THE ETIOLOGY, PATHOGENESIS AND TREATMENT OF ALS RELEASE DATE: August 8, 2003 RFA Number: RFA-NS-04-003 Department of Veteran's Affairs (VA) (http://www.va.gov/resdev/) National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) The Amyotrophic Lateral Sclerosis Association (ALSA) (http://www.alsa.org) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.853 (NINDS) LETTER OF INTENT RECEIPT DATE: September 30, 2003 APPLICATION RECEIPT DATE: October 22, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA With this Announcement, the Department of Veterans Affairs (VA), the National Institute of Neurological Disorders and Stroke (NINDS) and the Amyotrophic Lateral Sclerosis Association (ALSA) invite research grant applications that address the etiology, pathogenesis and treatment of Amyotrophic Lateral Sclerosis. RESEARCH OBJECTIVES Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which those motor neurons that control voluntary movement are progressively lost while those that subserve other functions such as cognition and sensation are spared. At this time victims have no effective treatment options; 50% die within three years of symptom onset and 80-90% within five years. ALS most likely represents a syndrome of very closely related disorders resulting from numerous causes. Although degeneration may start in either lower (spinal) or upper (cortico-spinal) motor neurons, both populations of neurons eventually become involved. Cytologically, neurons exhibit loss of dendrites, derangement of the cytoskeleton and accumulation of a variety of proteins, some of which may form inclusion bodies. Muscular atrophy occurs secondary to denervation; some degree of peripheral reinnervation has been observed relatively early in the course of the disease but the extent is markedly less than that observed in other motor neuropathies. The disease is strikingly specific for motor neurons; indeed one of the many tragedies of ALS is that patients suffer with their sensory, cognitive, and emotional faculties essentially unaffected. ALS has a complex and incompletely understood etiology. Approximately 5 - 10% of cases have another affected family member (fALS) but in the majority of cases the underlying cause and primary pathogenic mechanism remain unknown. While each series of cases has a distinct presentation, there is reason to believe that all cases can provide information concerning common or convergent pathogenic mechanisms relevant to sporadic ALS (sALS). Furthermore, new analytic methodologies can identify genetic factors that affect traits other than risk that may be important in sporadic ALS (e.g. rate of progression, site of onset). Notwithstanding the opportunities presented by the study of genetic forms of the disease, it is clear that ALS is in most cases a multifactorial disorder triggered by as yet unknown factors, including exposure to toxicants in the environment (either alone or in combination with specific genetic factors). Incidence and prevalence are observed to be generally uniform worldwide. While specific toxicants have been studied for decades in an isolated, at-risk population in the Western Pacific, recent reports have identified an approximately two-fold increase in the risk of developing ALS among military personnel deployed to SW Asia during the period of the Gulf War (Aug '90 to Jul '91) relative to non-deployed personnel. Four broad classes of pathogenic mechanisms are hypothesized to produce the cellular dysfunction and death that produce the clinical syndrome of ALS: 1) mitochondrial dysfunction/oxidative stress; 2) altered/disrupted protein processing; 3) excitotoxicity/altered calcium homeostasis; and 4) altered cytoskeletal function/axonal transport. While these hypotheses focus on motor neurons as the final common pathway of the expression of ALS, there is increasing recognition of the contributions of non-neuronal cells to the pathogenesis of ALS. These may represent novel opportunities to develop therapeutic strategies to address more "upstream" events in the primary pathophysiologic cascade or to ameliorate the effects of secondary pathogenic processes. At present there is no effective treatment for ALS. However, because spinal motor neurons extend beyond the blood brain barrier, they may be accessible to therapies that are not feasible for other neurons in the CNS. Alternatively, recent advances in neurobiology may allow the development of strategies to promote re-innervation of muscle. Regardless, the development of novel strategies and technologies for the development and delivery of therapeutics remains an important goal in ALS research. In summary, there remain important gaps in our understanding of the continuum of pathogenesis, pathophysiology, treatment and prevention of ALS. Accordingly, the NINDS, VA and ALSA have formed a public/private partnership to solicit applications to support research in three general lines of investigation: causative factors, pathobiology of motor neurons and associated cell types and the diagnosis and treatment of ALS. Specific topics include, but are not limited to: o Epidemiology Sporadic ALS constitutes the great majority of typical ALS but we do not have an adequate understanding of non-genetic risk factors. Identifying specific genetic and environmental causes typically requires large-scale, long-term, incidence-based studies that are not feasible with the resources available in this initiative. However, several strategies of lesser scope may be feasible including: studies that focus on candidate toxicants (glutamate and glutamate analogues, those relevant to the neuromuscular system, mitochondrial inhibitors, etc.), studies that focus on populations at elevated risk, data mining of existing databases or the development of epidemiologic resources such as a national case control series. o Genetic Factors Studies that focus on the interactions of genes with other genes and/or environmental factors are of particular interest. Appropriate topics include studies of genetic background effects (i.e., strain surveys, crosses with important other genetically modified mice, etc.), environmental interactions (non-mammalian systems present opportunities to study topics such as infectious agents as triggers and putative environmental toxicants), and the biologic basis of age- dependent motor neuron vulnerability. Classic gene discovery efforts are supported by complementary, ongoing efforts and will not be considered responsive to this RFA. o Cell / Cell Interactions Despite the increasing awareness that ALS is not a disorder of cell autonomous death, our understanding of the signaling between the cell types involved or even the certain identification of the cell types involved is relatively rudimentary. Other important considerations include the switch from protective to pathogenic contributions, the interaction between neuronal oxidative stress and cytokines elaborated by non-neuronal cells. Mice with genes expressed (or deleted) in a cell-specific manner may be particularly informative in this regard. o Cellular and Organellar Dysfunction Notwithstanding contributions from other cell types, ALS is ultimately the expression of motor neuron death and dysfunction resulting from incompletely understood mechanisms (including upstream activators, non-apoptotic contributions of mitochondrial pathology, endoplasmic reticulum stress, etc). There is also a re-emerging appreciation of the axon as an early pathological target in ALS. Recent advances in our understanding of axonal transport and axonal responsiveness to trophic factors may provide new opportunities to investigate pathogenesis in order to develop therapies and restorative strategies. o Protein and Molecular Dysfunction As discussed above, four general classes of pathogenic processes have been observed in patients and animal models. A better understanding of the contribution of each of these processes to the course of the disease may provide opportunities to alter the course of ALS. Other, new opportunities also include alterations in metal handling (Zn2+, effects of metallothionein knockouts), altered axonal transport and the question of whether aggregates are pathogenic or protective. o Novel Approaches to Delivery of Therapeutic Agents Spinal motor neurons may be uniquely unconstrained by the blood-brain barrier, nonetheless delivery of therapeutics remains a challenge and new approaches are clearly indicated. These may entail strategies directly targeting the neuron (specifically/receptor mediated or non- specifically/endocytic) or by exploiting motor neurons' close functional relationship with other cell types (e.g. muscle as a reservoir). o Biomarkers - Biomarkers are critical for early disease detection and more efficient clinical trials. Genomic, proteomic, metabolomic and other novel techniques may be very powerful in the search for biomarkers. MECHANISM OF SUPPORT This public/private partnership involves the research programs of the VA, NINDS and the ALSA. Applications are solicited from VA-based research laboratories, academic-based laboratories and other research enterprises. The RFA will use both VA and NIH award mechanisms: VA Merit Review Awards http://www.va.gov/resdev/directive/mrs.cfm ($500,000 direct cost over two years, no indirect costs) for VA-eligible research laboratories and NIH R21 Awards ($275,000 direct cost over two years, standard NIH indirect costs) for academic-based and other research laboratories. (See http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures at VA and the NIH. The anticipated award date is March 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications at either the VA or NIH using the standard guidelines and receipt dates for NEW applications. This RFA uses just-in-time concepts. It also uses the modular budgeting format for R21 awards. (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an R21 application, use the modular format. 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. FUNDS AVAILABLE Together, the participating organizations intend to commit a total of approximately $2.4 million in FY 04 to fund approximately 10 new grants in response to this RFA. An applicant may request a project period of up to 2 years and a budget for direct costs of up to $275,000 over the course of two years for NIH awards or a budget for direct costs of up to $500,000 over the course of two years for VA awards. This RFA is considered to be a VA special initiative and is open to all eligible VA investigators, regardless of their current VA funding. VA-eligible investigators selected for non-VA funding will be allowed to resubmit their budget to meet the NIH budgetary restrictions above (see "SPECIFIC INSTRUCTIONS FOR VA GRANT APPLICATIONS"). Although the financial plans of the participating institutions provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. Individuals wishing to apply for VA funding must meet all VA eligibility criteria. VA Central Office will verify the eligibility of all investigators applying for VA funding prior to review. SPECIAL REQUIREMENTS The sponsoring organizations have issued several solicitations in areas with significant intellectual or technical overlap with the current proposals. In order to preserve the focus of each initiative, applications will not be considered responsive to this RFA if their principal focus is: o Translational Studies including high throughput drug screens in disease models i.e. applications responsive to PAR-02-139 (NINDS Cooperative Program in Translational Research), PAR-02-138 (NINDS Exploratory/Developmental Projects in Translational Research) or NOT-NS-03-003 (NINDS Administrative Supplements: Testing of Candidate Drug Treatments for Neurodegeneration in Rodent Models) o Gene Discovery in human populations, i.e. applications responsive to PAS-03-092 (Gene Discovery for Complex Neurological and Neurobehavioral Disorders) o DNA Repositories or Patient registries, i.e. applications responsive to NOT-NS-02-012 (Human Genetic Resource Center: DNA and Cell Line Repository) or NOT-NS-02-002 (Genetic Resource Center) WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Paul A. Sheehy, Ph.D. Neurodegeneration Cluster National Institute of Neurological Disorders and Stroke 6001 Executive Blvd, Rm. 2214A Rockville, MD 20892-9525 (301) 496-5329 (v) (301) 480-1080 (f) sheehyp@ninds.nih.gov William J. Goldberg, PhD Medical Research Service (121E) Department of Veteran's Affairs 1400I St., NW Washington, DC 20005 (202) 408-3611 (v) (202) 275-6100 (f) william.goldberg@hq.med.va.gov o Direct your questions about peer review issues to: Alan Willard, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd, Rm. 3208 Rockville, MD 20892-9529 (for courier service) (301) 496-9223 (v) (301) 402- 0182 (f) willarda@ninds.nih.gov o Direct your questions about financial or grants management matters to: Michael Loewe Grants Management Officer National Institute of Neurological Disorders and Stroke 6001 Executive Blvd, Rm. 3258 Rockville, MD 20892-9525 (301) 496-9231 (v) (301) 402-4370 (f) loewem@ninds.nih.gov William J. Goldberg, PhD Medical Research Service (121E) Department of Veteran's Affairs 1400I St., NW Washington, DC 20005 (202) 408-3611 (v) (202) 275-6100 (f) william.goldberg@hq.med.va.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Paul A. Sheehy, Ph.D. Neurodegeneration Cluster National Institute of Neurological Disorders and Stroke 6001 Executive Blvd, Rm. 3208 Rockville, MD 20892-9525 (301) 496-5329 (v) (301) 480-1080 (f) sheehyp@ninds.nih.gov SUBMITTING AN APPLICATION All applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: The Research Plan section in applications for both NIH and VA awards may not exceed 15 pages. No appendices are permitted. Applications for NIH awards should use the modular budget format (see "SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS"). Applications for VA awards will initially also use the NIH modular budget format (see "SPECIFIC INSTRUCTIONS FOR VA GRANT APPLICATIONS"). SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: NIH applications requesting up to $275,000 direct cost over two years must be submitted in a 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 VA GRANT APPLICATIONS: Investigators eligible to apply for VA funding ($500,000 direct cost over two years, no indirect costs) should indicate their VA Medical Center as the academic institution and obtain the appropriate signatures. For the purpose of initial processing, the application submitted should include a modular budget of up to $250,000 per year for two years prepared according to the PHS 398 format (see above). Those selected for funding will be required to revise and resubmit budgets prepared on VA Merit Review budget forms 10-1313-3 and 10-1313-4. VA investigators who submit for VA funding may be selected for non-VA funding. If so, they will be requested to submit a revised cover page indicating their academic institution and appropriate signatures. VA investigators selected for non-VA funding will also be requested to revise and resubmit their budget to meet the NIH budgetary restrictions for this RFA ($275,000 direct cost over two years, in $25,000 modules, plus standard NIH indirect costs). It is anticipated that such awards will be rare. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Alan Willard, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd, Rm. 2214A Rockville, MD 20892-9525 (for courier service) (301) 496-9223 (v) (301) 402- 0182 (f) willarda@ninds.nih.gov APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the VA and the NINDS. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the sponsoring organizations in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a 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 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: o Significance o Approach o Innovation o Investigator o Environment 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. 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). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: September 30, 2003 Application Receipt Date: October 22, 2003 Peer Review Date: December 2003 Council Review: February 2004 Earliest Anticipated Start Date: March 1, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm MONITORING PLAN AND DATA AND SAFETY MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH- defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.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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