UNDERSTANDING AND PREVENTING BRAIN TUMOR DISPERSAL RELEASE DATE: March 25, 2004 PA NUMBER: PAS-04-079 The R01 portion of this funding opportunity has been replaced by PAS-07-196, which now uses the electronic SF424 (R&R) application for February 5, 2007 submission dates and beyond.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. Accordingly, the R21 portion of this funding opportunity 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-06-201) funding opportunity announcement has been issued for the submission date of June 1, 2006 and submission dates thereafter. EXPIRATION DATE: for R21 Applications: March 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 Cancer Institute (NCI) (http://www.nci.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.853 (NINDS), 93.393 (NCI) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA 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 Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA Many brain tumors are highly invasive and therefore extremely difficult to treat. Cells from the primary tumor often infiltrate into surrounding brain tissues, so that removal of the main tumor mass is not sufficient to prevent recurrence. The goal of this Program Announcement with set-aside funds (PAS) is to promote studies that: (1) identify the properties of brain tumor cells that cause them to migrate; (2) determine how interaction of tumor cells with normal brain elements affects migration; and (3) translate understanding of these parameters into interventions that target invading tumor cells. Interdisciplinary studies that apply new concepts and methodologies from developmental neuroscience, genomics, precursor cell biology and other related fields are particularly encouraged. RESEARCH OBJECTIVES Background In November 2000, NINDS and NCI conducted a joint, comprehensive planning effort called the Brain Tumor Progress Review Group (BT-PRG). The goal of the BT-PRG was to identify the highest priorities in brain tumor research (for a complete description of the results of the BT-PRG, see http://prg.nci.nih.gov/brain/finalreport.html). One of the key scientific goals established through this planning process was to increase our understanding of brain tumor dispersal and translate this understanding into more effective therapies for this devastating group of diseases. Malignant brain tumors consist of a core mass and surrounding individual cells that infiltrate into adjacent brain tissue. In recent years, technologies for imaging and surgically removing brain tumors have improved. However, neurosurgeons continue to observe that radical resection of primary gliomas, the most common type of brain tumor, is often followed by growth of secondary tumors that are not treatable by radiation or chemotherapy. This observation suggests that invading cells are able to activate a molecular and cellular program that makes them impervious to conventional therapies. The early stages of tumor cell migration are difficult to detect. Invading cells can follow myelinated axons, the basement membranes of blood vessels or other basement membrane-like structures, as well as the perivascular space. Invasiveness does not always correlate with degree of malignancy. Low-grade astrocytomas, for example, sometimes infiltrate extensively. Migration of cells from high-grade gliomas, however, often occurs more rapidly. When a glioma is removed a new tumor generally forms within a few centimeters of the original tumor mass, but satellite foci can develop at significantly greater distances. Invasiveness of brain tumors presents many problems for treatment. Even radical resection (e.g. hemispherectomy) may leave behind migrating cells that give rise to secondary tumor foci. Treatment of the core tumor mass by radiation or chemotherapy is similarly problematic. In all these interventions, a choice must be made between treating as large an area as possible around the tumor and preserving quality of life for the patient. One important example of this problem involves childhood brain tumors, particularly primitive neuroectodermal tumors that arise during brain development. To understand how brain tumor dispersal can be controlled, we must determine what causes tumor cells to migrate and investigate how migrating cells interact with normal neurons, glia, and extracellular matrix (ECM). Several kinds of cell-cell interactions may be critical, including gap-junctional communication, neurotransmitter-mediated events, synaptic disruption, and interactions with the immune system. It is likely that invading cells misexpress genes that control cell migration during normal development and also activate novel pathways that promote invasiveness. Examples of candidate gene products that could control migration include specific motor proteins, cytoskeletal elements, small GTPases that regulate interactions between external signals and the cytoskeleton, cell surface receptors involved in cell migration, proteases that remodel the ECM, ion channels that induce changes in cell shape or volume, G protein-coupled receptors, and ECM molecules produced by both tumor and surrounding normal cells. In addition to understanding what causes dispersal, identifying the genes that control the interrelated process of cell proliferation in migrating cells is also important. These cells often exhibit transient cell cycle arrest, which protects them from chemotherapy and radiation. Determining the properties unique to invading brain tumor cells, and understanding how these cells interact with normal brain elements will suggest rational strategies for blocking tumor dispersal. For example, once genes that promote or prevent migration have been identified, their activities can potentially be modulated through strategies such as the use of targeted antibodies, antisense oligonucleotides, siRNA, or the introduction of specific exogenous genes or cells. The ultimate goal is to develop interventions that block infiltration but cause minimal damage to adjacent brain tissue. Such interventions could potentially transform brain tumor into a manageable chronic disease. Scope Applications submitted in response to this PAS should focus on either: (1) determining the causes of brain tumor dispersal; (2) understanding the interactions of migrating tumor cells with normal brain elements; or (3) developing interventions that target migrating tumor cells. Analysis of either pediatric or adult brain tumors is appropriate. Studies that apply insights from other fields (e.g. developmental neuroscience, glial cell biology, stem or precursor cell biology) to the analysis of tumor spread are within the scope of this PAS and are encouraged. Translational studies using cell or animal models of brain tumor migration to test possible therapeutic interventions are also encouraged. This PAS is intended to promote interdisciplinary collaborations, as well as interactions between basic scientists and clinicians. Possible areas of investigation include, but are not limited to: o Analysis of candidate genes and signal transduction pathways that control brain tumor cell dispersal o Genomic or proteomic expression profiling aimed at identifying novel genes or proteins that control brain tumor cell dispersal o Analysis of molecular and cellular mechanisms that control normal brain cell migration and potentially regulate the dispersal of brain tumor cells o Determination of the cells of origin and specific properties of migrating brain tumor cells o Analysis of the interactions of brain tumor cells with normal brain elements that may contribute to understanding tumor dispersal o Studies of extracellular matrix properties that potentially control normal and aberrant migration of cells in the CNS o Determination of what causes brain tumor cells to exit the cell cycle during migration and reenter it during subsequent cell proliferation o Studies of neural progenitor cell biology that may shed light on brain tumor dispersal o Investigation of why invading brain tumor cells are resistant to chemotherapy or radiation o Establishment of novel in vitro and in vivo migration assays that can be used to elucidate mechanisms of brain tumor cell dispersal. Brain slice or whole animal models in which tumor cells can be studied as they move through the normal CNS are particularly encouraged. o Development of novel methodologies that permit more effective visualization of migrating brain tumor cells o Development of therapeutic interventions that target migrating brain tumor cells and prevent them from forming new tumors. These could include targeting immune cells towards migrating tumor cells, introducing therapeutic genes or cells expressing such genes, using chemoattractants to bring tumor cells back to the main tumor mass, or other novel strategies. MECHANISMS OF SUPPORT This PAS will use the NIH research project grant (R01) and exploratory/developmental grant (R21) award mechanisms. 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 and should be no more than 5 years for R01 grants. Applicants are encouraged to contact program staff for advice about choosing the appropriate grant mechanism. R21 grants are one-time awards intended to encourage new exploratory/developmental research projects by providing support for the early stages of their development. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models or applications that could have major impact on a field of biomedical, behavioral, or clinical research. 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 $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 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://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. Competing continuation applications submitted in response to this PAS will compete with all investigator-initiated applications and be referred and reviewed according to the customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The earliest anticipated award date is April 1, 2005. FUNDS AVAILABLE NINDS has set aside $1,000,000 in total costs per year for applications sent in response to this PAS. This is in addition to funds available for applications that score within the NINDS payline (see NINDS Funding Strategy http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm) and depends on the overall scientific merit of the applications and the availability of funds throughout the duration of this solicitation (3 years). NCI will consider programmatic priority, as reflected in this PAS, and scientific merit in making funding decisions regarding applications assigned to it in response to this PAS. Applications submitted in response to this PAS will compete with all investigator-initiated applications for funding. The total project period for an application submitted in response to this PAS may not exceed 5 years. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the Institute provide support for this program, awards pursuant to this PAS are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this PAS will be reissued. 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 Grantees will be required to attend at least one meeting per year that fosters collaboration among basic neuroscientists, developmental neuroscientists, neuroimmunologists, neurologists, neurosurgeons, and neuro- oncologists and facilitates the bidirectional translation of basic and clinical results. Attendance at these meetings must be described in annual progress reports. Plan for Dissemination of Data and Biomaterials Sharing of biomaterials, data, and software in a timely manner is essential for rapid progress in biomedical research. All applicants who respond to this PAS must propose plans for sharing data and biomaterials generated through the grant. 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). 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. 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: Direct inquiries regarding scientific/research issues to: Dr. Robert Finkelstein NINDS Neuroscience Center, Rm 2143 6001 Executive Blvd. Bethesda, MD 20892-9527 Telephone: (301) 496-5745 FAX: (301) 401-1501 Email: finkelsr@ninds.nih.gov Dr. Steven Krosnick NCI Clinical Grants and Contracts Branch Cancer Therapy Evaluation Program Division of Cancer Treatment and Diagnosis 6130 Executive Blvd, EPN 7009 Bethesda, MD 20892 Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: krosnicks@mail.nih.gov Direct inquiries regarding financial or grants management matters to: Ms. Kathleen Howe Grants Management Branch NINDS 6001 Executive Boulevard, Rm 3266 Bethesda, MD 20892 Telephone: (301) 496-7392 Email: howek@ninds.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 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) 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. 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. 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. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in the modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. 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: Applications must be received by or 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 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. An appropriate scientific review group 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 discuss the following aspects of 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 these 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 do they advance scientific knowledge? 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. 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 PA 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 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 AMENDMENT "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 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). 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 PAS is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under 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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