PAS-04-120: CNS THERAPY DEVELOPMENT FOR LYSOSOMAL STORAGE DISORDERS

Department of Health
and Human Services (HHS)

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CNS THERAPY DEVELOPMENT FOR LYSOSOMAL STORAGE DISORDERS RELEASE DATE: July 2, 2004 PA NUMBER: PAS-04-120 The R01 portion of this funding opportunity has been replaced by PAS-07-195, which now uses the electronic SF424 (R&R) application for February 5, 2007 submission dates and beyond.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-06-202) 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 ORGANIZATIONS: National Institutes of Health (NIH) (http://www.nih.gov/) Lysosomal Storage Disease Research Consortium (LSDRC) (http://www.LSDResearch.org) COMPONENTS OF PARTICIPATING ORGANIZATIONS: National Institute of Neurological Disorders and Stroke (NINDS/NIH) (http://www.ninds.nih.gov/) Office of Rare Diseases (ORD/NIH) (http://rarediseases.info.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.853 (NINDS) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanisms of Support 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 PA The goal of this Program Announcement is to solicit applications on lysosomal storage disorders (LSDs) focused on improving CNS treatment outcomes, enhancing the effectiveness of delivery and targeting of cells, enzymes, drugs and genes into the brain, and developing novel therapeutic modalities, such as implantable biocapsules and micro-electro-mechanical systems (MEMS)-based devices. Lysosomal storage disorders constitute a group of recessive genetic diseases resulting from cellular enzymatic deficiencies of acid hydrolases that normally catalyze the metabolism of glycoproteins, glycolipids and other macromolecules, or from defects in transporter proteins leading to pathogenic accumulation of these substances in lysosomes. Treatment modalities for LSDs are currently limited to bone marrow transplantation (BMT) and enzyme replacement therapy (ERT). These approaches while providing significant promise for treatment of the visceral manifestations of LSDs, do little to address CNS pathologies for this group of disorders. Thus this announcement specifically encourages the transition from basic studies in LSDs to translational research for improved delivery of therapeutic cells, proteins, genes, and small molecules across the blood-brain barrier. RESEARCH OBJECTIVES Background Lysosomal storage disorders encompass about 50 metabolic diseases, that include neuronal ceroid lipofucinoses, mucopolysaccharidoses (MPS), mucolipidoses IV, sphingolipidoses, sphingomylinoses (Niemann-Pick disease), gangliosidoses, glycoproteinoses, and other monogenic inborn errors of metabolism that collectively affect approximately 1 in 5000 live births. Each of these diseases has heterogeneous pathophysiology and clinical manifestation resulting from deficient activity of specific hydrolases that act to catabolize macromolecular substrates in the lumen of lysosmes. In some cases, the genetic defect can be in an activator protein for a lysosomal hydrolase or a transporter protein for the metabolites. All these deficiencies lead to a characteristic pathological accumulation and storage of the substrate for that enzyme in the lysosomes. The consequent accumulation of undigested metabolites in lysosomes leads to multi-systemic dysfunction, including progressive neurologic deterioration, mental retardation, organomegaly, blindness, and early death. In general, the residual amount of functional enzyme in the lysosomes of patients determines the severity and age at onset of the clinical symptoms, implying that even modest increases in enzyme activity might affect a cure. A critical issue for treatment of LSDs is the ability of soluble enzyme precursors to be secreted by one cell type and taken up by neighboring cells via receptor-mediated endocytosis. It has been estimated that as little as 10% of normal or restored enzyme level is sufficient for non-autonomous cell correction and clearance of the storage materials. Significant advances have been made in the treatment of non-neuronopathic forms of LSDs via enzyme replacement therapy (ERT) and bone marrow transplantation (BMT) where a number of clinical trails are already underway. However addressing the CNS aspects of these diseases remains a formidable challenge. To date ERT has shown no major effect toward reversing preexisting CNS disease in neuronopathic forms of LSDs though it is possible that ERT may slow the progression of CNS deterioration if administered early on in the disease process. Bone marrow transplantation with hematopoietic stem cells has been successful in some forms of MPS with long term survival following successful engraftment. However optimal prevention of CNS deterioration in MPS is possible only when BMT occurs before onset of neurologic manifestations, generally at less than 2 years of age. This would suggest that the presence of irreversible damage must be considered prior to the initiation of therapy, thus early diagnosis and determination of optimal timing of intervention could also be a key to improved therapy. However, there are few detailed natural history studies on clinical outcomes or disease progression addressing CNS aspects of neuronopathic forms of LSDs. In addition there is a higher rate of associated morbidity and mortality with BMT. Clearly, additional treatment regimen alone or in conjunction with ERT or BMT is needed to significantly alter the course of CNS deterioration in LSDs. Research Scope This initiative seeks to extend the recent advances in the treatment of the visceral aspects of LSDs to therapies geared towards the CNS abnormalities. The following are examples of topics that might be proposed for study in response to this announcement. These are only examples and are not meant to be limiting, however the focus should remain on therapy development for LSDs. o Novel delivery methods for drugs, cells, enzymes and genes across/or around the BBB. o New approaches for targeting the BBB, such as the use of endogenous transport systems, including carrier-mediated transporters like glucose and amino acid carriers; receptor-mediated transcytosis utilizing insulin or transferrin receptors; and active efflux transporters such as p-glycoprotein and the associated anti-porters. o Use of peptide or pharmaceuticals as molecular Trojan horses that can bind to endogenous receptor-mediated transporters in the BBB. o New types of therapy, including substrate reduction therapy. o RNAi-mediated therapy of downstream targets. o Use of microfluidic or MEMS devices for in-vivo spatial and temporal controlled delivery of exogenous biomolecules, such as drugs, gene transfer vectors, and cells. o Assessment of the behavior of host cells in response to the short-term and long-term presence of transplanted human stem cells and/or their derivatives. o Identification of therapeutic windows of opportunity by characterizing pathophysiological processes. o Applications of neuroimaging and neurophysiological biomarkers to monitor disease progression, effects of therapeutic interventions, or complications. o Use of non-invasive measures of organ function (e.g., functional MRI, magnetic resonance spectroscopy, ultrasound, PET) to identify, characterize, and validate diagnostic biomarkers, intermediate surrogate endpoints, and prognostic biomarkers. o Identification and validation of natural history biomarkers that may predict clinical outcome. o Estimation of the magnitude of treatment effects based on validated biomarkers that reflect underlying pathogenesis. o Development and validation of clinical tools, such as a rating scale or predictor of clinical outcome. This PA is not intended to support basic neuroscience research involving LSDs but instead emphasizes pre-clinical, translational and clinical research that targets the neurocognitive and neurodegenerative aspects of this group of diseases and is geared towards the development of therapeutic strategies. The NINDS supports in parallel other translational research projects, "NINDS Cooperative Program in Translational Research" (http://grants.nih.gov/grants/guide/pa-files/PAR-02-139.html) and "NINDS Exploratory/Developmental Projects in Translational Research" (http://grants.nih.gov/grants/guide/pa-files/PAR-02-138.html). MECHANISMS OF SUPPORT This PA 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 and http://www.ninds.nih.gov/funding/r21guidelines.htm. NINDS will not accept R21 applications that include non-exempt human subjects research. This PA 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 PA will compete with all investigator-initiated applications and be referred and reviewed according to the customary peer review procedures. FUNDS AVAILABLE Applications submitted in response to this PA will compete with all investigator-initiated applications for funding. The NINDS and ORD intend to commit a total of approximately $1,050,000 (total costs) 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). 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 PA 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 PA will be reissued. Additional funds may also be available through the Lysosomal Storage Disease Research Consortium (http://www.LSDresearch.org) for applications received and reviewed under this PA. ELIGIBLE INSTITUTIONS You may submit an application 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 Letter of Authorization In order for applications to be considered for funding by the LSDRC (http://www.LSDresearch.org), all applicants should provide NIH with a letter of authority permitting NIH to share applications and the corresponding summary statements with LSDRC. Letters of authorization should be prepared by the principal investigator and co-signed by the official signing for the applicant organization. This letter may be submitted as a cover letter accompanying the application. Plan 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). 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 PA 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: Danilo A. Tagle, Ph.D. National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 2133 Bethesda, MD 20892 Telephone: (301) 496-5745 FAX: (301) 402-1501 Email: tagled@ninds.nih.gov o Direct your questions about financial or grants management matters to: Sheila S. Simmons Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3250 Bethesda, MD 20892 Telephone: 301-496-9231 Fax: 301-402-0219 Email: ss433y@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. 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: 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 PA 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 PA 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 an 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? The NIH R21 exploratory/developmental grant is a mechanism for supporting novel scientific ideas or new model systems, tools or technologies that have the potential to significantly advance our knowledge or health-related research. Because the research plan is limited to 15 pages, an R21 grant application need not have extensive background material or preliminary information as normally expected in an R01 application. Reviewers will be instructed to focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will thus place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of R01 applications including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. NINDS will not accept unsolicited R21 applications that include non-exempt human subjects research. 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 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. 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 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. If human subjects are involved, applicants should contact the Program Director to discuss their project prior to submission of the application. 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. 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 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). 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 PA 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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