GENETICS AND PATHOBIOLOGY OF VASCULAR COGNITIVE IMPAIRMENT RELEASE DATE: August 20, 2004 PA NUMBER: PAS-04-149 The R01 portion of this funding opportunity has been replaced by PAS-07-194, which now uses the electronic SF424 (R&R) application for February 5, 2007 submission dates and beyond. March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through Grants.gov using the electronic SF424 (R&R) application. This announcement will stay active for only the May 1, 2006 AIDS and AIDS-related application submission date for these mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms expires on the date indicated below. Other mechanisms relating to this announcement will continue to be accepted using paper PHS 398 applications until the stated expiration date below, or transition to electronic application submission. A replacement R21 (PAS-06-265) funding opportunity announcement has been issued for the submission date of June 1, 2006 and submission dates for AIDS and non-AIDS applications thereafter. EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006 EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 Expiration Date for R01 Non-AIDS Applications: November 2, 2006 Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) National Institute on Aging (NIA) (http://www.nia.nih.gov/) National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): NINDS 93.853, NIA 93.866, NHLBI 93.837, 93.838 THIS PAS CONTAINS THE FOLLOWING INFORMATION o Purpose of the PAS 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 Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PAS The purpose of this Program Announcement with set-aside funds (PAS) is to invite applications to study the biological basis of vascular cognitive impairment (VCI). VCI causes a burden of illness similar to that caused by Alzheimer’s disease (AD), but has been far less well-studied. Recently, however, some important strides have been made in understanding the etiology of VCI. These include the discovery of a monogenic form of vascular dementia, CADASIL, and identification of the causative gene as Notch 3. In addition, MRI and other pathological data have provided a clearer delineation of the various clinical subtypes of VCI, and awareness of the synergistic interaction between vascular and classical Alzheimer’s pathologies in producing cognitive impairment. The goal of this PAS is to build on these first critical achievements to obtain a better understanding of the cellular and molecular mechanisms causing vascular, neural, and glial dysfunction in human VCI and animal models of VCI. RESEARCH OBJECTIVES The number of people affected by dementia in the US is expected to increase three-fold in the next 50 years, to a total of over 13 million. The best- known form of dementia is AD, whose definitive diagnostic sign is the presence of plaques and tangles in brain neurons upon autopsy. However, a large proportion of dementia cases in the aged population are not due to AD, but rather to cerebrovascular disease. Dementia due to cerebrovascular disease is referred to as vascular dementia , and can occur in the absence of Alzheimer’s pathology. In addition to this so-called pure vascular dementia, there are also cases of mixed dementia in which cerebrovascular and Alzheimer’s pathologies coexist. Recent studies suggest that pure vascular dementia and mixed dementia together comprise the majority of dementia cases in some populations. Vascular dementia can arise from any of several cerebrovascular disease conditions, but its two major causes are focal ischemic infarcts (i.e., strokes) and subcortical ischemic vascular disease. Focal ischemic infarcts result from occlusion of large vessels, in either cortical or subcortical locations, and are accompanied by acute clinical signs of neurological impairment. (Dementia arising from large infarcts is also sometimes referred to as multi-infarct dementia .) Subcortical ischemic vascular disease, on the other hand, results from occlusion of small vessels, and creates widespread small lesions(lacunae) and/or areas of demyelination. The areas affected are generally subcortical, including the basal ganglia, cerebral white matter and brainstem. This form of vascular disease generally does not produce sudden, acute symptoms, but rather causes longer-term, insidious changes in neurological function. In a significant portion of cases, this disease can even remain clinically silent for the life of the individual. Subcortical small vessel disease can be diagnosed by imaging even in cases where it is clinically silent. In recent years, the term vascular dementia has been replaced by the term vascular cognitive impairment (VCI) . This change reflects the realization that cerebrovascular disease can cause significant cognitive and functional decline in the absence of dementia as defined by standard criteria. In addition, there is increasing evidence that VCI differs from AD in terms of precise range of cognitive defects associated with each disease. AD is characterized primarily by episodic memory loss due to loss of cholinergic basal forebrain neurons and their projections to the hippocampus. In contrast, VCI in its purest forms seems to be characterized more by loss of executive function and attentional mechanisms associated with prefrontal circuitry. However, the spectrums of defects seen in VCI and AD overlap substantially. This fact, together with the frequent coexistence of vascular and Alzheimer’s pathologies within individual patients, renders it difficult to provide definitive diagnoses based strictly on cognitive tests. Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well studied than that of AD. This lack has been due in part to the clinical heterogeneity of the disease, and also to poor understanding of its pathology at the cellular level. Recently, however, research in VCI has taken some critical first steps forward. A genetic form of vascular dementia, CADASIL, has been discovered, and the mutant gene identified as Notch 3. Previous research in animal models had shown Notch 3 to be important in early neural and vascular development. The finding that mutation of Notch 3 leads to stroke and dementia (both seen in CADASIL) suggests that the gene also plays an important role in the function or maintenance of vascular and/or neural cells in the adult. Consistent with this possibility, a transgenic mouse carrying the mutant form of Notch 3 has now been generated which shows degeneration of smooth muscle cells similar to that seen in human patients. These findings provide an important foothold for understanding the cell biology as well as the genetics of VCI. Moreover, the known interaction of Notch with the presenilin proteins suggests a juncture in the disease pathways underlying VCI and AD, which also could be further explored in mouse models. Another major area ripe for exploration concerns the genes and other risk factors that link vascular pathology to neural pathology: eg., that render individuals susceptible to neuronal damage and cognitive impairment in response to cerebrovascular disease. Some progress has been made in recent years in defining genes that predispose individuals to stroke and cerebrovascular disease per se, but no studies have yet examined genes that control the ability of neural tissue to recover from ischemic injury. Identifying such genes would provide clear paths both to understanding the cell biology of VCI, and also to the design of protective agents and therapeutics. Research areas appropriate for this announcement would include, but are not limited by the following examples: o Genetics of VCI, in both animal models and humans; in particular, identification of genes that render individuals susceptible to cognitive impairment secondary to cerebrovascular disease o Analysis of cellular and molecular changes occurring in vascular, neuronal, and glial cells during the development of VCI in human patients, and correlation of these with MRI signs and changes in cognitive function o Studies of cellular and molecular pathological processes occurring in vascular, neuronal, and glial cells in animal models of VCI, such as mouse lines carrying mutant forms of Notch 3 or the stroke-prone spontaneously hypertensive rat o Studies of Notch 3 function in the maintenance and repair of vascular, neuronal, and glial cells in normal adult animals; studies of the cellular and molecular bases of the pathogenic actions of mutant Notch 3 o Studies of the cellular and molecular bases of the interaction between the VCI and AD pathways (for example, studies of vascular function and pathology in animal models of AD) o Development and characterization of new animal models for the study of VCI, and of the interaction between VCI and AD pathogenic mechanisms o Analysis of cognitive function in animal models of VCI, and correlation of changes in cognitive function with cellular and molecular pathologies o Studies on the cellular and molecular effects of hypertension, diabetes, hyperlipidemia, coagulant and anticoagulant proteins, inflammatory cytokines, and complement proteins on the vessel wall in appropriate animal models for VCI MECHANISM(S) OF SUPPORT This PAS will use the NIH R01 and R21 award mechanism(s). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The proposed project period during which the research will be conducted should adequately reflect the time required to accomplish the stated goals The R21 mechanism (see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. These one-time awards support innovative, high impact research projects that 1) assess the feasibility of a novel area of investigation or a new experimental system, 2) include the unique and innovative use of an existing methodology to explore a new scientific area, 3) involve considerable risk but may lead to a breakthrough in a particular area, or 4) develop new technology or methodology that could have major impact in a specific research area. Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications. R21 applications may request a project period of up to two years with a combined budget for direct costs of up to $275,000 for the two year period. For example, you may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of your project. Normally, no more than $200,000 may be requested in any single year. For further information on the R21 mechanism, including Institute-specific information, see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html. This PAS uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. FUNDS AVAILABLE NINDS has set aside a total of $2,250,000, in addition to funds available for applications sent in response to this program announcement that score within the NINDS payline (see NINDS Funding Strategy http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm), depending on the overall scientific merit of the applications and the availability of funds throughout the duration of this solicitation (3 years). NIA has set aside a total of $300,000, and NHLBI has set aside a total of $350,000. 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 Plans for Dissemination of Data and Biomaterials PHS policy requires that investigators make unique research resources available for research purposes to qualified individuals within the scientific community when they have been published (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/guide/notice-files/not96-184.html). In addition, NIH recently released a statement on the sharing of research data that applies to all investigator-initiated applications with direct costs greater than $500,000 in any single year (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html). All applicants who respond to this PAS must propose plans for sharing data and biomaterials generated through the grant. Applicants should explain how funds for the storage and distribution of data and biomaterials will be obtained, and may request such funds in the budget of the application. It is expected that the data to be shared will be clinical, diagnostic, and pedigree structure information, and information about the genetic backgrounds and phenotypes of mutant or transgenic animal strains. Biomaterials to be shared will include patient DNAs and cell lines, and mutant or transgenic animal strains. When possible, data and biomaterials should be placed in databases or repositories that will permit their efficient distribution to investigators throughout the scientific community. An example of such a facility is the NINDS Human Genetics Resource Center (http://locus.umdnj.edu/ninds). The Initial Review Group will evaluate the proposed sharing plan and comment on its adequacy in an administrative note in the summary statement. Reviewers will not factor the proposed data-sharing plan into the determination of scientific merit or priority score. The adequacy of the plan will be considered by NIH staff in determining whether the grant shall be awarded. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. Phenotyping Issues Our understanding of pathogenic mechanisms in VCI would benefit tremendously from the use of standardized criteria for diagnosing this condition, including standardized methods for measuring cognitive function. NINDS plans to encourage and coordinate the use of a minimal diagnostic dataset in studies funded by this PAS. Until such a dataset is defined, applicants to this PAS should provide detailed descriptions of the patient data to be collected, including methods for independently assessing (1) the presence and type of cerebrovascular disease, and (2) levels of cognitive function. Rationale for choice of specific cognitive test(s) should be included. In addition, plans should be included for entry of disease and cognitive phenotypic data into a computerized database that may be easily shared with other researchers. Attendance at Meetings Applicants to be funded under this PAS will be expected to travel to NIH in once a year to share progress with NIH program staff, other investigators funded under this PAS, and additional advisers as deemed necessary by NIH program staff. Applicants should include funds to support one trip per year to Bethesda, MD (for the principal investigator and co-principal investigators only). WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PAS and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Gabrielle G. Leblanc, Ph.D. Program Director, Neurogenetics National Institute of Neurological Disorders and Stroke Neuroscience Center, Suite 2136, MSC 9537 Bethesda, MD 20892 Telephone: (301) 496-5745 FAX: (301) 402-1501 Email: leblancg@ninds.nih.gov Creighton H. Phelps, Ph.D. Director Alzheimer's Disease Centers Program Neuroscience and Neuropsychology of Aging National Institute on Aging National Institutes of Health 7201 Wisconsin Ave., Suite 350 Bethesda, MD, 20892 Telephone: (301)496-9350 FAX:(301)496-1494 Email: phelpsc@nia.nih.gov Stephen S. Goldman, Ph.D. Vascular Biology Research Program Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10192, MSC 7956 Bethesda, MD 20892 Telephone: (301) 435-0560 FAX: (301) 480-2858 Email: goldmans@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Aaron Kinchen Grants Management Specialist National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard Room 3271 MSC 9537 Bethesda, MD 20892-9537 Telephone: (301) 496-7386 FAX: (301) 402-0219 Email: kinchena@ninds.nih.gov Deborah Stauffer Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue Suite 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: stauffed@nia.nih.gov Beckie Chamberlin Grants Management Specialist National Heart, Lung, and Blood Institute 6701 Rockledge Drive Room 7144, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0174 FAX: (301) 480-1948 Email: chamberr@nhlbi.nih.gov 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 D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B 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) 435-0714, 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: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions: o Research Plan For R21 applications only, items a d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required for R21 proposals, but may be included if it is available. Please note that a Progress Report is not needed for R21 awards; competing continuation applications for an exploratory/developmental grant will not be accepted. Appendix. Use the instructions for the appendix detailed in the PHS 398 except that for R21 applications, no more than 5 manuscripts, previously accepted for publication, may be included. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget grant format. The modular budget grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five 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) APPLICATION PROCESSING: APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PAS 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PAS will be assigned on the basis of established PHS referral guidelines. Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the appropriate national advisory council or board 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 application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting $500,000 or more in direct costs in any year of the proposed research are expected to 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. (http://grants.nih.gov/grants/policy/data_sharing) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PAS will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities o Adequacy of proposed data and biomaterials sharing plans REQUIRED FEDERAL CITATIONS ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. 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: 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. 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 PAS 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). 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 PAS 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 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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