CENTERS FOR THE DEVELOPMENT OF MEDICATIONS TO TREAT DRUG DEPENDENCE RELEASE DATE: May 23, 2003 RFA: DA-04-003 - (Reissued as RFA-DA-09-002) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.279 Letter of Intent Receipt Date: September 15, 2003 Application Receipt Date: October 14, 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 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 purpose of this RFA is to solicit applications for funding research centers called Medication Development Units (MDUs) directed towards the identification, evaluation and development of safe and effective medications for the treatment of cocaine, methamphetamine, club drug, opiate, and cannabis related disorders, including substance use (abuse and dependence) and substance-induced disorders such as substance withdrawal and intoxication. The applicants must have demonstrated the capability to conduct full-scale single site clinical trials (placebo-controlled (PC) or active controlled (AC), double-blind (DB)) using the proposed therapeutic approach. Applicants opting to propose multisite trials must have adequately demonstrated efficacy in a single site PC/AC, DB trial. Such applicants must also demonstrate the ability to affiliate rapidly with other sites (through subcontract or collaborative mechanisms) to launch a multisite Phase II or Phase III PC/AC, DB trial. Under this RFA, applicants may focus on human laboratory studies on medication interactions with other drugs; pharmacokinetic or pharmacodynamic studies, Phase I safety/tolerability or Phase II or III clinical efficacy studies; or, if justified, multisite efficacy studies. Research may focus on both currently approved and/or novel, investigational medications. Because the treatment of cocaine, methamphetamine, opiate, or cannabis related disorders necessitates a multidisciplinary approach, optimal pharmacological treatments require a behavioral treatment strategy. Therefore, applications may propose the concurrent evaluation of pharmacotherapy and behavioral treatment approaches in an integrated design, whereby behavioral treatment components should provide a platform for the medication trials proposed. Study designs should be of adequate size and well controlled. Proposals for the treatment of opiate dependence will only be considered if they address unmet clinical needs in this treatment area (i.e., non-opiate agonist medications, medications to treat opiate-dependent individuals who have not responded well to currently available medications, or the treatment of special populations such as opiate-dependent pregnant women and adolescents). RESEARCH OBJECTIVES Background - As part of NIDA's strategic plan to significantly reduce drug use-related disorders, the discovery of safe and effective medications for the treatment of cocaine and other stimulants, as well as opioid, cannabis and club drug related disorders, remains a top priority. This RFA solicits research on medications to treat a variety of aspects of the immediate and long-term effects of drug abuse and dependence, such as craving, relapse prevention, and the physiological and behavioral consequences resulting from drug abuse. As part of this undertaking, NIDA has made the development of an anti-cocaine dependence medication its number one priority. The NIDA Medications Development Program, aimed at identifying and screening new medications as potential pharmacotherapies, has become increasingly focused on the involvement of catecholaminergic systems in cocaine craving and relapse and the identification and testing of entities which directly or indirectly modulate these systems. The types of pharmacotherapies this suggests are dopamine or serotonin receptor agonists and antagonists, pharmacotherapies that, directly or indirectly, through modulation of GABA, glutamate, or endocrine systems, affect dopamine, serotonin or noradrenergic transmission. Additionally, any target medication justified as potentially effective in modulating aspects of cocaine dependence through other mechanisms is also appropriate. There is also a critical need to address the growing problem of methamphetamine abuse and dependence. The increased HIV risk behaviors and transmission amongst methamphetamine abusers corroborates the need for safe and effective pharmacotherapies to treat methamphetamine abuse. The highly addictive nature of this substance, in addition to its low cost and ease of production, as well as the serious physiological and neurological consequences of its abuse, has made methamphetamine dependence a problem of major proportions. There are currently no pharmacological treatments for dependence on methamphetamine. Medications, which affect dopaminergic or noradrenergic systems, or that directly or indirectly modulate their neurotransmission, may be useful to test as treatment agents for amphetamine abuse. Additionally, strategies to reduce methamphetamine plasma concentrations or counteract its pharmacological effects could serve as a useful adjunct in the management of the acute medical and psychiatric symptomatology of methamphetamine overdose and methamphetamine-induced cognitive impairment. Also of importance would be the development of treatments for specific drug abusing populations, such as polydrug abusers, individuals with a co-morbid substance abuse or psychiatric disorder, pregnant addicts, and adolescents, either as a main focus of the research plan, or as a component or components thereof. Research Themes - The following are some examples of research themes that the Medication Development Units (MDUs) might utilize: 1. Specific substance abuse disorders: The application may focus on the development of medications for the treatment of a specific substance use, or induced disorders with or without other psychiatric comorbidities. For example Phase I, II or III studies to develop a medication, or medications, for the treatment of cocaine dependence. 2. The targeting of neurochemical mechanisms implicated in substance abuse disorders, by the direct or indirect modulation of systems, such as: a. Cathecolaminergic b. Glutamatergic c. Cannabinoid d. GABA e. Opioid f. Endocrine (e.g., CRF) g. Multiple neurochemical systems 3. Paradigms to approach substance-related disorders: a. Initiation of abstinence b. Relapse prevention c. Prevention of complications d. Intervention of surrogate variables of drug abuse Research Components - The purpose of the MDU is to foster transdisciplinary collaboration on cutting edge questions in the treatment of substance-related disorders (SRDs). Some examples of research components may include, but are not limited to: o Developing and testing new chemical entities for treatment of substance- related disorders. o Phase I testing of the safety of new medications or medications previously approved for other indications that may be effective for treatment of SRDs. o Phase I testing of medications or combinations of medications, for which safety concerns may exist, or for which a safety assessment may be required by the Food and Drug Administration, before Phase II trials may begin. o Phase II clinical trials testing the efficacy of medications using rapid screening methods (Phase IIa) or large scale, randomized, well-controlled clinical trials (Phase IIb). o Multicenter clinical trials to test medications for specific clinical conditions for which it is difficult to recruit subjects in a timely manner. For example, studies testing medications for the treatment of substance use disorders in pregnant women or adolescents. o Testing of potentially additive or synergistic neurochemical mechanisms using one medication with action in multiple mechanisms of action, or combinations of medications each targeting a different mechanism. o Development of new human laboratory models for evaluation of medications for relapse prevention, initiation, and abstinence. o Developing and testing new paradigms of treatment success. o Optimizing the safety or efficacy of approved medications for substance- related disorders by testing them in specific patient populations o Testing drug-drug interactions between medications for treatment of SRDs and other drugs/medications, including but not exclusively, illicit drugs, anti-retroviral medications, anti-psychotic medications, etc. o Increasing the diversity of populations in whom the medications are tested by increasing the representation of women and minority groups in clinical trials or by designing clinical trials that specifically address the treatment needs of those groups. o Pioneering methods to design and conduct clinical trials that will be more cost-efficient while yielding reliable results. o Innovative statistical approaches to conduct sample size estimations, control covariates, and assess treatment outcome. o Using pharmacogenetics and pharmacogenomic techniques to assess genetic factors that may influence the outcome of treatment of SRD. o Investigating innovative imaging technologies to assess subjects' suitability for specific treatments as well as treatment progress and outcome. o Developing novel psychotherapeutic techniques to be utilized as a standardized co-adjuvant therapy for subjects participating in medications clinical trials. o Adapting behavioral therapies that have been shown efficacious and testing them as part of medication clinical trials. o Novel strategies for the treatment of multiple comorbid substance-related disorders. For example, illicit drug use plus alcohol and tobacco or comorbid opiate and cocaine ("speedball") dependence. o Innovative approaches of the treatment of substance-related disorders with other medical and psychiatric comorbidities including, but not exclusively, hepatitis C, HIV infection, anxiety-related disorders, mood disorders, personality disorders, etc. o Evaluation of biopsychosocial factors that may affect the treatment outcome of SRDs. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) specialized research center grant (P50) 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 July 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE NIDA intends to commit approximately $5.5 million in total costs in FY 2004 to fund 5 to 7 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to five 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 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. The size of individual awards will vary as a function of the nature and scope of the research proposed. It is anticipated the upper limit of each award will be $1,200,000 in total costs (direct plus indirect costs) and applications over this amount will not be accepted for review. Budget requests should be carefully justified and commensurate with the complexity of the project. 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. SPECIAL REQUIREMENTS The MDU Director must possess recognized scientific and administrative competence. The Center Director must show a substantial commitment of time and effort (minimum 25%) to the program and exercise leadership in steering the MDU direction and maintenance of its quality control. Center Directors must not direct more than one NIDA Center. Management support and shared functions may be accomplished through an administrative core and scientific core components. Scientific cores may propose plans for project management and sharing of clinical resources, laboratory equipment and support, statistical support, etc. The Administrative Core should provide for central operations, oversight activities, technical support and exercise of leadership for the overall project management, as well as integration, communication and coordination of the MDU. As part of the Core, each application should include a plan for data entry to the NIDA Clinical Trial Portfolio System (CTPS) and designation of dedicated staff for data entry to the system. Applicants may obtain information regarding the CTPS from the NIDA contact. Applicants may want to consider the addition of a plan for the contribution of data/samples for genotyping to NIDA's Human Genome Consortium. The applicant must demonstrate that he/she has plans and facilities for career development and mentoring of junior investigators in the area of drug abuse research and treatment. Pilot Projects 1. The applicants may propose and request funding for specific, already conceptualized pilot projects, which may be "research and development" pilots, feasibility studies, or other pilot work broadly defined as foundation work for further research. These pilot studies will be reviewed by the scientific review group as part of the assessment of scientific and technical merit. 2. In addition, applicants may request funds for pilot projects that are yet to be conceptualized. These projects should have the potential for developing into, or providing the foundation for, larger projects that could compete for funds on their own. The support of pilot project studies should be of relatively short duration (e.g., 1-2 years), depending upon the nature of the research. Because these projects cannot be reviewed by the scientific review group, applicants must describe and provide a process for a within-center scientific review of pilot projects. In general, the total amount of money allocated to yet-to-be-conceptualized pilot projects should not exceed 10% of the center grant's total annual direct costs, and exceptions must be strongly justified. 3. Whether specifically proposed in the application or developed later under center auspices, pilot projects must comply with applicable NIH policies, and the necessary human subject and animal welfare assurances must be submitted. 4. For projects not specifically proposed in the application, center grantees are to provide the NIDA program officer with written notification of the initiation of new pilot projects. The notification should contain a brief description of, and rationale for, the planned pilot project, the amount of pilot funds to be allocated to the project, the proposed length of the project, and a statement that the project will comply with applicable NIH policies and that the necessary assurances have been submitted and obtained. The program officer must also be provided with assurance that the projects have received an appropriate within-center scientific review. 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: Jamie Biswas, 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) 443-8096 FAX: (301) 443-9649 Email: jb168r@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 FAX: (301) 443-0538 Email: tl25u@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 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 NIDA 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 Telephone: (301) 443-2755 FAX: (301) 443-0538 Email: tl25u@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. 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. Applicants are encouraged to organize their application by initially presenting the face page, the abstract page with key personnel, a table of contents, summary budget pages for the entire MDU, and other documentation pertaining to the entire MDU. This should be followed by an Introductory Section of no more than three pages. It should be written for the proposed MDU application describing it as a whole with respect to the overall theme, goals, objectives, and overall research plan. The Introductory Section should contain information on i) the overall research theme, ii) timelines and milestones for each project in a graphic outline to clearly lay out the sequence of research events and how each project of the MDU relates to each other, iii) the capacity of the MDU to conduct adequately sized clinical trials for the targeted indications within a time frame of 2-3 years per project, and iv) the capability of the proposed Principal Investigator and his/her institution to carry out the scientific and administrative duties required in this RFA. After the introductory section, each core and research project should be presented with its accompanying individual budget, budget justification, biographical sketches, other support information, and research plan. For each core and research project component, there is a 25-page limit for the sections of the research plan (i.e., specific aims, background and significance, preliminary studies/progress report, and research design and methods) as indicated in the form PHS 398. Appendix material limits apply to each component separately; each component's appendix may include up to 10 publications, manuscripts, abstracts, patents, or other printed material directly related to the project. Surveys, questionnaires, data collection instruments, and clinical protocols may also be submitted in the appendix. Original glossy photographs or color images may be included, provided that a photocopy (that may be reduced in size) is included within the 25-pages of the research plan. Applications exceeding page limits, font limits, or appendix limits will be returned to the applicant without review. Appendices should not be placed within the body of the application, but should be bundled separately, component by component. Competing renewal applications must include final progress reports from their previous P50 grant-sponsored studies for evaluation. 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 the entire set of appendices 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 Telephone: (301) 443-2755 FAX: (301) 443-0538 Email: tl25u@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 NIDA. Incomplete and/or non-responsive 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 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. A. MDU as an Integrated Effort: (1) Quality of integration of center components to an over-arching theme that integrates and focuses the center, as well as the presence of an essential relationship of each component to the theme. Interdependency and linkages of components to each other need to be demonstrated for at least a significant nucleus of components. (2) Evidence of synergy as components are configured in the application. To aid in this determination, reviewers may look at the quality of provisions for the sharing of resources, procedures for formal and informal planning, and plans for developmental or pilot work in order to determine if the application reflects a depth and breadth of expertise and experience not normally present in an individual research project grant. (3) The involvement of different scientific disciplines or subdisciplines in the center's activities and the demonstration of substantial interaction among scientists from different disciplines or subdisciplines and different perspectives. (4) Research Environment and Facilities: (a) Plans for development and maintenance of an environment that promotes the conduct of the highest quality of research, innovation, and leadership. Demonstrations of past productivity are evidence of likely future productivity, especially in competing renewal applications. (b) Appropriateness and adequacy of facilities for administrative, research, and shared resources, including a clearly identifiable physical location for the center which assures necessary functions can occur. (c) Facilities that indicate the center is, or would soon be, a national scientific research resource. (d) Evidence that core components contribute toward cost-effectiveness and quality control in resource utilization. (e) Quality and extent of data analytic capacities, data base facilities, coordination, and data resources. (f) As needed, the quality of provisions for shared laboratory resources, the quality of laboratory space, and the quality of clinical facilities. (5) Qualifications of the Center Director: (a) Ability to lead a scientific program (including a program with training components, if included), as noted by scientific achievements, productivity, stature in a relevant field, and planned activities. (b) Ability to lead administrative and operational aspects of the center, as noted by administrative skills, achievements, and planned activities. (c) Evidence of ability to develop or maintain a role for the center as a national resource. (d) Adequacy of commitment of time and effort for the research and administration of the center. (A minimum of 35% effort on activities directly supported by the center funding is required.) 6. Qualifications of Investigators: (a) Quality of cadre of investigators and their productivity, as noted by their scientific achievements, honors, and recognition. (b) Quality of interactions among investigators and investigative teams. (c) Breadth of expertise represented among investigators. (d) Quality of investigators at collaborating sites and the nature of collaborations. 7. Administrative and Organizational Structure: (a) Organizational and administrative structure and support conducive to research, synergy, and joint planning. (b) Structure for long-range planning and evaluation of center activities. (c) Programmatic structure that effectively promotes productive scientific interactions and takes maximum advantage of the applicant institution's drug abuse research capacity. (d) Arrangements for internal quality control of research, publications, and grant applications. (e) An organizational structure with clear lines of authority that allow for efficient and cost-effective management and allocation of funds, as well as leverage of resources to enable additional or future work. Evidence of how the center has attracted additional sources of funding or leveraged resources is especially relevant for competing continuation applications. (f) Outside advisory structures that provide appropriate and objective advice and evaluation, as needed. (g) An appropriate, fully described internal process that allows for priority setting and decision making to sustain the center. (h) Appropriate specification of criteria and processes for determining and sustaining individual participation in the center based on productivity, research direction, and overall contribution. (i) Clear and convincing evidence of the applicant institution's substantial commitment to the center and appreciation of its goals and role in public health. (j) Adequacy of provisions, especially in core components, for sharing of data base development and analytic capacities. Innovative, state-of-the-art analytic capability. (k) As needed, plans for recruitment, training, and supervision of staff. 8. Mentoring and Career Development: The capacity (including plans and facilities) to provide career development and mentoring for potential drug abuse researchers. B. Criteria to be used for determination of scientific merit of individual scientific project components: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in evaluating your individual projects, weighting them as appropriate for each application. The projects do 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. SIGNIFICANCE: Does this study address an important problem or pharmacotherapy? 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? Would the generated data support the advancement of a pharmacotherapy toward advanced efficacy trials or support an NDA? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the proposal present a medication testing and development plan? Is the research theme clearly presented and supported by a strong rationale? Are timelines and milestones for each project presented in a graphic outline (Gantt and Pert charts)? Does it clearly lay out the sequence of research events and how each project of the MDU relates to each other? Are criteria for go/no go decisions included at critical points in the plan? Does it provide assurance of accessibility to patient populations and controls? Does the PI demonstrate the feasibility to recruit human subjects for the study? Does the proposal address data management and statistical resource? Does each project propose a plan for data management and demonstrate appropriate statistical resources to manage, analyze clinical data and draft summary reports to support an IND and possible NIDA submission? Does it propose a plan to publish and disseminate the findings to health professionals and the general community? 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: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and to that of other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? PILOT STUDIES: What is the likelihood that the proposed research will contribute to the development of more mature and important research projects? C. Criteria to be used for determination of scientific merit of core components: Core Units provide essential facilities or services for the individual projects, including administrative arrangements and organization to facilitate and monitor the attainment of objectives and quality control. For example, the cores may include plans to enhance communication and cooperation among the investigators involved in the program and mechanisms for the allocations of funds for day-to-day management, project management and tracking, contractual agreements and procedures for the replacement of key personnel, such as the principal investigators, if required on an interim or permanent basis. The evaluation of administrative and scientific cores will include the following criteria: SIGNIFICANCE: The importance and value of the proposed core? What crucial support is provided to the research projects? Are the most efficient means identified? How do they enhance the effectiveness of individual projects? Are mechanisms identified to promote research collaborations, to develop new strategies, or to conduct pilot experiments? Are specialized substance abuse research clinics available? Has the possibility of an advisory steering committee been considered to evaluate progress of the program? What standardized tests, interventions, and evaluations are administered through the core? Are uniform operating systems proposed? Does the plan give careful consideration to overall timelines, choice and accessibility of medications, patient recruitment issues, data management, and statistical resources? Is interface with FDA and other regularity agencies considered? APPROACH: The effectiveness of administrative arrangements and organizational structure to facilitate and monitor the attainment of objectives and internal quality control, and plans to enhance communication and cooperation among the investigators involved in the program. Establishment of mechanisms for the allocation of funds for day-to-day management. A well-designed management plan that clearly defines the lines of authority, development timelines, points of go/no go decisions, and clearly demonstrates that resources will be used efficiently in reaching the goals. INNOVATION: Are innovative ways proposed in utilizing shared resources or benefiting from the principal investigator's leadership to support research projects, retain integrity, achieve efficiency, or minimize utilization of resources? INVESTIGATORS: The leadership and administrative capability of the principal investigator. The need for an external advisory board. ENVIRONMENT: The quality and adequacy of available resources necessary to perform the research and the willingness to work as part of the cooperative program and with NIDA Scientific Coordinators. The documented commitment of the applicant institution and capability to serve as the Central Operations Office for the program. ADDITIONAL REVIEW CRITERIA In addition to the review criteria cited above and in the NIDA Center guidelines, sites submitting renewal applications must include final progress reports from their previous P50 grant-sponsored studies. Past progress will be evaluated. 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). Each clinical trial proposal is required to include an initial plan for data and safety monitoring. INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the National Center for Research Resources, NIH, or a comparably supported clinical research facility are encouraged to explore the possibility of using the facilities or arranging for other means to conduct some of the center's proposed research. If an applicant wishes to identify a GCRC or comparably supported clinical research facility as a source for conducting proposed research, a letter of agreement from the program director or PI of the GCRC or comparably supported clinical research facility should be included in the application material. The applicants may request funds for use of inpatient, residential, or outpatient facilities which are essential to the conduct of the research (e.g., patient bed costs, research ward costs, outpatient facility and other health services costs). In such cases of paying for beds, facilities, services, etc., funds will be provided only when it is clear that no other funds are available and the services are essential to the conduct of the research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: September 15, 2003 Application Receipt Date: October 14, 2003 Peer Review Date: February/March 2004 Council Review: May 2004 Earliest Anticipated Start Date: July 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 DATA AND SAFETY MONITORING PLAN OR 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 and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html), and http://www.drugabuse.gov/Funding/DSMBSOP.html. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02- 001.html); a complete copy of the updated Guidelines are available at http: //grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. 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 www.nida.nih.gov under the Funding, or may be obtained by calling (301) 443-2755. 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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