HIV/AIDS AND AGING: BASIC AND CLINICAL RESEARCH RELEASE DATE: October 10, 2002 RFA: MH-03-004 National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov/) National Institute on Aging (NIA) (http://www.nia.nih.gov/) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov/) LETTER OF INTENT RECEIPT DATE: December 13, 2002 APPLICATION RECEIPT DATE: January 13, 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 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 The National Institute of Mental Health (NIMH), the National Institute on Aging (NIA), and the National Institute on Drug Abuse (NIDA) invite research grant applications through this Request for Applications (RFA) to support research about older adults (greater than 50 years of age) infected with human immunodeficiency virus (HIV). This is an age group that has been overlooked or ignored by many researchers throughout the pandemic. A major goal of this RFA is to begin a process where basic and clinical scientists from various disciplines can overcome barriers to cross-disciplinary aging research in the context of HIV disease and its treatment. The purpose of this initiative is to: (1) focus the attention of basic and clinical scientists on the neurodegenerative processes contributing to the central nervous system (CNS) complications in HIV infection in the elderly; (2) promote the interaction of basic and clinical scientists conducting research in HIV disease in the elderly; and (3) develop integrative research programs that advance our understanding of the substrates underlying CNS complications in HIV disease in the elderly. The principal CNS complications addressed by this RFA include neurocognitive, neurobehavioral, and neuropsychiatric and drug abuse sequelae of HIV infection (these conditions as antecedents may also be of interest). Because this is an emerging area of interest, but poorly understood and understudied, it is necessary to address a wide range of scientific opportunities to move the field forward. We particularly encourage applications that demonstrate the establishment of collaborative research programs with researchers at existing centers of excellence with a focus on issues related to the elderly infected with HIV. RESEARCH OBJECTIVES Background People living with HIV disease are growing older. Additionally, between 1991 and 1996, the number of new AIDS cases rose twice as fast in persons 50-plus years of age than it did in persons younger than 50 (22% vs 9%, respectively; CDC, 1998). According to the CDC, reported rates of persons living with AIDS suggest that older adults account for up to 15% of the AIDS caseload, representing an increase of about 5% from 1997-1999. Further, as highly active antiretroviral therapy (HAART) prolongs periods of survival, the older population among those with HIV is likely to expand, as many persons who contracted HIV in their 30s and 40s are living well into their 50s, 60s, and 70s. In view of these trends, there is a need for basic epidemiological research on HIV and HIV-associated CNS complications in older adults. Compelling evidence exists that natural history and symptom manifestations of HIV infection in the elderly substantially differ from those seen in younger cohorts. Relative to their younger counterparts, older adults living with HIV/AIDS have a more severe HIV disease course and a shorter survival rate; have less desirable health indices at diagnosis (e.g., lower CD4+ cell counts); have shorter AIDS-free intervals; have a higher number of opportunistic infections; and have earlier development of tumors and lesions. These differences between older and younger HIV-infected adults could be due to immunosenescence; the presence of underlying conditions associated with aging; the existence of current and/or past history of drug abuse; HIV-related medical sequelae and CNS complications; and the adverse effects of certain medical treatments. Research is needed to determine the mechanisms at work in an aging immune system and to determine whether there is a difference in immune reconstitution following HAART between younger and older HIV-infected populations and how this difference might impact the development of neurocognitive dysfunction. In addition, older Americans have their own population-specific health challenges, such as Alzheimer's disease, osteoporosis, adult-onset diabetes, prostate cancer, menopause, and hypertension. There is even evidence that an interaction between HIV-induced pathophysiologies and Alzheimer's disease-related pathophysiologies may be occurring, and this interaction would have important implications for aging. HIV risk may also be intensified by a pre-existing compromised immune system caused by other health problems, drug abuse, or the aging process per se. Among health risks that may be associated with HIV or its treatment via HAART are neurologic complications (such as myelopathy, neuropathy and neuropathic pain, changes in cognition, and dementia) and psychiatric complications (such as mania, depression, schizophrenia, and substance abuse and dependence). It has been shown that increased neurocognitive complications occur as a function of chronological age, but we do not know whether this relationship can be accounted for by age-associated comorbidities. Studies have also shown that HIV infection may exacerbate psychiatric conditions, including major depression, bipolar disorder, and schizophrenia, but this exacerbation has not been clearly documented in a population of older adults. Moreover, since many individuals with HIV infection have either a history of and/or current drug abuse/dependence, the roles of these factors in the onset, pathophysiology, and course of HIV disease in the elderly need to be elucidated. Thus, research is needed to distinguish the medical complications of aging from the psychiatric, substance abuse, and neurocognitive sequelae. Presently, it is unclear whether the neuropsychiatric and neurocognitive complications in HIV disease are reflections of similar processes that cause functional aging or whether they are interactions of HIV disease with the aging process. Fundamental to all of this work is the need for reassessment and refinement of HIV-associated dementia (HAD) in the elderly. The pattern of cognitive impairment may be much different in older HIV-infected persons than in younger infected persons due to the presence of other dementing conditions in older adults (besides HAD) which confound the individual's cognitive dysfunction in the context of HIV. HAART has been effective in improving neurocognitive performance and decreasing the incidence of HIV dementia. However, prospective studies are needed among older persons to address appropriateness of current HAART dosage, susceptibility to HAART side effects, and the potential for increased vulnerability to adverse drug reactions due to changes associated with the aging process (e.g., body composition changes, decline in kidney function, and changes in the metabolism of older persons). Purely on a pharmacokinetic basis, one might predict higher and steadier plasma concentrations because of reduced clearance and/or other metabolic processes/effects. However, it is a significant concern that the metabolic complications of HAART therapy may compound or accelerate processes leading to vascular disease morbidity, which would become increasingly problematic with age and chronic use of the drugs. In addition, research will need to address age-dependent changes in the blood-brain barrier (BBB) to design optimum therapies. SCOPE This RFA solicits applications to evaluate a large variety of outcomes in older HIV seropositive adults, including observational, biological, clinical, and treatment variables, and to address research questions in the following domains: (i) HIV-related medical and CNS complications; (ii) neuropsychiatric conditions and substance use disorders; (iii) neurobehavior, neurocognitive disorders, and neuroimaging; (iv) virology and immunology; (v) neuropathogenesis mechanisms; and (vi) drug treatment research. Longitudinal designs may be needed for both observational cohort studies and hypothesis-driven experimental studies. There may be benefit in drawing upon existing multicenter databases in HIV/AIDS research. The areas of research below are illustrative; they are not intended to be exhaustive. However, the proposed research should fall within the major category areas: (1) Epidemiology, Natural History, and Transmission, (2) Basic Science, (3) Human Clinical Investigations, and (4) Human Clinical Interventions. Epidemiology, Natural History, and Transmission o Studies of the incidence, prevalence, and natural history of neurocognitive deficits and psychiatric and substance use disorders in older HIV-infected adults. Are the nature, severity, course, or treatment of HIV-associated neurocognitive and psychiatric disorders in older HIV-infected adults different from the nature, severity, course, or treatment of those disorders in older uninfected controls and in younger HIV+ comparison groups? Is there an additive/multiplicative effect of advancing age and brain disease? o Epidemiologic cohort studies in HIV-infected older adults to investigate the mechanisms of disease progression, key cofactors that modify HIV disease (i.e., infectious, nutritional, comorbidities), and the impact of therapy in changing the spectrum of HIV disease. o Investigations of HIV-associated neurocognitive deficits and psychiatric and substance use disorders in the elderly as predictors of later HIV-associated disease progression. How does neurocognitive function, neuropsychiatric status, and substance use disorder vary as a function of disease stage in the elderly? What are the factors associated with fluctuations in neurocognitive and neuropsychiatric complications (e.g., adherence)? o Studies that characterize the epidemiology of sexual and drug-use risk behaviors among older adults infected with HIV. What are the correlates and determinants of those behaviors and how does this inform the development of subsequent prevention efforts? o Research on the role of potential cofactors, correlates, and mediators of HIV disease progression in the elderly (e.g., gender, immunological decline, infectious agents, alcohol and drug use, neuropsychiatric status, neurocognitive dysfunction). Basic Science o Develop relevant animal models for studying neurocognitive deficits in older adults infected with HIV. o Research to determine the cellular and molecular bases of and pathogenic mechanisms in HIV-associated neurocognitive, neurobehavioral, and neuropsychiatric dysfunction in the elderly. o Determine factors associated with clinical response and lack of response to HAART and other therapeutic interventions for neurocognitive, neurobehavioral, and neuropsychiatric complications of HIV disease in the elderly. o Studies that delineate the role of opportunistic infections, co-infections (e.g., hepatitis C, tuberculosis), and other age-related disease complications (e.g., hypertension, diabetes, metabolic disorders) on neurocognitive, neurobehavioral, and neuropsychiatric complications of AIDS in the elderly (including CNS dysfunction and peripheral neuropathies) and their impact on immune dysfunction and disease progression. o Investigate aspects of HIV infection that uniquely influence the aging nervous system and impact on the neurocognitive, neurobehavioral, and neuropsychiatric dysfunction in the elderly. Human Clinical Investigations o Studies of the determinants of increased neurocognitive dysfunction in the elderly infected with HIV. What roles do comorbidities, host factors, treatment toxicities, aberrant immune reconstitution, and HIV infection per se play in its development? o Studies that utilize novel imaging techniques for human neuroanatomy to examine the neural systems damaged in HIV infection of the elderly (e.g., MRI brain morphometry; MRI perfusion methods; MRI diffusion tensor analysis; MRI cytoarchitechtonic). These studies should also investigate whether this information can be correlated with neurocognitive impairment and neuropsychiatric and substance use disorders seen in older HIV-infected patients. o Studies that examine the potential correlation between neurocognitive impairment and neuropsychiatric and substance use disorders with neuropathology in HIV-infected older adults. What is the temporal relationship between pathology identified at end stage disease and the actual onset of the motor/cognitive impairment seen throughout the disease process in the elderly? o Research on neurocognitive and neuropsychiatric substrates of adherence to prevention and treatment programs in the elderly infected with HIV, focusing on such issues as executive functioning, aspects of memory related to adherence, neural systems involved in motivation, etc. o Studies that compare the effects of aging processes in the brain (e.g., atrophy, neurotransmitter changes, alterations in BBB integrity), age-related neurodegenerative disease (e.g., Alzheimer's disease, vascular dementia), and neuro-AIDS abnormalities in older adults. o Studies of virological and immunological indicators in HIV infection in the elderly. These studies should also investigate whether this information can be correlated with neurocognitive impairment and neuropsychiatric and substance use disorders seen in older HIV-infected patients. What immune dysfunctions are common to aging and to HIV infection? Is there increased immune activation in the elderly? Can this be tied to the development of neurocognitive dysfunction in the elderly? Human Clinical Interventions o Clinical trials to determine the optimal therapeutic approaches to the management of HIV infection in the elderly, including when to start, change, or sequence therapy. How can regimens be modified according to age, age-related comorbidities, and age-related deficiencies in the immune system and alterations in CD4 lymphocyte function? o Studies of the impact of antiretroviral therapies (with differing abilities to penetrate the CNS) on neurocognitive, neuropsychiatric, and substance use disorders in the elderly; drug interactions between antiretrovirals; and pharmacotherapeutics for neuropsychiatric and CNS complications and for other comorbid disorders. o Research to develop and evaluate new agents and strategies for preventing and treating opportunistic infections (shown to be increased in the elderly) or other co-infections (especially hepatitis C and tuberculosis) and for reducing the increased antiretroviral-related toxicity that might be anticipated because of immunocompromise in the elderly. o Studies to develop and evaluate therapeutic approaches that will improve and sustain immune function in the elderly. What markers predict the efficacy of immune-based therapies in the elderly? Investigations to develop neuroprotective agents for immune reconstitution to minimize impairment due to neurocognitive dysfunction and neuropsychiatric disorder in the elderly. o Studies of antiretroviral-associated age-dependent differences in toxicities, metabolic complications, and immune reconstitution and their impact on improved neurocognitive function. MECHANISM(S) OF SUPPORT This RFA will use the NIH research project grant (R01), Collaborative R01, and exploratory/developmental (R21) award mechanisms. 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. The earliest anticipated award date is July 1, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see https://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. FUNDS AVAILABLE The NIMH intends to commit approximately $1,500,000 in FY 2003 to fund 6 to 8 new and/or competitive continuation grants in response to this RFA. The NIA intends to commit approximately $750,000 to fund 3 to 5 new and/or competitive continuation grants in response to this RFA. The NIDA intends to commit approximately $750,000 to fund 3 to 5 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 3 years and a budget for direct costs of up to $125,000 per year for an Exploratory/Developmental Grant (R21). For those applications that include a subcontractual/consortium arrangement, direct costs of up to $150,000 per year may be requested to allow for facilities and administrative (F&A) costs on those consortium arrangements. A research project grant (R01) may involve either a single Principal Investigator or a group of investigators using the Collaborative R01 mechanism; applicants may request a project period of up to 5 years, with a budget determined by the work proposed. Applicants for the Collaborative R01 Grant are strongly encouraged to familiarize themselves with the NIMH announcement (https://grants.nih.gov/grants/guide/pa-files/PA-01-123.html), most notably, the requirement to list all performance sites on page 2 of the 398 application kit and the requirement to provide an overview no longer than 2 pages to describe the overall rationale for applying as a collaborative study, the role of each site, any elements unique to a site, and the approach to project management. Questions regarding the use of the Collaborative R01 mechanism may be directed to program staff listed under INQUIRIES. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the participating ICs 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. At this time, it is not known if this RFA 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 o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institutions to develop applications for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. 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: David M. Stoff, Ph.D. Center for Mental Health Research on AIDS Division of Mental Disorders, Behavioral Research and AIDS National Institute of Mental Health 6001 Executive Boulevard, Room 6210, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301) 443-4625 FAX: (301) 443-9719 Email: dstoff@nih.gov Andrew A. Monjan, Ph.D., M.P.H. Chief, Neurobiology of Aging Branch National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307, MSC 9205 Bethesda, MD 20892-9205 Bethesda, MD 20814(for express/courier service) Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: am39m@nih.gov Sander Genser, M.D., M.P.H. Head, Medical Consequences Unit Center on AIDS and Other Medical Consequences of Drug Abuse (CAMCODA) National Institute on Drug Abuse 6001 Executive Boulevard, Room 5198, MSC 9593 Bethesda, MD 20892-9593 Telephone: (301) 443-1801 FAX: (301) 594-6566 Email: sg73f@nih.gov o Direct your questions about peer review issues to: Michael Kozak, Ph.D. Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6138, MSC 9608 Bethesda, MD 20892-9608 Telephone: (301-) 443-6471 FAX: (301) 443-4720 Email: mkozak@nih.gov o Direct your questions about financial or grants management matters to: Brian Albertini Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6135, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301-) 443-0004 FAX: (301) 443-6885 Email: albertinib2@mail.nih.gov Linda Whipp Grants and Contracts Management Officer National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: whippl@nia.nih.gov Gary Fleming, J.D. Chief, Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301-) 443-6710 FAX: (301) 594-6847 Email: gf6s@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows 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: David M. Stoff, Ph.D. Center for Mental Health Research on AIDS Division of Mental Disorders, Behavioral Research and AIDS National Institute of Mental Health 6001 Executive Boulevard, Room 6210, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301) 443-4625 FAX: (301) 443-9719 Email: dstoff@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://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. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs 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 https://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 https://grants.nih.gov/grants/funding/modular/modular.htm. 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: https://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 (and appendices) must be sent to: Jean G. Noronha, Ph.D. Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6154, MSC 9609 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 44303367 FAX: (301) 443-4720 Email: jnoronha@mail.nih.gov APPLICATION PROCESSING: Applications must be received by 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. 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. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the participating ICs. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR 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 participating ICs 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 the National Advisory Mental Health Council, the National Advisory Council on Aging, and the National Advisory Council on Drug Abuse (NIDA). 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 your 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 your application's overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your 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? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: 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 included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o 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: December 13, 2002 Application Receipt Date: January 13, 2003 Peer Review Date: March 2003 Council Review: May 2003 Earliest Anticipated Start Date: July 1, 2003 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 MONITORING PLAN AND DATA SAFETY AND 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 Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://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 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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://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 https://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 https://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 https://grants.nih.gov/grants/stem_cells.htm and at https://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 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 https://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. 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 No. 93.242, 93.866, and 93.279 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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