STRESS AND DRUG ABUSE: EPIDEMIOLOGY, ETIOLOGY, PREVENTION, AND TREATMENT RELEASE DATE: January 14, 2003 (see correction NOT-DA-03-001) RFA: DA-04-001 National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) LETTER OF INTENT RECEIPT DATE: May 19, 2003 APPLICATION RECEIPT DATE: June 18, 2003 THIS REQUEST FOR APPLICATIONS (RFA) CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 purpose of this RFA is to solicit applications for innovative research on chronic stress and drug abuse or dependence. Research is encouraged on the epidemiology, etiology, prevention, and treatment of drug abuse/dependence, as it relates to either chronic stress or Post Traumatic Stress Disorder (PTSD). More specifically, research is sought to examine the relationship between chronic stress or PTSD and drug use, abuse, and dependence. Also of interest is the relationship between chronic stress or PTSD and withdrawal/abstinence, remission, and relapse. The focus of this RFA is on drug abuse or dependence as they relate to chronic stress, not acute stress. Applications responsive to this RFA should include clearly articulated definitions of the chronic stress construct. Chronic stress has been operationalized and measured in various ways in relevant research. It is incumbent upon applicants to link proposed projects to a method of assessing/measuring chronic stress that meets conventional research standards (e.g., replicable, meets psychometric criteria for reliability) and is appropriate for the type of project that is proposed. Once developed, PTSD can be considered as a type of chronic stress (even though it may follow an acute stressor). In contrast to chronic stress, the construct of PTSD is associated with a generally accepted definition (i.e., a set of psychiatric diagnostic criteria developed by the American Psychiatric Association). Although NIMH is not a direct sponsor of this RFA, research (etiology, epidemiology, prevention and treatment) on chronic stress and PTSD as related to mental health and common comorbid conditions (e.g., substance use and abuse, delinquency, physical health) is of interest to NIMH. RESEARCH OBJECTIVES Background and significance Scientific knowledge about the epidemiology of stress and drug use has been expanding and advances in this area have been significant. In addition, the relationship between stress and drug abuse behaviors has been documented in a number of preclinical studies that focus on the biological and neurobiological basis of the relationship. For example, findings indicate that animals will readily self-administer drugs when exposed to stressors. Human studies that include patients in drug abuse and other health settings have found that stress is a factor leading both to drug use and escalation of use to abuse. However, as yet little is known about the relationship between stress and drug abuse, and the transition from drug use to dependence from epidemiologic studies of population-based samples. Epidemiologic studies, particularly those in which longitudinal designs are used, are critical for advancing the understanding of the pathways from chronic stress to the initiation of drug use and the development of abuse/dependence. Both drug use and stress can affect individuals across the life span. Children and adult victims of sexual and physical abuse or violent assault consistently report higher use of alcohol and drugs. In turn, it has been reported that children who are victims of abuse are more likely to engage in delinquent behavior, crime, and other deviant behavior. Research that uses a developmental perspective is needed to further understanding of the relationship between stress and drug abuse across the lifespan, particularly in childhood and adolescence. Early childhood stress can have major influences on brain development, which in turn could directly affect the etiology of drug use behaviors and the development of abuse and dependence. Despite growing findings from preclinical studies, more research is needed on how chronic stress and PTSD in children and adolescents might be manifested in brain alterations that could increase vulnerability to drug abuse/dependence. Also needed is research to identify genetic predispositions to stress that might influence drug abuse behavior. Given clear links between drug abuse and exposure to chronic stress, including apparent vulnerability for escalation from use to abuse and dependence due to chronic stress, research is needed to characterize neurobiological changes induced by chronic stress that might underlie its relationship to drug abuse. Some recent findings reveal specific effects of stress on brain structure and function. Exposure to stress results in a cascade of biological responses that aids in the assignment of salience to the stressor, resulting in a behavioral response. Chronic stress might compromise the normal function of the hypothalamic pituitary adrenal (HPA) axis. Moreover, chronic stress results in biobehavioral responses that over time can result in neurobiological changes that can be long-lasting. A growing number of studies indicate traumatic stress, arising from various sources, can result in PTSD. In turn, PTSD has been associated with measurable changes in the brain, including reduction in volume in brain areas such as the hippocampus. Findings of this type suggest that stress associated with PTSD, in fact, can be neurotoxic. Yet, it is not entirely clear if stress causes cell loss, or perhaps if individuals with reduced volumes in certain brain areas are particularly vulnerable to chronic stress. Also, the mechanisms by which chronic stress (in individuals with and without PTSD) might lead to drug abuse remain unknown. In sum, studies are needed to help understand how stress interacts with brain systems and how related neurobiological alterations might drive drug abuse behavior, as well as potentially interfere with treatment. Research indicates that accumulated stress may be associated with both the onset and escalation of drug use. That is, the more stressful events or environments experienced, the greater the likelihood of drug problems. In fact, findings support the possibility that a threshold of accumulated risk can be reached beyond which protective factors cease to ameliorate the effects of stressors. Also, children, adolescents and adults can experience ongoing stressors that may place them at risk for future drug abuse. Ongoing stressors include both sub-optimal environments (e.g., homes that are conflictual and discordant, homes in which a parent, guardian or sibling is a substance abuser, or neighborhoods with high levels of crime and drug use) and certain life experiences (e.g., ongoing physical or sexual abuse; living with chronic pain; repeated or long-term unemployment). A variety of behavioral interventions to prevent or manage chronic stress have been produced through research, such as teaching problem-solving and affect management, restoring one's sense of purpose and meaning, and training in relaxation and meditation methods. Existing or novel stress management interventions might be used in the development or refinement of behavioral interventions for the prevention or treatment of drug abuse in the context of chronic stress or PTSD. Findings on individual differences in response to potential stressful events suggest that moderators and mediators play an important role in the human stress response. For example, variables such as cognitive appraisal, coping, personality features, and social relationships have been found to moderate responses to potentially stressful life events. Models of successful coping with stress include constructs like resilience, hardiness, and post-traumatic growth. Given that drug abuse is sometimes conceptualized as a maladaptive response to stressors, findings on moderators and mediators of stress might be applied in prevention and treatment research for drug abuse. For example, the relationship between gender, chronic stress, and drug abuse needs to be better understood. Findings on the co-occurrence of drug abuse and PTSD (e.g., 50% of treatment- seeking drug abusers meet criteria for PTSD during their lifetime) suggest that PTSD might have particular relevance to the etiology, prevention, and treatment of drug abuse and dependence. Some studies suggest that drug abuse may precede PTSD; others suggest that PTSD symptoms function as a "trigger" for drug use, thereby contributing to the development and maintenance of drug abuse and dependence as well as relapse. Such research suggests the potential value of developing interventions to prevent the onset and escalation of drug abuse in individuals exposed to trauma, even where questions about causal pathways are not resolved. Comorbid drug abuse or dependence can complicate existing treatments for PTSD. Research suggests that individuals with PTSD tend to have poorer outcomes with existing behavioral drug abuse treatments than those without PTSD. A number of pharmacotherapies have shown beneficial effects when used for PTSD. Yet, few medications have been tested for drug abusing individuals with comorbid PTSD, or tested in combination with behavioral treatments for such populations. There is a growing body of literature indicating that stress does not play an equal role in males and females. In rodents, for example, stress facilitates classical conditioning in males, but impairs classical conditioning in females. In humans, males exhibit a greater cortisol response than females to acute psychological stress, and brain imaging studies have shown that stressful emotional tasks produce gender differences in regional cerebral activation patterns. Females have higher lifetime rates of PTSD and there is considerable evidence for sex differences in coping with stress. The conditional risk of developing PTSD following trauma exposure is two times greater in women which is attributable to women having a much greater risk of PTSD following assaultive violence than men. For women, sexual abuse is associated with more psychopathology than is physical abuse, but the inverse relationship holds for men. Among individuals in drug abuse treatment, females have significantly higher rates of comorbid PTSD than do males, and PTSD is more likely to precede drug dependence in females than in males. And, there is evidence that stress many play a larger role in relapse in females than males. Given such gender differences in PTSD and the impact of stress, researchers are encouraged therefore to take a gender-based approach in their study designs and to propose gender-based hypotheses. In sum, more research is needed to better understand the epidemiologic and etiological relationships between chronic stress and drug abuse, and how to prevent and treat drug abuse in individuals experiencing chronic stress. Similar research needs exist on PTSD as it relates to drug abuse and dependence. Investigators interested in chronic stress relative to service delivery, including organization and financing issues should note PA-01-097, Drug Abuse Health Services Research (http://grants.nih.gov/grants/guide/pa-files/PA-01-097.html). Areas of Research Interest The examples listed in the sections below illustrate the types of research that would be responsive to this RFA. Types of research encouraged include but are not limited to: Epidemiology Population-based and clinical research on the extent to which exposure to chronic stress signals an increase in the risk of drug use, abuse and dependence is of interest. Epidemiological studies that focus on individual and environmental factors specific to chronically stressed individuals that enhance vulnerability to drug use or relapse to drug use are specifically sought. Studies are sought examining the epidemiology of co-occurring chronic stress and drug abuse or dependence in the general population. This includes research investigating moderators of the relationship between these variables. For example, it is important to understand gender differences in the effects of chronic stress and the effects of biological and physiological mechanisms that contribute to differential response to stress. Also, the identification of "protective" factors that might attenuate the impact of chronic stress on drug abuse is particularly important due to implications for prevention and treatment. o Studies to examine social, cultural and environmental influences on chronic stress and drug abuse/dependence within and across racial and ethnic groups. o Differential effects of chronic stress during stages of drug use and the influence of other co-existing psychiatric disorders. o The influence of gender on pathways from chronic stress to stages of drug use. o Studies to examine the influence of environmental conditions (e.g., neighborhood disadvantage, crime, violence) on the co-occurrence of chronic stress and drug abuse/dependence. o Studies to examine differential effects of continued, repetitive, traumatic events on drug use across different age groups, especially during adolescence and young adulthood (to expand our understanding the relationship between chronic stress and drug abuse). Etiology This RFA encourages human research studies on how chronic stress across the developmental trajectory (e.g., prenatal, perinatal, childhood, adolescence, early/mid/late adulthood) affects risk for drug-seeking or drug-taking behavior and abuse/dependence or relapse. Studies utilizing objective measures of stress-induced developmental changes are sought. This includes studies measuring physiological (e.g., pupillary dilation, cortisol secretion) reactivity to stressful situations or to laboratory events such as acoustic startle. While such physiological responses to stress currently are studied, their relationships to vulnerability to drug abuse are virtually unexplored. Genetic effects are strongly associated with drug abuse as are environmental effects, but the contribution of each of these factors, and especially gene-environment interactions, are much less studied and constitute a research gap. Personality characteristics of children and their interaction with home (including, for example, foster care) and school environments constitute one research focus relevant to the gene-environment question. Less obvious sources of early stress, such as natural disasters or death of a parent, might be contributory and thus, constitute an important additional focus for research. Examples include: o Effect of long-term early stress on adult stress response and drug abuse, particularly with respect to neurobiological aspects of stress. o Effects of early stress on neurobiological and neurobehavioral processes in development, and how changes may place a child or adolescent at risk for drug abuse. o Studies on how drug abuse may contribute to or bring about stress (e.g., physical or sexual assault, victimization, violence) and/or PTSD. o Studies on how drugs can be used to "self-medicate" or to produce relief from stress. o Objective measures of chronic stress either as a precursor to, or concurrent with, drug abuse. o Studies of biological/psychological/environmental/social factors that might protect an individual from stress and thereby reduce drug abuse risk. o Investigations of individual differences in response to chronic (external) stressors and their relation to drug abuse. o Characterization of etiological effects of early sub-optimal environments (e.g., orphanages, poverty- or crime-ridden neighborhoods) and later drug use. o Determination of the role of chronic stress in drug abuse relapse. Studies on the neurobiology of trauma, particularly as related to the subsequent experience of PTSD concurrent with drug abuse Prevention Applications are desired for interventions to prevent the onset of drug use or its escalation to abuse as a result of chronic stress. Interventions can be delivered in many types of environments, including hospitals, emergency rooms, faith-based and community organizations, schools, workplaces, etc. Examples include: o Development and testing of strategies to prevent drug abuse initiation among individuals who have experienced long-term physical, sexual, and/or psychological/emotional abuse. o Testing community-based interventions designed to prevent onset of use or escalation to drug abuse among chronically stressed children, youth, and families living in neighborhoods with characteristics that have been associated with chronic stress (e.g., crime, victimization, chronic unemployment, unsafe streets, etc.) o Testing strategies designed to prevent dependence on prescription drugs in chronically stressed individuals who live with chronic pain. o Development and testing of early prevention interventions that target chronically stressed children who have lived in multiple out-of-home placements such as foster care, group homes, and institutions. o Development and testing of strategies for preventing drug abuse conditions in chronically stressed individuals who are part of minority groups and communities that may have experienced intergenerational stress or historical trauma (such as American Indians and African Americans). Treatment Research is encouraged on the treatment of drug abusing or dependent individuals who concurrently are experiencing chronic stress or PTSD. This includes research on innovative approaches to stop the progression from drug use to abuse and dependence due to the effects of chronic stress, including the development and testing of behavioral treatments, alone or in combination with pharmacotherapies, for drug abusing or dependent individuals with comorbid PTSD or chronic stress. Given that individuals with the foregoing problems also can be at high risk for HIV/AIDS and other medical conditions, research also is encouraged that includes attention relevant to these factors. Behavioral treatment and combined behavioral and pharmacological treatment studies in response to this RFA should be guided by NIDA's Behavioral Therapies Development Program, PA NUMBER: PA-99-107 http://grants.nih.gov/grants/guide/pa-files/PA-99-107.html. Although PA-99- 107 delineates three stages of behavioral therapy research, this RFA solicits only applications for Stage I and Stage II studies of all forms of behavioral treatment, including psychotherapy, relapse prevention, counseling, group therapy, family therapy, couples therapy, etc. Stage I research involves the development, modification, and pilot testing of novel behavioral interventions. Stage I projects also may focus on incorporating novel technologies (e.g., information technologies such as hand-held computers, multimedia CD ROM programs, and instant messaging) into behavioral interventions. Stage II behavioral treatment research involves testing behavioral interventions and studies that are designed to identify the efficacious components of behavioral interventions. Behavioral treatment studies also can extend to the identification of moderators and mediators of the effects of potentially efficacious components of behavioral interventions. Treatment research proposals responsive to this RFA should focus on drug abusing/dependent individuals who also are experiencing chronic stress or PTSD. Examples are: o Enhancement of treatments with existing or novel stress management interventions. o Using innovative models of successful coping with stress (e.g., resilience, toughening) to inform the development of novel treatments. o Studies to determine if additional trauma-specific interventions enhance the outcome of treatment when used for drug abusers with PTSD. o Studies to determine new or more effective ways to combine medications with behavioral treatments for individuals with concurrent drug use disorders and PTSD. o Treatments designed to treat individuals who are dependent upon or abusing prescription drugs for chronic pain or for other medical conditions that are associated with chronic stress. o Treatments to enhance adherence to medication, including medication for comorbid psychiatric conditions, HIV, or for other infectious disease o Treatments that incorporate behavioral risk-reduction interventions for HIV or other infectious diseases for drug abusers who also suffer from chronic stress. o Studies of efficacious therapies in which dismantling or additive designs are used to identify their main active components, and/or the moderators and mediators of potential effects of active components of efficacious treatments. o Studies of the role of chronic stress in behavioral treatment engagement, retention, and/or maintenance of treatment gains. o Evaluation of potential efficacy of medications which alter responsiveness of HPA axis, in combination with behavioral therapy, as potential therapies for drug dependence. o Studies examining the value of gender-specific treatment of individuals with comorbid drug abuse and PTSD MECHANISM OF SUPPORT This RFA will use NIH research project grant (R01) award mechanism. 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 anticipated award date is June 2004. This RFA 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. FUNDS AVAILABLE NIDA intends to commit approximately $2,500,000 in FY 2003 to fund 8 to 10 new grants in response to this RFA. An applicant may request a project period of up to 5 years. 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 NIDA provides 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. 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: Lisa Onken, Ph.D. Division of Treatment Research and Development National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 4123, MSC 9551 Bethesda, MD 20892-9551 Telephone: 301-443-2235 Fax: 301-443-8694 E-mail: Lisa_Onken@nih.gov o Direct your questions about peer review issues to: Teresa Levitin, Ph.D. Office of Extramural Affairs National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Telephone: 301-443-2755 Email: tlevitin@mail.nih.gov o Direct your questions about financial or grants management matters to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3131 MSC 9541 Bethesda, MD 20892-9541 Telephone: 301-443-6710 E-mail: gfleming@mail.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: Director Office of Extramural Affairs National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD 20852 (for express/courier service) Telephone: 301-443-2755 Fax: 301-443-0538 Email: tlevitin@mail.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 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. 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 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. 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/DHHS 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: Director Office of Extramural Affairs National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD 20852 (for express/courier service) 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 substantial revisions of applications already reviewed, but such applications 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 NIDA. 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 NIDA 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 Council on Drug Abuse 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 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: May 19, 2003 Application Receipt Date: June 18, 2003 Peer Review Date: November/December 2003 Council Review: February 2004 Earliest Anticipated Start Date: June 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 MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phases 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: 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 AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm 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 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. HIV/AIDS COUNSELING AND TESTING POLICY FOR THE NATIONAL INSTITUTE ON DRUG ABUSE: Researchers funded by NIDA who are conducting research in community outreach settings, clinical, hospital settings, or clinical laboratories and have ongoing contact with clients at risk for HIV infection, are strongly encouraged to provide HIV risk reduction education and counseling. HIV counseling should include offering HIV testing available on-site or by referral to other HIV testing service for persons at risk for HIV infection including injecting drug users, crack cocaine users, and sexually active drug users and their sexual partners. For more information see http://grants.nih.gov/grants/guide/notice-files/NOT-DA-01-001.html. NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS: The National Advisory Council on Drug Abuse recognizes the importance of research involving the administration of drugs to human subjects and has developed guidelines relevant to such research. Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Home Page at http://www.nida.nih.gov under the Funding, or may be obtained by calling (301) 443-2755. 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. 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. 93.279, 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 http://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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