NATIONAL DRUG ABUSE TREATMENT CLINICAL TRIALS NETWORK Release Date: December 20, 1999 RFA: DA-00-002 National Institute on Drug Abuse Letter of Intent Receipt Date: February 17, 2000 Application Receipt Date: March 16, 2000 PURPOSE The National Institute on Drug Abuse (NIDA) invites cooperative agreement applications from established clinical investigators to participate in the National Drug Abuse Treatment Clinical Trials Network (CTN). CTN research is carried out in community-based treatment settings, in collaboration with other awardees and with NIDA. Each awardee functions as a CTN Research NODE, consisting of a Regional Research and Training Center (RRTC) that is linked in partnership with community-based treatment programs (CTPs). The CTN consists of multiple NODEs, and each NODE works in concert with other NODEs and NIDA to conduct multi-site and cross-regional (nationwide) clinical trials research. Awardees will deliver and test an array of both behavioral and pharmacological treatments and determine conditions under which novel and efficacious treatments are successfully adopted. Studies to be conducted will span multiple sites engaging diverse patient populations in dispersed geographical regions. As a cooperative agreement, there is substantial NIDA involvement in the management and administration of the CTN, including determining which trials are implemented through the Network. The CTN, with its core of CTPs engaging diverse populations, is also designed to provide a much-needed vehicle to recruit subjects for studies on such related topics as the medical consequences of long-term drug use and the genetics of vulnerability to addiction. Although these studies might use the CTN as a research platform, the studies themselves would be funded through separate research grants. This Request for Applications (RFA) is a second issue with the intention to develop a geographically diverse and encompassing national Drug Abuse Treatment Clinical Trials Network. In 1999, five Awards were made to Northwest NODE, Health Science University of Oregon; Pacific Region NODE- University of California at Los Angeles; Southern New England NODE, Yale University; Delaware Valley NODE, University of Pennsylvania; and Mid Atlantic NODE, Johns Hopkins University. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS- led national activity for setting priority areas. This RFA, National Drug Abuse Treatment Clinical Trials Network, is related to the priority areas of tobacco, alcohol and other drugs, and HIV infection. Potential applicants may obtain a copy of Healthy People 2000 at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and nonprofit organizations, private and public, such as universities, colleges, hospitals, laboratories, units of state or local governments, and eligible agencies of the federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Foreign applicants are not eligible, and domestic applications may not include a foreign site. Because of 1) the objective to bridge the gap of research to practice, 2) the complexity of the proposed infrastructure and operation, and 3) the need for multi-site collaboration, it is important for the Principal Investigators to commit a minimum of 50% time to CTN and to document a substantial history of leadership in complex multi-site clinical trials research and an extensive research publication record. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U10), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial National Institutes of Health (NIH) scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the awardee recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the studies to be funded under cooperative agreement(s) are discussed in this document under the section "Terms and Conditions of Award." Potential applicants are encouraged to review definitions of key terms used throughout this announcement. All policies and requirements that govern the grant program of the PHS and NIH apply. FUNDS AVAILABLE NIDA has set aside $11 million to support total costs of establishing additional CTN NODEs in FY 2000. This level of support is dependent on the receipt of a sufficient number and diversity of applications of high scientific merit. NIDA expects to make up to five awards under this RFA for project periods of up to 5 years of support. It is anticipated that there will be subsequent RFAs to expand the CTN and that competing continuation applications will be invited upon expiration of the initial funding period of awards made under the previous RFA, subject to the availability of funds. Because the nature and scope of the research activities proposed in response to this RFA may vary, it is anticipated that the size of individual awards will vary also. Budget requests should be carefully justified and commensurate with the complexity of the project. Although this program is provided for in the financial plans of the NIDA, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background The CTN has been established and will continue to grow to meet two major research-related needs. First, a clinical trials research infrastructure is needed to test the effectiveness and usefulness of new and improved treatments in community-based treatment settings with diverse patient populations. Second, a mechanism is needed for the systematic study of processes and factors involved in the incorporation of new and improved interventions into community-based drug treatment. The development of such a network has been recommended by the National Advisory Council on Drug Abuse and is consistent with conclusions of Physicians Leadership on National Drug Policy. It also is the principal recommendation of the Institute of Medicine/National Academy of Sciences report Bridging the Gap Between Practice and Research: Forging Partnerships with Community-Based Drug and Alcohol Treatment. These organizations consider such a network to be essential for improving the quality of treatment of drug abuse and addiction in this country. The CTN is expected to forge partnerships among NIDA, treatment researchers, and community-based treatment providers. Establishment of strong partnerships between researchers and practitioners is essential to assure that new treatments address the critical needs of community-based treatment programs and are suitable for those settings. Through this joint effort, the gaps in current treatment approaches will be addressed, yielding treatments proven in community treatment settings ready for adoption into clinical practice. Research has provided substantial evidence to support the concept that drug addiction is in many cases a chronic relapsing disease. As is the case for other chronic disorders, effective treatments for addiction exist. However, as is the case for other illnesses, the treatment of addiction can be improved through advances in research on medications and behavioral treatment approaches. Although considerable research has been directed toward continuous improvement in the quality of treatment alternatives, the CTN is designed to accelerate significantly both the pace of treatment research and its application in real-life treatment settings. The improvement of existing treatments and development of new treatments based upon findings in basic behavioral and neurobiological sciences are important national research goals. For example, in recent years this research effort has yielded an array of promising new behavioral treatment approaches. However, the efficacy of these new treatments has been demonstrated primarily in specialized treatment research settings, with somewhat restricted patient populations. As a consequence, few of these new treatments are now applied on a wide-scale basis in real-life practice settings. Research is needed to validate new science-based treatments for drug abuse and addiction across a variety of community-based treatment settings and with diverse patient populations and to determine how to implement or adapt these treatments in community-based practice. For medications, the situation is somewhat different. Only three medications have been approved by the Food and Drug Administration (FDA) for the treatment of opiate addiction: methadone, LAAM, and naltrexone. There are no approved medications for the treatment of cocaine, methamphetamine, or marijuana abuse and addiction. Thus, the range of options available for the use of medications to treat drug addiction is quite limited. However, NIDA- supported researchers have tested an array of both new and existing medications for specific applications, and some are now ready to test under controlled conditions in community settings. The engagement and participation of community-based treatment providers in large-scale clinical trials of potential therapeutic agents is essential for full and appropriate testing, and to ensure the acceptability and availability of new agents after FDA approval. Definitions of CTN Organizations and Functions Clinical Trials Network (CTN). A collaborative group of geographically diverse Regional Research NODEs working collaboratively with NIDA to conduct multi-site and cross-regional (nationwide) clinical trials research on promising behavioral, pharmacological, or integrated drug abuse treatments. NODE. A NODE is the functional unit within the CTN. The NODE consists of the Regional Research and Training Center (RRTC) and its affiliated Community Treatment Programs (CTPs). The RRTC serves as the coordinating core and arranges a research partnership between the RRTC and CTPs. The CTN will be comprised of multiple NODEs. Regional Research and Training Center (RRTC). The RRTC is the recipient of the cooperative study award. It is one of the two components of a NODE. It usually resides in the Principal Investigator’s research institute or organization. The RRTC provides a core of administrative and study operations services, as well as scientific leadership and management of clinical trials. The RRTC, acting as the local operation center for a NODE, has primary responsibility for 1) establishing an infrastructure, 2) generating a research agenda, 3) providing administration and operations support, and 4) building partnerships with the CTPs. - Infrastructure. This includes but is not limited to, 1) arranging and managing the participation of at least 5 CTPs in the first year, and at least 10 in subsequent years, 2) maintaining scientific and technical personnel for protocol development and implementation, 3) coordinating intra-NODE activities, and 4) providing resources for intra-NODE activities. - Research Agenda. In partnership with its affiliated CTPs, the RRTC develops and submits research concepts and protocols to the CTN Steering Committee for review and approval. For each approved protocol, a protocol specific project team will be established to develop and implement the research project. It is expected that there will be a Project Director from the NODE where the research concept and protocol originate. NIDA scientists will be designated as the scientific and administrative collaborators on the project team. The Project Director will assume the leadership role for all aspects of that specific protocol and will serve as the primary liaison to CTN-wide coordination/support centers as needed. - Data Acquisition and Management. The RRTC will provide intra-NODE data acquisition, data management training, and data quality assurance according to each specific protocol. This data management system must follow the policies and procedures of the CTN Steering Committee, to 1) monitor adverse events and report data and other information to the CTN Data and Safety Monitoring Board (DSMB), and 2) provide timely data to the CTN central data management center (CDMC) for monitoring protocol progress and for contributing study specific data to a NIDA central data repository. - Responsibility toward Affiliated CTPs. The RRTC provides CTPs with 1) additional therapists, counselors, physicians, physicians' assistants, nurses, and other staff, as well as the additional training needed for the CTP, to implement a study protocol; 2) hardware, software, and training to support CTP-based data acquisition activities. Each RRTC will establish a data acquisition system to collect intake, in-treatment, and outcome data for all study participants, according to protocol-specific requirements, and 3) additional support, such as quality control, to ensure the successful completion of the scientific goals of a research project. Staff selections will be made by the CTP with the concurrence of the RRTC. Community Treatment Programs (CTPs). Drug abuse treatment programs in the community (typically non-university-based) setting that have a history of providing quality treatment to large and diverse patient populations, including women, pre-adolescents and adolescents and have the capability for and interest in participating in controlled clinical trials. Each CTP must: - Agree to participate in controlled clinical trials, including randomization methods for assignment of patients to experimental or control groups or randomization of therapists to different conditions; - Recruit adequate numbers (at least 75/year) of patients required for specific studies; - Agree to provide routine clinical care to patients participating in protocols; - Agree to provide experimental/standard care in accord with approved research protocols; - Provide HIV risk reduction counseling and HIV testing; - Maintain patient records required for each protocol; - Collect clinical and laboratory data, including biological specimens when indicated; - Cooperate with quality control activities of the CTN and adhere to guidelines set by the RRTC, the Steering Committee, and NIDA; - Participate in the development of the concept and protocol of trials to be run in the CTN; - Agree not to report data prior to collaborative reporting; - Agree to periodic on-site audits by representatives of its RRTC, NIDA, or a NIDA designee to ensure use of investigational drugs; compliance with regulations for IRB approval or informed consent (compliance with 45 CFR 46); compliance with protocol specifications; quality control and accuracy of data recording; and completeness of reporting of adverse drug reactions. CTN Steering Committee. The Steering Committee will constitute the primary governing body of the Network. The committee membership consists of the Principal Investigators of each RRTC, representatives from CTPs, and the NIDA CTN Director. This group will review and approve the research agenda, formulate and monitor policies and procedures guiding the research activities, and oversee communications within the CTN, as well as with the greater scientific community and the public. All major scientific decisions will be determined by majority vote of the Steering Committee. All participating RRTCs must agree to abide by the study designs and policies approved by the Steering Committee. It is important to note that research to be undertaken within the CTN is not limited to research concepts contained within awardees applications, but will be determined by the Steering Committee based on input from the NODEs and subject to the approval of the external Network Advisory Board and NIDA. Future research must be within and consistent with the scientific objectives of the RFA. The Steering Committee, by majority vote, will elect a Chair from among the Principal Investigators. It is anticipated that the Steering Committee will establish subcommittees and workgroups to assist it in carrying out its functions. The Steering Committee may meet up to six times per year, usually in the Washington, D.C., area. Applicants should include budgets for travel to these Steering Committee meetings and subcommittee/workgroup meetings in their applications and should assure that adequate provisions are made to allow Principal Investigators and CTP representatives to participate fully in activities of the Steering Committee and its subcommittees/workgroups. NIDA Protocol Review Board. An expert board authorized by the Director of NIDA that will review the final draft of the protocol submitted by the CTN Steering Committee for scientific and regulatory approval. Data and Safety Monitoring Board (DSMB). The DSMB is an independent expert board, appointed by and reporting to the Director of NIDA, that will oversee and monitor the conduct of the clinical trials to ensure the safety of participants and the validity and integrity of the data. The DSMB will also make an independent assessment of treatment effectiveness and whether a trial will continue. One or more NIDA staff will serve as non-voting members on the DSMB. CTN Advisory Board. An independent expert board, appointed by and reporting to the Director of NIDA, hat oversees all activities conducted under the CTN. The Board will advise the NIDA Director regarding the programmatic advisability of proceeding with studies proposed by the Network Steering Committee and will assist the Institute in prioritizing and approving final protocols. Protocols will be implemented with the approval of NIDA Director. Central Data Management Center (CDMC). Data information systems operated by each NODE are required to implement standards established by the CTN Steering Committee. Such standards guide the development of the protocol-specific electronic case report form (eCRF) applications that each NODE is responsible for implementing at participating CTP sites. The CDMC reports directly to NIDA, although functions as a resource to the CTN Steering Committee in all matters related to data management--from study design data acquisition and analyses to report of study findings and conclusions. Administrative Coordinating Center (ACC). A contract awarded by NIDA will support some of the administrative coordinating functions of the CTN to includes: 1) Coordinating of logistical functions of meetings of the Network CTN Steering Committee, subcommittees, workgroups, and other boards (e.g., the Advisory Board, the DSMB, etc.) and logistical functions including production and distribution of committee minutes. [NOTE: Funds for participant travel to meetings will not be disbursed by the ACC; applicants should make adequate provision for these funds in the budgets submitted under the present RFA.] 2) Reproducing and distributing research materials (including treatment protocols, training manuals, and instrumentation) and educational materials. 3) Developing, reproducing, and distributing materials publicizing the activities of the CTN. 4) Monitoring and managing clinical supplies for medication trials. 5) Supporting other operational needs, such as protocol development, regulatory assistance, monitoring/quality assurance, trial material distribution, central labs for analysis of biological fluids, etc. NIDA Office of CTN. An office within NIDA responsible for the scientific, administrative, and operational management of the CTN research program funded by NIDA. Objectives and Scope The overall goal of the National Drug Abuse Treatment Clinical Trials Network is to improve the quality of drug abuse and addiction treatment throughout the Nation using science as the vehicle. Specific objectives include: - Supporting studies of behavioral, pharmacological, and combined behavioral and pharmacological treatment interventions of established efficacy in rigorous, multi-site clinical trials to determine effectiveness across a broad range of treatment settings and patient populations. - Encouraging research on the translation of science-based, effective treatment interventions into clinical practice by establishing effectiveness in community-based treatment programs and by determining effective strategies for transporting effective treatments. - Furthering the development of effective treatments by integrating behavioral and pharmacological research. - Ensuring that treatment research in drug abuse and addiction meets the needs of the wider community, including minorities, women, children, adolescents, and underserved populations. - Fostering the collaboration of community treatment practitioners and treatment researchers, to provide opportunities for bi-directional education and for the exchange of ideas, information, and values between the treatment and academic communities. - Investigating the impact of advances in treatment research on community level treatment practices. - Determining the impact of the transport of novel, effective treatments to the community on the incidence and prevalence of various other illnesses and conditions, such as blood-borne infections (e.g., HIV and hepatitis). Characteristics of the CTN The CTN will provide the Nation a stable, broadly representative infrastructure for drug abuse treatment research. It is anticipated (pending availability of funds to continue expanding the CTN) that regional NODEs will be distributed throughout the country. Each NODE will encompass a substantial geographical area and a variety of treatment settings, patient populations, and drug abuse problems. RRTCs must have demonstrated expertise in conducting drug abuse clinical trials and in research and clinical training. The CTPs will reflect the isparate sites where treatment is now delivered. For the CTN to be maximally effective, the CTPs must be partners in the research enterprise, including participation in decisions concerning selections of trials to be implemented and protocol design. Through its associated CTPs, each NODE must demonstrate the capacity to recruit and treat a broad range of patients, including children, women, patients with co- occurring mental disorders, those at high risk for HIV infection, members of various racial/ethnic groups, and those abusing or addicted to various drugs of abuse. All Network NODEs must demonstrate the capacity to deliver and test a variety of both pharmacological and behavioral therapies. Examples of the types of studies appropriate for the CTN include: - Studies to determine 1) if behavioral therapies found to be efficacious in smaller-scale studies are effective in community clinics and for different patient profiles, including adolescents, and how such therapies may be transported to the community. The term "behavioral therapy" is used here in the broadest sense and is meant to include, for example, counseling, various aspects of therapeutic community approaches, cognitive behavioral therapy, operant behavioral therapy, and family therapy. - Studies to develop effective techniques for transporting new behavioral therapies into community-based treatment groups. For example, the effectiveness of various approaches to therapist training could be compared within the clinical trial context. In this fashion, information can be gained not only about whether a therapy performs better than standard care, but also about how a therapy may be transported. - Studies examining the impact of drug addiction treatment and AIDS risk reduction counseling on HIV risk behaviors and/or sero-conversion in both heroin and cocaine addicts. The CTN could provide a sample representative of diverse drug addicted populations sufficient to determine relative efficacy of various approaches in different subgroups. - Studies pursuing the identification and development of pharmacological interventions for drug dependence treatment in multi-site settings. The safety and efficacy of the investigational pharmacological agents will be tested in accordance with FDA regulations, typically by use of double blind, placebo-controlled or active-controlled designs. - Studies aimed at optimizing the access to and effectiveness of currently marketed pharmacotherapies for treatment of drug abuse and addiction. Examples are studies to determine the optimal approach for integrating medications with behavioral therapies at optimal levels and doses, such as naltrexone with cognitive behavioral therapy, or LAAM with drug addiction counseling. - Studies of behavioral interventions aimed at improving compliance with medication regimens in patients with co-morbid addictive and mental or physical disorders. For example, studies could be done to determine the best behavioral interventions to ensure antiviral medication compliance in drug addicted individuals with AIDS, or to investigate the effectiveness of a new behavioral intervention for patients with bipolar disorder. - Research to develop models for integrating new behavioral interventions into existing clinical practices. - Research into the most effective approaches to outreach and risk reduction counseling. Drug addiction and the spread of HIV/AIDS are intertwined epidemics, and the CTN will provide a vehicle to help facilitate reduction in risk behaviors given that all CTPs will provide HIV risk reduction counseling and offer HIV testing. - Studies on the efficacy of drug abuse treatment that include among its AIDS related outcomes: 1) the early treatment of HIV, Hepatitis B and C and Sexually Transmitted Diseases, 2) the rate of progression to AIDS, and 3) the prevention and early treatment of co-morbid medical and mental health conditions associated with HIV/AIDS infection. Studies may incorporate the most current methodological advances for assessing a) biological and mental health risks and HIV status, and b) adherence and compliance to antiretroviral and other medical/mental health therapies. The CTN, with its core of CTPs engaging diverse populations, is also designed to provide a much needed vehicle to recruit and study subjects for such related topics as the medical consequences of long-term drug use and the genetics of vulnerability to addiction, to be funded under separate research grants. Although not all NODEs would be expected to have the capacity to conduct such studies, all NODEs will be expected to collaborate in research focusing on such issues and to aid in recruitment of appropriate subjects. The CTN, as a national network of community treatment programs, may provide a platform to study the factors impacting transmission of knowledge, change of treatment organizations, and adaptation of new treatments and their adoption into widespread clinical practice. NIDA encourages researchers to study such treatment issues at the organizational/program levels under separate research project grants. Research will be conducted collaboratively involving NIDA, RRTCs, and CTPs. The structure of the CTN will permit rapid and concurrent multi-site testing of a wide range of promising science-based therapies in statistically powerful designs. It is the intent of this national network that virtually all studies will involve multiple NODEs working in concert. SPECIAL REQUIREMENTS To promote the development of a collaborative program among award recipients, a number of issues need to be addressed in applications as discussed under Application Procedures, below. Applicants should document their ability to recruit a sufficient number of participants, and should demonstrate their ability and willingness to work cooperatively with NIDA, other awardees, and CTPs, and to follow common protocols. The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official at the time of award. Terms and Conditions of Award These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement, an assistance mechanism (rather than an acquisition mechanism) in which a substantial NIH scientific and/or programmatic involvement with the Awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and /or coordinate the recipient’s activity by involvement and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the Awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the Awardees and NIDA and its contractors. This cooperative agreement funding mechanism will require collaboration between the Director of NIDA’s CTN Unit and the PIs of the CTN NODEs. The NIDA CTN Unit will assist in coordinating of activities of the CTN as defined below and will facilitate the exchange of information. 1. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the details for the project within the guidelines described in the Request for Applications and for performing the scientific activity, and agree to accept close coordination, cooperation, and participation of NIDA staff in those aspects of scientific and technical management of the project described in these terms and conditions. Specifically, awardees have primary responsibilities as described below. a. Steering Committee: The National Drug Abuse Treatment Clinical Trials Network (CTN) shall establish a Steering Committee that will serve as the governing body of the CTN. The voting membership of the Steering Committee consists of the principal investigators of each RRTC, representatives from CTPs, and the NIDA CTN Director.The Steering Committee, by majority vote, will elect a Chair from among the Principal Investigators.The Steering Committee will review and approve the research agenda, formulate and monitor policies and procedures guiding the research activities, oversee communications within the CTN as well as with the greater scientific community and the public. All major scientific decisions will be determined by majority vote of the Steering Committee. All participating RRTCs must agree to abide by the study designs and policies approved by the Steering Committee. Research to be undertaken within the CTN will be determined by the Steering Committee based on input from the NODEs and subject to the approval of the external Network Advisory Board and NIDA. Future research must be within and consistent with the scientific objectives of the RFA. The Steering Committee will establish bylaws and standard operating procedures to govern all aspects of the CTN including, but not limited to, protocol design and development, protocol review and approval, study operations and standards, data acquisition and management, and data analysis and publication. The Steering Committee will also establish CTN performance goals and standards and monitor progress throughout the life of the CTN and its research projects. It is anticipated that the Steering Committee will establish subcommittees and workgroups to assist it in carrying out its functions. b. Bylaws/Operating Procedures The Steering Chair will be responsible for ensuring that there are well documented policies and operating procedures guiding all aspects of CTN activities (e.g. protocol development, review, initiation, conduct, and clousure, data collection, publication, etc.) and bylaws delineating the requirements and expectations of collaborating institutions, membership criteria, and standards of performance, and procedures for removing institutions due to poor performance. 2. Responsibilities of the CTN Regional Research and Training Center (RRTC): Generally, Awardees under this agreement have the following rights and responsibilities as a National Drug Abuse Treatment Clinical Trials Network (CTN) RRTC: The RRTC provides a core of administrative and study operations services, as well as scientific leadership and management of clinical trials. The RRTC, acting as the local operation center for a NODE, has primary responsibility for 1) establishing an infrastructure for core functions, 2) generating a research agenda, 3) providing NODE with administration and operations support, and 4) building partnerships with the CTPs. - Infrastructure for core functions This includes but is not limited to 1) arranging and managing the participation of at least five CTPs in the first year, and at least ten in subsequent years, 2) maintaining scientific and technical personnel for protocol development and implementation, 3) coordinating intra-NODE activities, and 4) providing resources for intra-NODE activities. - Research Agenda - In partnership with its affiliated CTPs, the RRTC develops and submits research concepts and protocols to the CTN Steering Committee for review and approval. For each approved protocol, a protocol specific project team will be established to develop and implement the research project. It is expected that a Project Director will come from the NODE where the research concept and protocol originate. NIDA Scientists will be designated as the scientific and programmatic collaborators on the project team. The Project Director will assume the leadership role for all aspects of that specific protocol and serves as the primary liaison to CTN-wide coordination/support centers as needed. - Data Acquisition and Management - The RRTC will provide intra-NODE data acquisition, data management training, and data quality assurance according to each specific protocol. This data management system must follow the policies and procedures of the CTN Steering Committee, to 1) monitor adverse events and report data and other information to the CTN Data and Safety Monitoring Board (DSMB), and 2) provide timely data to the NIDA Clinical data management center (CDMC) for monitoring protocol progress and for contributing study specific data to a NIDA central data repository. - Responsibility towards its affiliated CTPs- The RRTC provides CTPs with 1) additional therapists, counselors, physicians, physicians' assistants, nurses, and other staff as well as the additional training needed for the CTP to implement a study protocol, 2) the hardware, software, and training to support CTP-based data acquisition activities. Each RRTC will establish a data acquisition system to collect intake, in-treatment and outcome data for all study participants, according to protocol-specific requirements, and 3) additional support, such as quality control to ensure the successful completion of the scientific goals of a research project. Staff selections will be made by the CTP with the concurrence of the RRTC. a. Protocol Development: The Principal Investigator of a RRTC shall initiate the development of a trial concept/protocol and expeditiously draft the protocol according to Steering Committee guidelines for protocol content and format. The Steering Committee will define and manage the review and approval of RRTC initiated protocols. Such review will include provisions for NIDA scientific review and comment, including review by an independent NIDA based CTN Protocol Review Board. The RRTC will be responsible for providing ancillary information about the protocol to permit review of the proposed project’s scientific rationale, feasibility, costs, and compatibility with NIDA research priorities and existing clinical research programs. b. Administrative Support: NIDA will establish separate Administrative Coordinating Center (ACC) contracts to support some of the administrative coordinating functions of the CTN. This includes: 1) Coordination of logistical functions of meetings of the Network CTN Steering Committee, subcommittees, workgroups and other Boards, e.g. the Advisory Board, the DSMB, etc. and logistic functions including production and distribution of committee minutes. 2) Reproduction and distribution of research materials (including treatment protocols, training manuals, and instrumentation), and educational materials. 3) Development, reproduction, and distribution of materials publicizing the activities of the CTN. 4) Monitoring and managing clinical supplies for medication trials. 5) Supporting other operational needs, such as protocol development, regulatory assistance, monitoring/quality assurance, trial material distribution, central labs for analysis of biological fluids, etc. c. Data Management and Analysis: The CTN RRTCs will be required to establish clinical data acquisition and data analysis systems within their Node to gather and analyze data collected as part of CTN multi-site studies. The RRTC data systems will support data management activities within the Node and its affiliated Community Treatment Programs. Data information systems operated by each NODE are required to implement standards established by the CTN Steering Committee. Such standards guide the development of protocol-specific electronic case report form (eCRF) applications each NODE is responsible for implementing at participating CTP sites. NIDA maintains a central Clinical Data Management Center (CDMC) under separate contract to provide a repository of clinical trial data from all the CTN NODEs. The CDMC reports directly to NIDA and functions as a resource to the CTN Steering Committee in matters related to data management, from study design and data acquisition through study analysis and reporting of study findings and conclusions. The NIDA CDMC provides guidelines and technical support on matters related to clinical data management and informatics activities throughout a clinical trial project. The RRTC data centers are expected to provide incremental clinical and other trial performance data to the NIDA CDMC as determined by the CTN Steering Committee. Each protocol proposed under the CTN will include a data management plan that defines specific data acquisition methods and tools and identifies responsibility for data management throughout the trial life cycle. The Principal Investigators of RRTCs agree to cooperate with the CDMC by implementing CTN-wide data standards for collection and analysis of data generated under the CTN, and to provide the CDMC timely data for purposes of monitoring the safety and progress of clinical studies conducted under the CTN. RRTCs agree to provide the CDMC final study data according to schedules developed and approved by the Steering Committee for individual research projects conducted through the CTN. d. Data Rights: The CTN is intended as a national resource for the advancement of treatment for addicted individuals and other affected persons. The Awardee of this agreement acknowledges that NIH has access to any and all data generated under this cooperative agreement and the Awardee agrees to provide royalty- free, nonexclusive, and irrevocable license for the government to reproduce, publish, or otherwise use the material and data derived from research conducted under this cooperative agreement. Data collected or derived under this cooperative agreement must be shared upon request with the Steering Committee, or its designee, for external monitoring pursuant to NIDA responsibilities under agreements with other government agencies (e.g. Food and Drug Administration) or commercial pharmaceutical companies where NIDA may co-develop investigational agents. e. Quality Control and Monitoring: For medication trials, the holder of the investigational new drug application (IND) is primarily responsible for study control and monitoring as defined by FDA rules and regulations. If, NIDA should hold the IND, the RRTCs will be subject to additional review by NIDA to ensure adherence to FDA Good Clinical Practice (GCP). The Awardee agrees to provide material and documentation needed to assure GCP compliance. For Investigational Drug Management, NIDA’s regulatory affairs specialists, under direction of the Steering Committee, will review RRTC operations and advise Investigators of specific requirements concerning investigational drug management. For Laboratory Quality Control and Data Management, the RRTCs agree to participate in protocol-defined measures to ensure methodological and analytic guidelines established by NIDA through the Steering Committee are followed. All RRTC participating laboratories performing analytic studies or services as part of CTN activities must participate in laboratory and data quality assurance programs established by NIDA to ensure cross NODEs standards. f. Subject Safety/Oversight The RRTC will develop protocol-specific measures to assure the safety and protection of the rights of volunteers involved in the clinical studies to be conducted under this cooperative agreement. The Principal Investigator assumes and accepts the primary responsibility for ensuring CTN studies are conducted in compliance with all federal regulations and NIDA policies and procedures. These include but not limited to, Title 21 CFR 50,56,312, and Title 45 CFR 46. The RRTTC must be able to demonstrate that each institution and CTP has a current, approved, Assurance on file with the NIH Office for the Protection of Research Risks (OPRR), that each protocol and informed consent is approved by the recognized Institutional Review Board (IRB) prior to enrollment of subjects in any study; that each investigator has a current Food and Drug Administration Form 1572 curriculum vitae on file at the RRTC; and that each subject (or legal representative) has given written informed consent prior to admission to any study conducted under this cooperative agreement. The Principal Investigator agrees and assures that adequate records will be maintained, and that access to these records will be available, to enable outside monitors to assess compliance with applicable federal laws and regulations. g. Unexpected Adverse Experience Reporting: The Principal Investigator of the RRTC agrees to implement and adhere to an adverse event tracking system designed by the Steering Committee . h. Reporting Requirements: In addition to periodic financial and administrative reports required by NIH for administration of this cooperative agreement, the Awardee agrees to furnish the following reports according to the schedule indicated: Program Operations Reports: Awardees are required and agree to provide quarterly reports of program activities to the Steering Committee by the 10th day of the Month following the end of programmatic quarters (90 days from the date of award). The CTN Steering Committee will define a recommended format and specify minimum content for these Program Operations Reports. Protocol-Specific Reports: Awardees are required and agree to provide periodic reports of protocol- specific projects according to the policies and procedures established by the Steering Committee. At minimum the RRTCs must provide timely enrollment information in a format and according to a schedule defined by the Steering Committee. Other protocol-specific reports, such as those needed to monitor the safety and clinical effectiveness of drugs or other interventions under investigation will be required to allow the Steering Committee and Data and Safety Monitoring Board to monitor the research projects undertaken in the CTN. The Steering Committee will determine the nature, frequency, and content of reports as part of the protocol review and approval process. Investigational New Drug (IND) Reports: Awardees are required and agree to provide reports according to regulations and guidelines established by the Food and Drug Administration (FDA). Data and other reports required of IND sponsors will be provided to the Steering Committee prior to dates established by the Steering Committee. i. Publication of Data: Prompt and timely presentation and publication in the scientific literature of findings resulting from research undertaken in the CTN is strongly encouraged. The Awardee agrees to acknowledge NIDA support in the publications and oral presentations resulting from research conducted under cooperative agreement. Prior to the submission of manuscripts for publication Awardees agree to provide preprint copies to the Steering Committee according to policies and procedures the Steering Committee may establish to monitor the presentation and publication of CTN results. j. Progress Review The CTN Steering Committee will establish procedures for monitoring the performance of the RRTCs and the CTPs participating in research under this cooperative agreement. Performance metrics, such as budget execution, subject enrollment, data acquisition and transmission, and study analysis and reports will be defined to permit NIDA and the Network Oversight Committee a means to assess progress of the CTN and provide information needed to support future funding decisions. The inability of an RRTC to meet performance requirements and responsibilities defined in these Terms and Conditions, and further elaborated by the Steering Committee may result in an adjustment of funding, withholding of support, restriction of funds already awarded, or suspension or termination of the award. k. National Meetings: The Steering Committee may meet up to six (6) times each year. The Principal Investigator agrees to provide adequate support for participation in CTN meetings as required by the Steering Committee. The Principal Investigator agrees to support participation by CTP personnel as required by CTN projects. l. Conflict of Interest: The Steering Committee will develop and monitor compliance to a Conflict of Interest Policy applicable to CTN Awardees. The Conflict of Interest Policy will, at minimum, address issues that may arise through financial ties between RRTC and CTP participants and the private sectors. The Steering Committee will collaborate with NIDA in developing the Conflict of Interest Policy. m. Protocol Closure: Throughout the term of the cooperative agreement NIDA may request that a protocol study be closed for reasons including: 1) insufficient subject accrual; 2) accrual goal for the protocol is met; 3) poor performance in conducting the protocol; 4) safety of the subjects in the study; 5) achievement of conclusive study results; and, 6) emergence of new information that diminishes the scientific importance of the study question. Financial support from NIDA through this cooperative agreement will cease upon protocol closure, except for patients already enrolled in the study. 3. RRTC and CTPs: a. The RRTC agrees to identify and establish subcontracts with at least ten community treatment programs (CTPs) to conduct research and training projects under this cooperative agreement. Each CTP must: - Agree to participate in controlled clinical trials, including randomization methods for assignment of patients to experimental or control groups, or randomization of therapists to different conditions; - Recruit adequate numbers (at lease 75/year) of patients required for specific studies; - Agree to provide routine clinical care to patients participating in protocols; - Agree to provide experimental/standard care in accord with approved research protocols; - Provide HIV risk reduction counseling and HIV testing; - Maintain patient records required for each protocol; - Collect clinical and laboratory data, including biological specimens when indicated; - Cooperate with quality control activities of the CTN and adhering to guidelines set by the RRTC, the Steering Committee, and NIDA; - Participate in the development of concept and protocol of trials to be run in the CTN; - Agree not to report data prior to collaborative reporting; - Agree to periodic on-site audits by representatives of its RRTC, NIDA, or a NIDA designee for use of investigational drugs, compliance with regulations for IRB approval or informed consent (compliance with 45 CFR 46), compliance with protocol specifications, quality control and accuracy of data recording, and completeness of reporting of adverse drug reactions. b. The RRTC shall establish agreements with CTPs that include, at minimum, 1) a statement of work defining the goals and objectives of the research projects to be undertaken under this cooperative agreement; 2) a budget for support of the research projects that clearly identifies the personnel, equipment, materials, and other costs required to successfully conduct high quality research in the community treatment program according to the requirements of specific protocols approved for implementation by the CTN Steering Committee; and 3) a financial and program reporting requirement, including access to data and materials, to facilitate CTN program operation and research project oversight and monitoring. 4. NIDA Staff Responsibilities Staff of the NIDA will have substantial scientific and programmatic involvement throughout the life of this cooperative agreement through technical assistance, and advice and coordination extending beyond normal program stewardship for grants, as described below and elsewhere. The role of the NIDA staff as described throughout these Terms and Conditions is to assist and facilitate, but not to direct the research activities. Communication and interaction will occur primarily with the scientific leadership of the RRTC; however, NIDA may also interact directly with the Directors of any of the collaborating CTPs as needed. The NIDA CTN Director will be responsible for the normal stewardship and oversight of the awards as the responsible program official, and will have primary responsibility for periodic review and approval of RRTC progress. In addition, the NIDA CTN Director will be substantially involved as described in these terms and conditions. a. NIDA's Scientific Role NIDA Collaborating Scientists (CSs) with expertise in behavioral therapies, medications development, and practice research will participate in the development of study plans and protocols, quality assurance and control activities, and in coordinating projects across scientific disciplines and CTN nodes. NIDA CSs may initiate or participate in publications in accordance with established professional and NIH guidelines for authorship. The NIDA CSs will not, however, have a direct role in assessment, testing, or treatment of human subjects participating in studies under this cooperative agreement. The NIDA CTN Director, and/or designated staff, will work closely with the CTN Steering Committee to assure that the research efforts are consistent with NIDA’s research objectives and complement other clinical trial activities supported by NIDA under other means. NIDA will serve as a resource, and will disseminate information regarding promising new therapies. NIDA staff will advise the clinical investigators, as requested or needed, of results from other trials (e.g., adverse experiences and study termination) that could influence the design, development, or conduct of clinical trials under this cooperative agreement. NIDA Protocol Review Board: An expert board authorized by the NIDA Director that will review the final draft of the protocol submitted by the CTN Steering Committee for scientific and regulatory approval. Data and Safety Monitoring Board (DSMB). The DSMB is an independent expert board appointed by and reporting to the Director of NIDA, that will oversee and monitor the conduct of the clinical trials to ensure the safety of participants and the validity and integrity of the data. The DSMB will also make independent assessment of treatment effectiveness and whether a trial will continue. One or more NIDA staff will serve as non-voting members on the DSMB. CTN Oversight Advisory Board. An independent expert board, appointed by and reporting to the Director of NIDA, that oversees all activities conducted under the CTN. The Board will advise the NIDA director regarding the programmatic advisability of proceeding with studies proposed by the Network Steering Committee and will assist the Institute in Prioritizing and approving final protocols. Protocols will be implemented with the approval of NIDA Director. b. NIDA’s Role in Protocol Review and Approval In order for a clinical trial to be initiated, the study proposal must be mutually approved by the CTN Steering Committee and a NIDA Protocol Review Board. Once notified that a trial is under consideration, NIDA will evaluate the proposed trial according to NIDA’s treatment research agenda, its likelihood of timely completion; patient safety; compliance with Federal regulatory requirements; plans for interim monitoring and final analysis of results; and resource requirements. NIDA CSs will estimate required resources associated with the proposed clinical protocol and provide the CTN Director with advice on proposed resource requirements. The NIDA CTN Director will return comments and recommendations in writing to the CTN Steering Committee within 30 days. In the event a protocol is disapproved, the NIDA CTN Director may work with the CTN Steering Committee to resolve specific deficiencies or concerns about the proposed project so that the protocol can be approved and implemented. Prior to protocol approval as defined above, NIDA will provide no trial materials or permit expenditure of CTN funds unless and until the proposed protocol is approved. Disagreements arising during the protocol approval process may be submitted to an arbitration panel for resolution. A panel composed of one CTN designee, one NIDA designee, and a third member with drug abuse clinical trials expertise chosen by the other two members will be formed to review the NIDA decision and recommend an appropriate course of action to the Director, NIDA. These special arbitration procedures in no way affect the Awardee’s right to appeal an adverse determination in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. c. NIDA’s Role During Protocol Conduct For ongoing clinical trials, a NIDA Medical Officer will monitor the safety of the treatment being evaluated. Therefore, interim and final reports on safety for all sponsored clinical trials will be routinely provided to the NIDA Medical Officer. In addition, for protocols in which NIDA is the IND sponsor, NIDA will assign medical monitors to review safety and efficacy data with the protocol statistician and the CTN Data and Safety Monitoring Board. d. NIDA’s Role in Protocol Closure The NIDA CTN Director, and/or designated staff, will monitor the progress of CTN studies by reviewing data and other reports periodically submitted to NIDA. The independent NIDA Data and Safety Monitoring Board, consisting of experts from several disciplines, may determine a need to alter, suspend, or close an ongoing trial due to safety concerns. Additionally, NIDA may deem it necessary to deny access to further investigational drug supplies and deny the expenditure of additional NIDA funds (except where volunteers are already enrolled) if any of the following reasons apply: (1) scientific question no longer relevant, (2) slow accrual, (3) study will not answer questions intended in the proposed study plan, or (4) misuse of federal funds. Appeal of such a decision by the RRTC would proceed in the same manner as an appeal regarding the disapproval of a protocol prior to opening. e. NIDA Access to Data The NIDA CTN Director, and/or designated monitoring staff, shall have access to all data generated under this cooperative agreement and may periodically review data recorded on clinical source documents, case report forms, or in electronic form in a RRTC local database system. Data must be available for external checking against original source documents as required by NIDA and Federal regulations pertaining to the responsibility of NIDA as an IND sponsor. The awardees will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies, including a policy to provide public access to selected, significant data sets generated with the use of public funds, within a reasonable period of time after primary analysis and publication by the CTN. f. Clinical Trials Agreements It is expected that for some clinical trials proposed by the CTN Steering Committee, a pharmaceutical company collaborator will provide investigational agents for the trials. In order for the CTN, NIDA and the company to understand their respective responsibilities and rights, a Clinical Trials Agreement (CTA) will be negotiated and signed by NIDA and the company. Important terms of the agreement include IND sponsorship, safety and data monitoring, and access to trial data. Concurrence with the RRTC Principal Investigator will normally be obtained prior to execution of any final agreement that deviates significantly from the standard NIDA CTA. In general, terms in the CTA covering data access and sharing will conform to policies developed jointly by the CTN leadership and NIDA. g. NIDA Review of CTN Compliance with Federally Mandated Regulatory Requirements The NIDA CTN staff will review applicable regulatory requirements and advise CTN members of mechanisms to meet; (1) FDA regulations for studies involving investigational agents, and (2) the NIH Office for Protection from Research Risks (OPRR) regulations for the protection of human volunteers in clinical research studies. h. Review of Performance The NIDA CTN Project Officers will review the performance of the CTN as a whole and of individual RRTCs at least annually. Such reviews will include periodic reviews of the RRTC and its CTP sites for compliance with clinical and regulatory guidelines and success in achieving any performance standards established by the Steering Committee. The annual review will be based primarily on information provided in periodic progress reports defined elsewhere in these Terms and Conditions, and evaluations of site performance conducted by the Steering Committee, or its subcommittees. Insufficient patient accrual, substandard data management or quality, inadequate progress in executing the research agenda, or noncompliance with the Terms and Conditions of Award may result in a reduction in budget, withholding support, suspension, or termination of award. 5. Arbitration When agreement between an awardee and NIDA staff cannot be reached on scientific/programmatic issues that may arise after the award, an arbitration panel will be formed. A panel composed of one CTN designee, one NIDA designee, and a third member with drug abuse clinical trials expertise chosen by the other two members will be formed to review the NIDA decision and recommend an appropriate course of action to the Director, NIDA. These special arbitration procedures in no way affect the Awardee’s right to appeal an adverse determination in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided 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 research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. LETTER OF INTENT Prospective applicants are asked to submit by February 17, 2000, a letter of intent that includes a descriptive title of the overall proposed research; the name, address, telephone number, and institution of the Principal Investigator; the names of other key investigators and their respective institutions; and the number and title of this RFA in response to which the application is submitted. Although the letter of intent is not required, is not binding and is not a factor in the peer review of the application, the information it contains is helpful in planning for the review of applications. It allows NIDA staff to estimate the potential review workload. The letter of intent is to be sent to: Director, Office of Extramural Program Review National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD (for express/courier services) APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these awards. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC-7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: Grantsinfo@nih.gov. SPECIAL INSTRUCTIONS Specific content must be present in the application to document the technical and scientific merit of the applicant's plan for a NODE that will be able to address the fundamental goals and collaborative nature of the CTN. The use of tables, diagrams, and organizational and flow charts is strongly encouraged. APPLICATION PACKAGE Applicants should include budget estimates and plans for participating in the CTN, organized around the areas of research planning, core functions, RRTC and CTP collaboration, and administrative and management plans. Applicants should not propose detailed research protocols, but provide 2 or 3 specific examples of research concepts that could be undertaken that are consistent with the RFA and that would take advantage of the unique capabilities of the CTN, including collaboration across NODES. The examples should encompass clinical trials on drug abuse treatment. Such examples might include discussions of the types of research questions that could be addressed, research methods that might be used, and patient populations that might be employed. Particular emphais should be placed on how the applicant proposes to ensure that the RRTC and the CTPs of the NODE will work collaboratively at all levels, and that the NODE will be able to work collaboratively with other NODEs and NIDA in multi-site clinical trials. It should be understood that the concepts given in the application will not necessarily be implemented in the CTN. A pplicants must demonstrate access to diverse racial and ethnic populations through the aggregrate of their proposed community treatment providers. Evidence of current or previous successful collaborations with community treatment programs and of participation in successful multi-site trials in collaboration with other research centers would be desirable. An application package should include the following: Research concepts and planning: The research plans for the proposed controlled clinical trials should include descriptions of study design, interventions, and statistical considerations; access to appropriate patients; procedures for data management, quality control and follow-up; procedures for monitoring and reporting adverse events. Core infrastructure functions: The plans should document the availability of appropriate expertise within the RRTC to design, implement, and analyze the results of the proposed trials. Description of the infrastructure for core functions, e.g., including but not limited to:arranging and managing the participation of at least five CTPs in the first year, and at least ten in subsequent years; maintaining scientific and technical personnel for protocol development and implementation; coordinating intra-NODE activities; and providing resources for intra-NODE activities. Describe the available resources and personnel for administration of the NODE. Describe the infrastructure capabilities in research administration, operational management, protocol development, clinical data information systems and management of regulatory documents. The plans should describe the framework and procedures for training and supervision of treatment providers in the experimental and standard interventions that will be utilized in the CTN. RRTC and CTP collaboration: The application should provide documentation (letters of agreement from CTP directors) of participation of five or more CTPs in the first year, with detailed descriptions of each CTP’s characteristics, including patient population characteristics; patient throughput; types of treatment currently delivered; and number, characteristics, and structure of staff. It will be critical for the NODE to recruit and retain sufficient CTPs to participate in multiple simultaneous trials and to bring the number of participating CTPs to at least 10 by the second year of award. The ability to do this should be evident. An organizational chart to describe the functional structure for involving appropriate RRTC and CTP personnel in the design and implementation of a variety of therapies should be provided. An organizational chart and a description of the RRTC operation should describe the relationship between the research and administrative functional units within the NODE. In each of these areas, it is crucial that the applicant describe how the treatment providers will function in true partnership with the RRTC in terms of study origination, design, execution, and administration. Applicants should anticipate potential problems and challenges that may arise in this process and propose mechanisms for collaborative resolution among the NODE participants. The NIH policy regarding consortium agreements must be considered in describing the relationship between the RRTC and the CTPs Administrative and Management Plan The qualifications and experience of the Principal Investigator must be described. An individual should be designated as the coordinator for intra- NODE research activities. His or her qualifications and experience should also be described. Each application must also demonstrate the ability to access professionals with the appropriate expertise to design and implement the proposed interventions and controlled clinical trials. It is important to establish the Principal Investigator’s ability to contribute to the scientific agenda and adequate time commitment (a minimum of 50%) to provide protocol mandated leadership for the clinical trial. The accrual of geographically diverse CTPs should be evident. Evidence of current or previous successful collaborations with community treatment programs and of participation in successful multi-site trials in collaboration with other research centers would be desirable. Plans for intra-NODE data management and information management systems should be specified (encompassing all of the NODE's CTPs). Diagrams and descriptions of proposed within-NODE committee structures should be given. Each applicant must demonstrate the ability to train and maintain the proficiency of CTP personnel to successfully manage treatment and clinical trials research. This will include training in data management, data collection, trials monitoring, and implementation of research protocols. Budget The applicant should prepare a separate detailed budget for 1) infrastructure to enable the RRTC to provide core functions for the NODE (e.g., personnel, facilities, equipment, supplies, training cost, logistic support, travel, etc.) and; 2) protocol specific costs such as training (of therapist or data manager), data management, clinical associated expenses, laboratory costs, monitoring costs, publications costs; and 3) CTP support to conduct the clinical trials. Page Limits The total length of the Research Plan, including the CTP descriptions and research concepts, administrative and management plan, and budget should not exceed 45 pages. Descriptions of CTPs should not exceed 2 pages per program. Descriptions of research concepts should not exceed 3 pages per concept. No specific page limits apply to the Human Subjects, Literature Cited, or Consortium/Contractual Arrangements sections. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 two of the face page of the application form, and the YES box must be marked. The RFA number must be typed on label as well. The sample RFA label is available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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, MSC-7710 6701 ROCKLEDGE DRIVE, ROOM 1040 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight services) At the time of submission, two additional copies of the application must be sent to: Director, Office of Extramural Program Review National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD 20852 (for courier/overnight services) Telephone: (301) 443-2755 Applications must be received by March 16, 2000. If an application is received after this 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the 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. As part of the initial merit review, all applications will receive a written critique. Those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council on Drug Abuse. Applications will be reviewed for scientific and technical merit using the following criteria. Applicants should note that the criteria incorporate consideration of the quality and feasibility of the proposed activities as well as consideration of past performance. Research Plan Adequate understanding of the scientific agenda of the CTN. Feasibility of contributing to the goals and enhancing the capability of the CTN. Significance of the research concepts proposed and knowledge of state-of-the- art research designs and methodologies. Research Infrastructure Time availability, qualifications, and research experience of the RRTC Principal Investigator and named scientific leadership, including but not limited to, previous experience with design, administration, and management of multi-center clinical trials. Qualification of key personnel and scientific staff in the areas of proposed research. Qualification of staff in providing statistical and data management expertise for multi-site clinical trials. Adequacy of the available resources and personnel for administration of the NODE. Evidence of infrastructure capabilities in research administration, operational management, protocol development, clinical data information systems, and management of regulatory documents. CTPs and RRTC (collaboration) Previous experience and adequacy of plans for involving CTPs in research and organizational activities. Adequacy of RRTC's criteria for selecting community-based treatment programs (CTPs) that have diverse geographic and population representation, balanced by the constraints of reasonable management. Adequacy of the quality and variety of CTP programs and experience of the program directors. Ability to accrue a demographically diverse patient population and adequacy of the plan for patient enrollment, and retention, as well as program evaluation. Ability to accrue patients at an adequate rate to support multisite clinical trials. Administrative and management plan Adequacy of the plans for overall NODE management and operations, including the structure and mechanism for effective intra-NODE communication and collaboration. Previous experience and adequacy of plans for training therapists and research associates in implementing multi-site clinical trials. Adequacy of plans for intra-NODE data management, including adequacy of the plan for incorporating CTN-wide data standards, data collection, analysis, and site-specific training. Adequacy of plans for effective interaction and coordination with other NODES and NIDA. Budget Adequacy of budget estimates for 1) infrastructure to enable the RRTC to provide core functions for the NODE (e.g., personnel, facilities, equipment, supplies, training costs, logistic support, travel, etc.) and; 2) protocol specific costs such as training (therapist or data manager), clinical expenses, laboratory costs, monitoring costs, publications costs; 3) CTP support to conduct the clinical trials; and 4) adequacy of plans for budgetary control and oversight. AWARD CRITERIA Applications recommended for further consideration by the National Advisory Council on Drug Abuse will be considered for funding based upon a) scientific and technical merit; b) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative study a reasonable likelihood; c) geographic location of applicant organization; and d) availability of funds. An application will not be funded until a site visit has taken place. SCHEDULE Letter of Intent Receipt Date: February 17, 2000 Application Receipt Date: March 16, 2000 Scientific Review Date: Summer 2000 Council Meeting Date: September 2000 Earliest Award Date: September 30, 2000 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Betty Tai, Ph.D. Office of Clinical Trials Network Division of Treatment Research and Development National Institute on Drug Abuse 6001 Executive Boulevard, Room 4129, MSC 9551 Bethesda, MD 20892-9551 Telephone: (301) 443-2397 FAX: (301) 443-2599 Email: bt26r@nih.gov Jack D. Blaine, M.D. Division of Treatment Research and Development National Institute on Drug Abuse 6001 Executive Boulevard, Room 4226, MSC 9551 Bethesda, MD 20892-9551 Telephone: (301) 443-0107 FAX: (301) 443-8674 Email: jb167n@nih.gov Direct inquiries regarding peer review issues to: Teresa Levitin, Ph.D. Office of Extramural Program Review National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Telephone: (301) 443-2755 FAX: (301) 443-0538 Email: tlevitin@nida.nih.gov Direct inquiries regarding fiscal matters to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 443-6847 Email: gf6s@nih.gov AUTHORITY AND REGULATIONS This program is described in the catalog of Federal Domestic Assistance No. 93.279. Awards are made under the authority of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 122372 or Health Systems Agency Review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-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 of 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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