NHLBI CLINICAL PROTEOMICS PROGRAMS RELEASE DATE: March 22, 2004 RFA Number: RFA-HL-04-019 EXPIRATION DATE: October 15, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National, Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S) 93.837, 93.838, 93.839 LETTER OF INTENT RECEIPT DATE: September 17, 2004 APPLICATION RECEIPT DATE: October 14, 2004 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 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 RFA This RFA will establish Clinical Proteomics Programs to promote systematic, comprehensive, large-scale validation of existing and new candidate protein markers that are appropriate for routine use in the diagnosis and management of heart, lung, blood, and sleep diseases. These Programs will facilitate validation of protein panels that may be used to predict disease susceptibility or to assist in differential diagnosis, disease staging, selection of individualized therapies, or monitoring of treatment responses. In addition, this RFA seeks to establish a high quality education and skills development program to encourage and ensure that scientists develop competencies and expertise needed to address the complex, multifaceted challenges in clinical proteomics. RESEARCH OBJECTIVES Background Heart, lung, blood, and sleep diseases are major causes of morbidity and mortality. Cardiovascular disease is the number one killer in the United States in both men and women, across all major racial groups and totals nearly one million deaths a year. Lung diseases such as chronic bronchitis, emphysema, asthma and other obstructive or interstitial conditions account for more than 230,000 deaths annually, placing an enormous burden on our healthcare system. Blood diseases such as venous thrombosis and pulmonary embolisms are causes of significant public health concern, as well. Sleep disorders and insufficient sleep represent severe health concerns for tens of millions of Americans. Improving patient care through the use of protein markers is well established clinically. For example, the definition of heart attack, as well as the determination of the benefit derived from antithrombotic treatments, rests on serum troponin measurement. The detection of extremely small quantities of this protein identifies patients at high risk for adverse outcomes as well those that will derive greater benefit from antithrombotic and other interventional strategies. Assay of the B-type natriuretic peptide also contributes to standard clinical information in the diagnosis of congestive heart failure. Myeloperoxidase was recently shown to help in the diagnosis of atherosclerosis and acute coronary syndromes. The predictive values, sensitivity, and specificity of many of the individual protein markers, currently in clinical use, could potentially be enhanced if analyzed and measured in a panel. Observational studies have shown that combining protein markers troponin I, C-reactive protein and B-type natriuretic peptide into panels can provide valuable information on stratifying risk for acute coronary syndromes. Panels of protein markers, appropriately validated, could facilitate better and earlier diagnosis, improve disease staging and selection of individual therapies and lead to more reliable monitoring of treatment responses, leading to substantial improvements in public health. The application of proteomics in the clinical environment is limited due to a lack of knowledge regarding which proteins are most useful for analysis and how data are interpreted and represented. Important research needs include the identification of panels of protein markers that are likely to provide useful clinical information, design of practical assays for these panels, and validation of these panels and assays in well characterized populations of human subjects. The emergence of clinical proteomics promises major advances in disease management, provided that a continuous channel exists for translating protein discoveries into tangible clinical benefits. Scope The purpose of this RFA is to establish an infrastructure for research teams to validate protein panels and to measure multiple candidate markers accurately, for heart, lung, blood, and sleep diseases. The Clinical Proteomics Programs established for this purpose will (1) design panels of candidate proteins for disease areas, (2) develop high throughput analytic methods, (3) assess the predictive value of these proteomic measurements using biological specimens and clinical data from existing study populations, and (4) establish procedures and standards for quality control. A major shortfall of clinical proteomics is the lack of a robust infrastructure for clinical candidate panel validation. Validation is necessary to confirm the relationship to the target disease in large numbers of patient samples and requires highly standardized protein measurement systems. The samples must be derived from well characterized sample sets with associated high-quality clinical information. The validation process provides the critical evidence necessary for translating protein knowledge into practices impacting public health. A significant opportunity now exists to enhance the validation stage and help translate protein discoveries into clinical practice. Many completed and ongoing clinical trials and epidemiologic studies have disease associated biological samples in addition to detailed clinical data. Leveraging this investment will enhance validation efforts. Panels of protein markers in the following areas would represent appropriate topics for proposed projects. This list is not intended to be all-inclusive and other topics should be considered. o Predict susceptibility to coronary artery disease or acute and chronic pulmonary disease o Assess the severity and rate of progression of atherosclerosis or pulmonary disease o Differential diagnosis for patients presenting with shortness of breath, chest pain or elevated blood pressure o Detect occult myocardial infarction and subclinical cardiac disease and/or damage o Select optimal, individualized medical management strategies o Monitor therapeutic and adverse responses to antihypertensive drugs or drugs for asthma and other lung diseases such as inhaled corticosteroids, bronchodilators, and leukotrienes o Identify early stages of pulmonary disease before significant pathogenesis has occurred o Evaluate risk of thrombosis in individuals with a predisposition to cardiovascular disease or stroke o Evaluate risk of bleeding and appropriate management strategies in patients with bleeding disorders - hemophilia, autoimmune blood disorders, von Willebrand disease o Manage anticoagulation therapy in patients with thromboembolic disorders o Identify markers for early diagnosis and prognosis of heart, lung, blood, and sleep disorders o Develop tests to rapidly and accurately distinguish thromboembolic stroke from hemorrhagic stroke. Projects outside the scope of this RFA will not be considered responsive and include: o Studies that do not address heart, lung, blood, or sleep disorders o Studies that are focused on developing new proteomic technologies to identify protein markers o Proteomic discovery efforts We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. It is highly recommended that prospective applicants contact program staff (Please see address questions about scientific/research issues under Where to Send Inquiries , below) about proposed projects. Program Structure A Clinical Proteomics Program should be an identifiable organizational unit formed by a single institution or a consortium of cooperating institutions. Each Clinical Proteomics Program must provide a multidisciplinary team structure, ensuring effective coordination and integration between the selection and validation components of the Program. The team should encompass multi-disciplinary expertise and should include proteomic researchers, bioengineers, clinical chemists, protein chemists, experts in biostatistics and bioinformatics, clinical investigators, and epidemiologists. The marker selection process should focus on the design of protein marker panels that are most useful in clinical situations with under met needs. The team should primarily be responsible for prioritizing candidate protein markers and panels for validation. The selection component should actively develop candidate protein marker panels from a wide range of sources, such as proteomic discovery efforts, published reports, differential expression based research studies and in silico sequence-based predictions. The use of biological samples obtained by minimally invasive methods (e.g., blood, sputum, and urine) is encouraged. Samples from ongoing studies can also be used provided appropriate Institutional Review Board (IRB) amendments to existing protocols have been obtained. Since quantitative measurements of candidate markers in large and well defined clinical samples is central to the validation effort, criteria for the selection of the source material as well as the criteria for validation of the candidate markers must be specified. Where possible, existing technology platforms should be explored as multiplexing tools during panel development. Efforts to minimize sample consumption are encouraged to ensure the maximum number of assays. Emphasis will be placed on: (1) development of panels with high predictive value, specificity, and sensitivity, (2) development of flexible assay protocols to accommodate the inclusion of newly identified proteins into ongoing validation efforts, (3) refinement and development of innovative biostatistical tools and methods for selection of protein marker panels and for increasing the diagnostic sensitivity and specificity, and (4) assay development applicable to clinical settings. The multidisciplinary team will also evaluate preanalytic issues, (including those relating to sample collection, storage, processing, and handling), and set criteria, standardize, and implement preanalytic protocols prior to validation. Each Clinical Proteomics Program should have access to characterized samples with well defined clinical data and the appropriate IRB approvals before funding. Furthermore, they should operate on an open source model system, making the data, statistical and bioinformatic tools that are generated and developed in the Programs, accessible to the public domain within a time period to be determined at the first meeting of the Inter-Program Steering Committee. An Inter-Program Steering Committee (with membership from all the Programs) will be appointed and will have scientific management oversight and responsibility for developing communication, coordination and collaboration among the Programs. In addition, there will be an External Scientific Panel, advisory to NHLBI that will evaluate the progress of the Clinical Proteomics Programs. In order to facilitate the functions that are common to each Program, one of the programs will be selected to function as an Administrative Coordinating Center (ACC) for all the Programs. Therefore, applicants must include as a separate section in their proposal, a description of an Administrative Coordinating Center that will be reviewed separately, independent of the scientific application. Specification for the ACC application can be found under the section, Packaging the Clinical Proteomics Program Application . Educational Component Each Program is expected to develop mechanisms towards education of skills necessary for clinical proteomics. Full implementation of a nationwide effort in translational research for clinical proteomics requires availability of trained M.D., M.D. /Ph.D., and Ph.D. scientists. These individuals must be knowledgeable about the diverse aspects of clinical proteomics and able to integrate the translational and clinical concepts necessary for application to heart, lung, blood, and sleep diseases. One unique feature of the Clinical Proteomics Program is to function as a spring board for advancing education, at the National level, by establishing various mechanisms, such as specialized short courses, and hands on programs that will focus on guiding graduate students, trainees, technical personnel, M.D./Ph.D. and Ph.D. scientists in translation research for clinical proteomics. Both Clinical Proteomics Program and NHLBI-supported investigators would be eligible for these educational opportunities. MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01) award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award" FUNDS AVAILABLE NHLBI intends to commit approximately $4.5 million in FY 2005, $6 million in FY 2006, and $7.5 million in FY 2007 and FY 2008, in total costs, to fund 3 to 5 new grants in response to this RFA. An applicant may request a project period of up to 4 years. The anticipated award date is July 2005. Since the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary. Additionally, an applicant may request up to $100,000 in direct costs for an Administrative Coordinating Center, for each of the four years. Although the financial plans of the NHLBI 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 Domestic institutions/organizations o Foreign institutions are not eligible to apply as Principal Investigators. However, collaborative projects may include work at foreign site when the expertise at the foreign site is not present in the United States o Faith-based or community-based 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 Projects outside the scope of this RFA will not be considered responsive and include, (a) studies that do not address heart, lung, blood, or sleep disorders, (b) studies that are focused on developing new proteomic technologies to identify protein markers, and (c) proteomic discovery efforts. Applications that do not include an educational component and a separate section that details the plan for an Administrative Coordinating Center will not be considered responsive as well. Inter-Program Steering Committee: An Inter-Program Steering Committee comprised of representatives (PI and co-PI) from each of the Clinical Proteomics Program and the designated Program Scientist from the NHLBI, will be established. This Committee will be responsible for overall guidance and coordination among the Clinical Proteomics Programs; establishing coordination and collaboration among the Programs; establishing policies and procedures for, (1) resources that might emerge from the Programs, (2) for NHLBI investigators applying for their markers to be included in the validation panels, and (3) educational offerings. Each Clinical Proteomics Program will have two votes and the NHLBI will have one vote on the Steering Committee. The Committee will discuss and consider emerging scientific opportunities and needs or barriers that are relevant to the goals of the Clinical Proteomics Programs. This Committee has the additional responsibility of ensuring that an educational plan is in place and operational. This Committee will meet twice a year in Bethesda and have ongoing communication through monthly conference calls. One of the meetings will be in conjunction with the Awardees meeting. Subcommittees may be established by this group to cover specific cross-cutting areas, such as quality control, proteomic strategies, sampling protocols, data analysis, bioinformatics, education, ethical, legal and social issues (ELSI), intellectual property rights, and publication policies and procedures. External Advisory Panel: An External Advisory Panel consisting of NHLBI appointed scientists, not affiliated with the Clinical Proteomics Programs, will be established. This Panel is advisory to the NHLBI and will help assess progress, evaluate whether goals are being met, identify strengths and weaknesses, and make recommendations to the NHLBI regarding the program’s success. The External Advisory Panel will meet on an annual basis in conjunction with the Awardees meeting in Bethesda. Awardees Meetings: A scientific meeting of all the Program Investigators will be held in Bethesda, MD. There will be two meetings the first year and one meeting every year thereafter. These meetings will highlight progress, promote interaction, and exchange information, and provide an opportunity to solve difficult problems. The annual meetings will also serve as an evaluation platform for the External Advisory Panel. Administrative Coordinating Center: One of the Programs will serve the additional function of an Administrative Coordinating Center. Therefore each applicant must include in a separate section in their proposal, a plan for the Administrative Coordinating Center, which will be reviewed and scored independently of the scientific application. The center will coordinate meetings, conference calls, distribute minutes, and serve a range of functions common to the Programs. This includes the fiscal responsibility for the travel of the External Advisory Panel (6-8 members). The center will also establish an intranet web site to compile and manage a range of information that will be generated by the Programs. Such information may include: markers selected for panels, results of ongoing validation studies, markers with sub- optimal results; information on seminars and short courses being offered at the various Programs, other educational activities; and other information that the Steering Committee determines necessary to be compiled and maintained. The principal investigator of the scientific application should not be the PI of an Administrative Coordinating Center. Cooperative Agreement Terms and Conditions of Award The cooperative agreement is an award instrument establishing an Assistance relationship (in contrast to an Acquisition relationship) between NHLBI and a recipient, in which substantial NHLBI scientific and/or programmatic involvement with the recipient is anticipated during performance of the activity. The NHLBI purpose is to support and/or stimulate the recipients activities by involvement in and otherwise facilitating the activities in a partner role, but avoiding a dominant role, direction, or prime responsibility. The terms and conditions below, elaborate on these actions and responsibilities, and the awardee agrees to these collaborative actions with the NHLBI Project Scientist toward achieving the project objectives. It is anticipated that these terms and conditions will enhance the relationship between the NHLBI staff and the principal investigator(s), and will facilitate the successful conduct and completion of the study. These agreements will be in addition to, and not in lieu of, the relevant NIH procedures for grants administration. The terms will be as follows: 1. The awardee(s) will have lead responsibilities in all aspects of the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Inter-Program Steering Committee. 2. Administrative Coordinating Center: One of the Programs will serve the additional function of an Administrative Coordinating Center. The center will also establish an intranet web site to compile and manage a range of information that will be generated by the Programs. 3. The NHLBI Project Scientist will serve on the Inter-Program Steering Committee; he/she or another NHLBI scientist may serve on other study committees, when appropriate. The NHLBI Project Scientist (and the other cited NHLBI scientists) may work with awardees on issues coming before the Inter-Program Steering Committee and, as appropriate, other committees. 4. External Advisory Panel: An External Advisory Panel consisting of NHLBI appointed scientists, not affiliated with the Clinical Proteomics Programs, will be established. This Panel is advisory to the NHLBI and will help assess progress, evaluate whether goals are being met, identify strengths and weaknesses, and make recommendations to the NHLBI regarding the program’s success. The External Advisory Panel will meet on an annual basis in conjunction with the Awardees meeting in Bethesda. 5. Awardee(s) agree to the governance of the study through an Inter-Program Steering Committee comprised of representatives (PI and co-PI) from each of the Clinical Proteomics Program and the designated Program Scientist from the NHLBI, will be established. This Committee will be responsible for overall guidance and coordination among the Clinical Proteomics Programs; establishing coordination and collaboration among the Programs; establishing policies and procedures for, (1) resources that might emerge from the Programs, (2) for NHLBI investigators applying for their markers to be included in the validation panels, and (3) educational offerings. Each Clinical Proteomics Program will have two votes and the NHLBI will have one vote on the Steering Committee. The Committee will discuss and consider emerging scientific opportunities and needs or barriers that are relevant to the goals of the Clinical Proteomics Programs. This Committee has the additional responsibility of ensuring that an educational plan is in place and operational. This Committee will meet twice a year in Bethesda and have ongoing communication through monthly conference calls. One of the meetings will be in conjunction with the Awardees meeting. Subcommittees may be established by this group to cover specific cross-cutting areas, such as quality control, proteomic strategies, sampling protocols, data analysis, bioinformatics, education, ethical, legal and social issues (ELSI), intellectual property rights, and publication policies and procedures. The collaborative protocol and governance policies will involve procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data and records of individuals. 6. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The collaborative protocol and governance policies will involve procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data and records of individuals. The NHLBI Project Scientist, on behalf of the NHLBI, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Inter-program Steering Committee (i.e., cooperative agreement awardees). 7. Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NHLBI support; or special access to study results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI. 8. Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and governance. Within three years of the end of the period of NHLBI support for the project, data not previously released and other study materials or products not previously distributed, are to be made available to individuals who are not study investigators, provided such release is consistent with the study protocol and governance and with above paragraph. In addition, study investigators must establish a plan for making data sets and materials available to the scientific community and to the NHLBI immediately upon completion of the three year period following the end of the period of NHLBI support. Upon completion of the project, awardees are expected to put their intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NHLBI, for the conduct of research at no charge other than the costs of reproduction and distribution. 9. All awards that list direct costs of $500,000 or more per year must also have a data sharing plan. 10. The NHLBI reserves the right to terminate or curtail the study (or an individual award) in the event of (a) data reporting, quality control, or other major breach of the protocol, (b) substantive changes in the agreed-upon protocol with which NHLBI cannot concur, (c) human subject ethical issues that may dictate a premature termination. 11. Any disagreement that may arise in scientific/programmatic matters, within the scope of the award, between award recipients and the NHLBI may be brought to arbitration. An arbitration panel will be composed of three members--one selected by the Inter-Program Steering Committee (with the NHLBI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NHLBI, and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NHLBI under applicable statutes, regulations and terms of the award. 12. These special terms of award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant administration policy statements. 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: Pothur R Srinivas, Ph.D., MPH Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10188 Bethesda, MD 20892 Telephone: (301)435-0550 FAX: (301) 480-2858 Email: ps241q@nih.gov o Direct your questions about peer review issues to: Anne P. Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7214, MSC 7924 Bethesda, MD 20892-7924 Bethesda, MD 20817 (for express/courier service) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: ac42y@nih.gov o Direct your questions about financial or grants management matters to: Norma DeGuzman Division of Extramural Affairs Grants Operations Branch 6701 Rockledge Drive, Room 7167 Bethesda, MD 20892 Telephone: (301) 496-6740 FAX: (301) 480-1948 Email: nd76f@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 RFA 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 NHLBI 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 by mail or email to Dr. Anne Clark at the address listed under Where to Send Inquiries. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. Packaging the Clinical Proteomics Program Application Each application to establish a Clinical Proteomics Program must be submitted as one application by a Clinical Proteomics Program Director, who will be responsible for organizing and maintaining effective integration and interaction of the Program. A clear description of interaction among the various components, plans for communication, collaboration and sharing among investigators in the Clinical Proteomics Program should be included. The Clinical Proteomics Program Director should also indicate the mechanism for handling day-to-day administrative details, program, coordination, planning and evaluation. The Director will be required to have a minimum of 25% level of effort, and the responsibility of oversight and coordination of all projects or components of the Program, whether or not they are at his/her institution. Each Program should clearly outline its administrative and organizational structure. Applications should include appropriate budget forms providing adequate budget justification with all applicable direct and facilities and administrative costs. Estimating of staffing needs, including principal investigator, other professional and support staff must be included. During the course of the project period, it is anticipated that technologies will improve and the proposed studies may change. Accordingly, it is expected that the principal investigators will be allowed adjustments in their scientific projects to accommodate such things. Budgets should include travel costs for Awardees Meetings and Inter-Program Steering Committee meetings, as detailed under the section title, Special Requirements along with statements indicating willingness to participate in these meetings and abide by its governance. An educational component is another integral part of each Clinical Proteomics Program. A clear description of the efforts to educate and cross train across disciplines of clinical proteomics must be outlined, including the plans for developing short courses and hands on programs. The process of selection and monitoring of candidates for these educational activities must be portrayed as well. A separate section not exceeding 5 pages, detailing plans for an Administrative Coordination Center, should be included in each Clinical Proteomics Program application. This section should be placed following the section on the Research Plan. The Center will facilitate functions common to all the Clinical Proteomics Programs, coordinate meetings of the awardees, the Inter-Program Steering Committee and the External Advisory Panel, and manage a Clinical Proteomics Program intranet web site. The Center will also be responsible for setting up the monthly conference calls of the Steering Committee. This section should also include separate budget justification pages for the operation of the Administrative Coordination Center not to exceed 100,000 direct costs in any year. Applications should provide adequate budget justification with all applicable direct and facilities and administrative costs, including estimated costs associated with the travel of the External Advisory Panel (6-8 members). Estimation of staffing needs and communication costs must be included. The award will be subject to administrative review annually. APPLICATIONS NOT CONFIRMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. 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: Anne P. Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7214, MSC 7924 Bethesda, MD 20892-7924 Bethesda, MD 20817 (for express/courier service) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: ac42y@nih.gov 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 8 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 NHLBI. 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 NHLBI 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 NHLBI 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? Does the proposed study have access to characterized sample sets with well defined clinical data? Is sufficient justification provided for the proposed markers? Are criteria on how to design panels of protein markers described? 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? Are the proposed plans likely to advance education in clinical proteomics? 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? Does the proposal describe a multidisciplinary team structure? 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 Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. ADMINISTRATIVE COORDINATING CENTER FUNCTIONS: Reviewers will consider the plan for the Administrative Coordinating Center independently and will not factor the plan into the determination of the scientific merit or the primary priority score. Each plan will receive a separate priority score which is separate from the primary priority score of the scientific application. The following review criteria will be used. APPROACH: Are the proposed activities appropriate for facilitating coordination and communication among awardees? Are state-of-the-art coordinating strategies proposed? INVESTIGATOR: Is the applicant well suited to or experienced in carrying out coordinating functions? Does the applicant have prior experience in performing coordinating functions? Is the Administrative Center team appropriate? ENVIRONMENT: Is there evidence of institutional support? Are the facilities appropriate to conducting the business of the Administrative Center. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: September 17, 2004 Application Receipt Date: October 14, 2004 Peer Review Date: February 2005 Council Review: May 2005 Earliest Anticipated Start Date: July 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). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). 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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