DEVELOPING TRANSLATIONAL RESEARCH ON MECHANISMS OF EXTINCTION LEARNING RELEASE DATE: August 20, 2003 RFA Number: RFA-MH-04-005 National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.272, 92.279 LETTER OF INTENT RECEIPT DATE: November 18, 2003 APPLICATION RECEIPT DATE: December 18, 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 The National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA) seek to encourage the development of collaborative research projects between basic scientists studying animal models of extinction learning and clinicians focused on the treatment and prevention of anxiety and drug addiction in humans. Recent advances in characterizing the neural mechanisms mediating extinction learning in both animals and humans present new opportunities for translational research focused on understanding how deficits in extinction learning are related to psychiatric disorders characterized by maladaptive fear responses (e.g., PTSD, phobias, OCD, panic disorder, GAD). Accordingly, the NIMH and NIDA are issuing this RFA to foster collaborations between basic and clinical researchers who are focusing their research interests on extinction mechanisms. The goal of this RFA is to promote the development of innovative pilot projects that incorporate multidisciplinary approaches to the study of extinction learning and to accelerate the development of novel pharmacological, behavioral, and cognitive therapies for anxiety and drug disorders that are marked by deficits in extinction learning and/or the inability to consolidate safety signals. RESEARCH OBJECTIVES Background NIMH estimates that anxiety and related fear disorders affect more than 19 million people in the US alone, resulting in significant losses in productivity, reductions in quality of life, and increased rates of suicide. In addition, according to the 2001 National Household Survey on Drug Abuse, the estimated number of past month illicit drug users in the US was 15.9 million. Furthermore, of all adults diagnosed with severe mental illness, it is estimated that 20.3 percent are also dependent on or abuse alcohol or illicit drugs. Studies of fear conditioning in animals have led to significant advances in our understanding of the behavioral and neural mechanisms mediating the acquisition, consolidation, and expression of fear responses. However, much less is known about how fear associations are acquired and consolidated in humans and the neural substrates involved in uncoupling these associations in order to eliminate maladaptive fear responses. The inability to extinguish fearful responses when they are no longer appropriate is a hallmark of most anxiety disorders, and in particular, PTSD. Consequently, the objective of most behavioral therapies is to reduce resistance to extinction learning and promote the formation of new associations that eliminate the fear response. Recent findings characterizing extinction processes in animals suggest that the neural populations mediating extinction memory are distinct from those mediating the acquisition, memory, and expression of fear responses. These findings suggest the field is now poised to generate data providing additional insights into the neural and behavioral mechanisms underlying the ability to extinguish previously learned fear associations. Extinction is also significant in substance use disorders, and addressing it in treatment is presumably relevant to outcome. Drug addiction is a chronic relapsing disorder that has many characteristics that may include a persistent desire or compulsion to use a drug, loss of control of drug intake, reduction in other important activities because of drug use, continued use despite knowledge of harm, marked tolerance, characteristic withdrawal symptoms, and an increased negative emotional state or stress when the drug is unavailable. The process of becoming addicted to drugs often begins with non-compulsive or occasional use, which, over time, can lead to intense craving and compulsive, uncontrollable drug taking, and relapse following periods of abstinence. This process has been characterized as one of learning, involving instrumental and classical conditioning. Moreover, basic drug addiction research has shown that exposure to drugs of abuse involves neuroadaptations in learning and memory systems and that extinction of drug-associated stimuli and responses can decrease drug-seeking behavior and modify the underlying neural substrates. In contrast, research has shown that relapse behavior occurs following exposure to drug-related cues; for example, in the absence of specific extinction procedures, the motivation to self-administer cocaine increases during a 60-day course of abstinence. However, knowledge of these processes is often not incorporated explicitly into treatment. As with anxiety disorders, the field is now poised to investigate the mechanisms underlying extinction of learned associations and drug-taking behaviors. Basic research on extinction learning can now be used to inform and accelerate the development of novel therapies for these disorders. In turn, clinical studies of substance abuse disorder can lead to the development and validation of animal models. In addition, because anxiety and substance use disorder often co-occur, this initiative provides a unique opportunity to investigate the role of extinction in treating these comorbid disorders. Objectives and Scope At a recent workshop organized by NIMH entitled "Mechanisms of Extinction Learning: Basic, Clinical and Translational Research," current findings from basic research on extinction mechanisms and from clinical research on treatment strategies for anxiety disorders were presented, evaluated, and discussed. There was agreement that knowledge gained from animal studies on the normative mechanisms of extinction learning and consolidation (neurobiological, behavioral, and molecular) could inform the development of improved treatments for anxiety disorders and drug addiction. Another opportunity for translational advances is clinical studies of patients suffering from fear and anxiety disorders that can inform the development of animal models that more closely parallel the behavioral and psychological abnormalities associated with these disorders. Specific issues related to the unique circumstances surrounding the etiology and treatment of human disorders were identified and recommendations were made to refine existing animal models to better reflect the factors contributing to the onset, time-course, and successful treatment of these disorders in humans. Clinical and basic scientists agreed that collaborative activities between these two groups of researchers could accelerate the development of novel treatments for anxiety disorders and substance abuse. Accordingly, NIMH and NIDA are issuing this RFA to build on recent basic and clinical research findings regarding the mechanisms underlying extinction learning and exposure therapy, resistance to extinction and current treatment procedures, and factors that contribute to the consolidation of extinction learning and the prevention of relapse. Some of the scientific areas that are likely to have important implications for understanding the basic mechanisms underlying extinction processes and that would benefit from translational approaches include: 1) In humans and animals, recent studies have begun to elucidate the respective roles of the amygdala, prefrontal cortex, and anterior cingulate cortex in extinction learning and its consolidation. Of primary importance is establishing the extent and limits of the homology of these regions and their connections between rodents and primates (human and non-human). If multiple sites of plasticity for extinction processes exist, as suggested by these recent studies, what are the implications of this for translational research and therapy development? 2) During behavioral therapy, habituation procedures are often used in conjunction with other forms of exposure. Are habituation and extinction mediated by separate neurobiological mechanisms? Additional studies comparing the effects of extinction versus habituation in both humans and animals are necessary to determine if there is a clinically relevant distinction between these two forms of learning. Similarly, animal studies focused on identifying the neural circuitry mediating these different forms of learning could provide important insights with clinical relevance. 3) While there is a large literature on the effects of context during fear conditioning and, to a lesser degree, during extinction, much of this work has been done in animals. More recent clinical studies suggest that contextual cues can be used to strengthen extinction learning and prevent relapse. Additional work in both animals and humans incorporating multiple contextual factors (external and internal cues, cognitive instruction, etc.) is critical to determining the role of context in extinction learning and consolidation. 4) Various neurotransmitter systems have been implicated in both the acquisition and consolidation of fear conditioning and extinction and certain agonists and antagonists have been shown to block or facilitate these processes. Identification of compounds potentially capable of altering these processes, and the characterization of their effects could provide novel insights into the neuropharmacological substrates mediating anxiety disorders and drug addiction. Identification of suitable candidate compounds for future use in clinical trials would be a significant advance. 5) Very few animal or human studies have examined early risk factors (e.g., social, behavioral, environmental, and genetic) that contribute to the inability to extinguish inappropriate fear responses or consolidate safety signals. Accordingly, research aimed at identifying both external conditions and internal characteristics that impact extinction mechanisms in later life is critical. Specific activities to be supported under this RFA include: 1) the development, organization, and implementation of collaborative research networks; 2) pilot studies to demonstrate the feasibility of particular translational research approaches; 3) the development of basic research methodologies that could be applied to a clinical setting. Emphasis should be placed on how data will be integrated between basic and clinical studies so that the goal of achieving clinical relevance may be realized. Applications must include a short introductory paragraph in the research plan section identifying which of these categories is relevant for the application. It is expected that these initial collaborative activities will lead to larger research proposals (e.g., R01 applications) focused on specific hypotheses about the neural basis of extinction and the development of novel approaches to the treatment of disorders characterized by deficits in extinction learning. Some examples of potential research topics for both human and animal studies include, but are not limited to: o Imaging and lesion studies in both animals and humans focused on identifying the neural substrates critical for extinction learning, retention, and consolidation, including the development of extinction paradigms for use with fMRI. o Neurophysiological studies in humans (e.g., Event-related Potentials (ERP)) and animals (single and/or multipleunit recordings)) focused on identifying the neural processes mediating extinction and how those processes may be disrupted in subjects with extinction deficits. o Extinction studies in patients with anxiety and/or substance abuse disorders aimed at determining whether they have compromised extinction mechanisms or show resistance to extinction. o Studies evaluating the effectiveness of combinations of behavioral and pharmacological treatments for facilitating extinction and preventing relapse. o Behavioral and neurobiological studies examining ways in which to enhance the potency of exposure therapy using contextual cues, neutral stimuli, concurrent exciters, spaced and massed exposure that could lead to more enduring behavioral changes in animal models and clinical populations. Are the effects of context different for humans and animals? o Identification of the optimal time-course and arousal level for successful extinction training and consolidation and follow-up studies to evaluate potential for relapse. o Characterization and identification of developmental factors that might predispose subjects to poor extinction, including the development of primate models to assess the effects of early aversive experiences on adult conditioning and extinction mechanisms. o Identification of molecular and genetic factors contributing the inability to extinguish memories associated with anxiety or drug abuse disorders. o Studies using immediate-early gene expression and gene knock-out techniques to elucidate the circuitry critical for extinction learning and consolidation as well as to identify the time-course over which extinction learning and consolidation occur. o Studies examining how individual differences contribute to the rate of extinction learning and probability of relapse. o Studies to determine whether there are differences in the ability to extinguish acute fear reactions versus generalized anxiety and the implications of these results for treating different forms of anxiety. o Combine operant and classical conditioning extinction procedures in the development of novel animal models and behavioral therapies. o Study the role of placebos in facilitating extinction of drug abuse (e.g., use of de-nicotinized cigarettes to eliminate smoking behavior). Investigators are encouraged to consider designing their research so as to permit the analysis of data by gender whenever possible. This RFA seeks to foster the development of new collaborations as well as novel and innovative research focused on facilitating extinction learning in clinical populations. Accordingly, its intent is to support work that has not yet amassed substantial preliminary data. However, applications should include any data demonstrating the feasibility of their research approach. Applications are expected to have well-documented plans for how collaborations between basic and clinical scientists are to be implemented and the nature of the activities to be supported. The contributions of each investigator should be clearly stated. For applications seeking support for pilot studies and the development of novel research methodologies, it is expected that there will be a concrete plan to integrate research findings across laboratories. In addition, the potential relevance for clinical treatment must be established. In order to be judged responsive, applications submitted under this RFA must be focused on integrating basic and clinical research on extinction learning and consolidation and show the relevance of this research for the understanding and treatment of anxiety disorders and drug addiction. Only applications that have a significant translational component will be deemed responsive. Research on other forms of learning and memory or applications focused primarily on fear conditioning are not appropriate for this RFA. Similarly, applications focused exclusively on basic mechanisms of extinction learning are not appropriate. Applicants are strongly encouraged to contact one of the NIH program staff listed under INQUIRIES with any questions regarding the responsiveness of their proposed project to the goals of this RFA. MECHANISM OF SUPPORT This RFA will use the NIH Exploratory/Developmental Grant (R21) award mechanism. Under this RFA, applicants may request direct costs of up to $150,000 per year for up to three years. This limit on direct costs includes any direct costs of a subcontract but does not include the indirect costs on the subcontract. These awards are not renewable. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. The earliest anticipated award date is July 1, 2004. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, since all applications will have direct costs in each year that are less than $250,000, the modular format should be used. RESUBMISSION OF UNFUNDED APPLICATIONS Applications that are not funded in the competition described in this RFA may be submitted as NEW investigator-initiated applications only, as described at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-019.html). These NEW applications must be submitted on the standard receipt dates (https://grants.nih.gov/grants/funding/submissionschedule.htm). Those who wish to resubmit their applications as R21s, will also submit them as NEW, and will be expected to conform to the requirements of the standard NIH Exploratory/Developmental Grant award mechanism, which limits the award to 2 years with a combined direct cost budget of up to $275,000 for the 2-year period, and limits the application to a 15-page research plan (see https://grants.nih.gov/grants/guide/pa-files/PA-03-107.html). FUNDS AVAILABLE The NIMH intends to commit approximately $1,250,000 and NIDA plans to commit approximately $500,000 in FY 2004 to fund 5 to 8 new 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 $150,000 per year. 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 Institutes 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 o Faith-based or community-based organizations Foreign institutions are not eligible to apply. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS One of the primary goals of the NIH is the translation of basic research into clinical practice. In accordance with this goal, NIMH and NIDA are using this RFA to facilitate the establishment of synergistic research programs between basic and clinical researchers in order to foster the development of effective treatments for diseases characterized by deficits in extinction learning. To achieve these goals, there are two special requirements for applications submitted in response to this RFA: (1) All applications to this RFA must include a minimum collaborative arrangement involving two investigators, one basic behavioral or neuroscientist and one clinical researcher. Each investigator must demonstrate their commitment to the project by allotting a significant percentage of effort to the project. Each primary investigator must devote equal amounts of time to the project. Larger groups of collaborators are encouraged. Investigators need not demonstrate any history of prior collaboration as long as they can specify factors that will facilitate the success of the collaborations. (2) During the course of the award period, the principal investigators along with their primary collaborators will be invited to meet with NIH staff in a public forum to review and share scientific progress. Other scientists external to and knowledgeable about these areas of research also may be invited to participate. NIMH and NIDA will organize this meeting. Application budget requests should include travel funds for the Principal Investigator and primary collaborator(s) to attend one meeting in the Washington DC area during the award period. 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: Kathleen C. Anderson, Ph.D. Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7172, MSC 9637 Bethesda, MD 20892-9637 Telephone: (301) 443-1576 FAX: (301) 443-4833 Email: kanders1@mail.nih.gov Bruce N. Cuthbert, Ph.D. Division of Mental Disorders, Behavioral Research and AIDS National Institute of Mental Health 6001 Executive Boulevard, Room 6186, MSC 9625 Bethesda, MD 20892-9625 Telephone: (301) 443-3728 FAX: (301) 443-4611 Email: bcuthber@mail.nih.gov David Shurtleff, Ph.D. Division of Neuroscience & Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 443-1887 FAX: (301) 594-6043 Email: dshurtle@mail.nih.gov o Direct your questions about review matters 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 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-1340 FAX: (301) 594-0702 Email: kozakm@mail.nih.gov o Direct your questions about financial or grants management matters to: Carol Robinson Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6118, MSC 9605 Bethesda, MD 20892-9605 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-3858 FAX: (301) 443-6885 Email: crobinso@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: Kathleen C. Anderson, Ph.D. Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7172, MSC 9637 Bethesda, MD 20892-9637 Telephone: (301) 443-1576 FAX: (301) 443-4833 Email: kanders1@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document 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. SUPPLEMENTARY INSTRUCTIONS: Applications must include a short introductory paragraph in the research plan section identifying which of the categories of specific activities are relevant for the application. That is, does the application propose: 1) the development, organization, and implementation of collaborative research networks; 2) pilot studies to demonstrate the feasibility of particular translational research approaches; and/or 3) the development of basic research methodologies that could be applied to a clinical setting. 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 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 20892-9609 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-3367 FAX: (301) 443-4720 Email: jnoronha@mail.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 NIMH and NIDA. Incomplete applications will be returned to the applicant without further consideration. 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 NIMH 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 appropriate Institute's National Advisory Council. 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 and the type of application? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are both basic and clinical research components incorporated into the proposal and do they represent a feasible and potentially valuable translational project? 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? Does the collaborative network or team involve both basic and clinical expertise? Is the work proposed appropriate to the experience level of the principal investigator and collaborative researchers? 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. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. SPECIFIC R21 REVIEW CRITERIA Innovation of the project and potential significance of the proposed research will be major considerations in the evaluation of the R21 exploratory grant mechanism. Because the R21 is designed to support innovative ideas, preliminary data as evidence of feasibility of the project are not required. However, the applicant is responsible for presenting the background literature that provides some basis for the approach and for developing a rigorous research plan. Relevant pilot data should be cited when available. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: November 18, 2003 Application Receipt Date: December 18, 2003 Peer Review Date: March 2004 Council Review: May 2004 Earliest Anticipated Start Date: July 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: 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 "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. 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 RFA 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 https://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 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. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. 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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