Review: February 2005 Earliest Anticipated Start Date: April 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 DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (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). 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 are 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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this 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 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 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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