EXPANSION OF THE NATIONAL DRUG ABUSE TREATMENT CLINICAL TRIALS NETWORK Release Date: November 20, 2001 RFA: RFA-DA-02-003 National Institute on Drug Abuse (http://www.nida.nih.gov) Letter of Intent Receipt Date: January 22, 2002 Application Receipt Date: February 22, 2002 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). Applications from geographic areas not currently well represented in the CTN are particularly encouraged. This Request for Applications (RFA) is the third solicitation for participation in the CTN. As a nation-wide partnership among drug abuse treatment providers, researchers, and NIDA staff, the mission of the CTN is to conduct studies of behavioral, pharmacological, and integrated behavioral and pharmacological treatment interventions in rigorous, multi-site clinical trials to determine these interventions' effectiveness across a broad range of community-based treatment settings and diverse patient populations. In addition, the CTN seeks to disseminate proven treatments to physicians, providers, and their patients to improve the quality of drug abuse treatment throughout the country, using science as the vehicle. CTN clinical trials are carried out in community-based treatment settings. 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 clinical trials research. Awardees deliver and test an array of both behavioral and pharmacological treatments and determine conditions under which novel and efficacious treatments are successfully adopted. Studies 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. Current CTN Nodes are located in California, Colorado, Connecticut, Florida, Michigan, New York, North Carolina, Ohio, Oregon, South Carolina, Maryland, Pennsylvania, and Washington. NIDA recognizes a need for greater geographic distribution of CTN sites as well as a need to encompass more subpopulations of minority groups and to broaden the range of treatment providers who work under varying systems of reimbursement and organization of care. By expanding in these areas, greater variety in the types of studies conducted and greater confidence in the generalizability of those studies will be assured. Therefore, a particular purpose of this Request for Applications (RFA) is to expand the geographic distribution of CTN sites, and applications are encouraged from investigators in those geographic areas without CTN Nodes and where the CTN is not well represented. 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, "National Drug Abuse Treatment Clinical Trials Network," 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/. 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. The Principal Investigators must commit a minimum of 50 percent time to CTN and document a substantial history of leadership in 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. The anticipated award date is September 30, 2002. All policies and requirements that govern the grant program of the PHS and NIH apply. FUNDS AVAILABLE NIDA intends to commit approximately $5 million to support first year total costs of establishing additional CTN Nodes in FY 2002. Additional funds will be allocated to Nodes in subsequent years to support conduct of specific protocols. 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 three awards under this RFA for project periods of up to 5 years of support. More funding may be made available to fund additional sites if sufficient applications of high merit are submitted. It is anticipated that there will be subsequent RFAs to expand the CTN. It is projected that competing continuation applications will be invited upon expiration of the initial funding period of awards made under this and previous RFAs, 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 development of the CTN was based, in part, upon a recommendation from the National Advisory Council on Drug Abuse and conclusions of the Physicians Leadership on National Drug Policy. 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" also recommended a national network for drug abuse treatment trials. Following the first NIDA CTN solicitation in 1999, six CTN awards were made to awardees in California, Connecticut, New York, Oregon, Maryland, and Pennsylvania. After a solicitation in 2000, awards were subsequently made to eight additional sites in Colorado, Florida, Michigan, New York, North Carolina, Ohio, South Carolina, and Washington. These sites represent a variety of treatment traditions that include pharmacological as well as behavioral and other psychosocial interventions. Furthermore, NIDA ensured a wide variety of patient populations in the selection of CTN recipients, and women, minority groups, and adolescents are well represented. The CTN is now established and is making progress toward its goals of (1) providing a clinical trials research infrastructure to test the effectiveness and usefulness of new and improved treatments in community-based treatment settings with diverse patient populations and (2) serving as a mechanism for the study of dissemination of new and improved interventions into community-based drug treatment settings. A number of functional committees to provide governance to the CTN are established, protocols for the study of both pharmacological and behavioral interventions are currently underway, data management and safety monitoring procedures are in place, and new studies are being planned and approved. Details on the status of the CTN initiative may be found on the NIDA web site at: http://www.nida.nih.gov/CTN/Index.htm. Strong partnerships and bi-directional collaboration between researchers and practitioners are an essential and defining characteristic of the CTN. Although treatments for drug abuse exist and considerable research has been directed toward the improvement of treatment alternatives, most addiction treatment research prior to the CTN was conducted primarily in specialized research settings. Through the researcher-practitioner partnership that characterizes the CTN, the CTN accelerates the pace of research and its application to real-life treatment settings by conducting large scale multi-site clinical treatment studies in community based treatment programs (CTPs). Knowledge gained through the CTN is also expected to further the dissemination and adoption of research-based treatments. That is, CTN research will not only help determine which treatments should be implemented, it will also inform the process of implementation and dissemination to ensure the acceptability and sustainability of new approaches. CTN DEFINITIONS, ORGANIZATION, 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 is comprised of multiple Nodes. Activities that occur primarily within a single Node (e.g., hiring of staff, RRTC-CTP activities) are called "Intra-Node" activities, as opposed to CTN-wide or "Inter-Node" activities such as implementation of protocols across one or more Nodes, development of CTN-wide policies, etc. 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 typically 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 operational center for a Node, has primary responsibility for 1) establishing the infrastructure, 2) generating a research agenda in collaboration with the CTPs, 3) providing administration and operations support, 4) building partnerships with the CTPs, and, 5) collaborating with NIDA and other Nodes to develop, implement, and disseminate findings from CTN research projects. --Infrastructure. Infrastructure refers to the capacity of the RRTC and CTPs to 1) arrange and manage collaborative activities of at least five CTPs with the RRTC; 2) maintain scientific and technical personnel for protocol development and implementation, 3) coordinate intra-Node activities, and 4) provide resources for intra-Node activities. It also refers to the physical resources (buildings, clinics, etc.) available. --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 concept, a protocol specific project team is established to develop and implement the research project across the CTN. It is expected that there will be a Lead Investigator (LI) from the Node where the research concept and protocol originate. NIDA scientific and technical personnel are designated as collaborators on the project team. The LI assumes the leadership role for all aspects of that specific protocol and serves as the primary liaison to CTN-wide coordination/support centers as needed. The project team for each CTN research project includes personnel and experts across the network from all disciplines required for the development and implementation of the project. --Administrative and Operations Support. The RRTC ensures appropriate administrative and operations support for Node activities. The support must ensure adherence to the Terms and Conditions of the Award and the policies and procedures of the CTN Steering Committee to: 1) design and develop CTN research projects; 2) develop and implement data acquisition and data management systems for CTN research projects conducted within the Node; 3) formulate and conduct general research and project specific training; 4) develop patient safety and other regulatory documents to obtain approvals needed to implement studies within the Node; and, 5) ensure the quality of research within the Node through on-site monitoring at participating clinical sites. --Partnership with and Responsibility toward Affiliated CTPs. The RRTC functions as a partner with its associated CTPs. It 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 provide for 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. 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, members of minority groups, and adolescents, and have the capability for and interest in participating in controlled clinical trials. Working as an equal partner with its RRTC, 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 100/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 access to HIV testing; -- Maintain patient records and other source documents 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 research concepts and protocols for trials to be conducted 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 appropriate 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 constitutes the primary governing body of the Network. The committee membership consists of the Principal Investigators of each RRTC, representatives from CTPs, and two NIDA representatives one of which is the NIDA Director of the Center for Clinical Trials Network (CCTN). This group reviews and approves the research agenda, formulates and monitors policies and procedures guiding the research activities, and oversees communications within the CTN, as well as with the greater scientific community and the public. All major scientific decisions are determined by majority vote of the Steering Committee. All participating RRTCs and CTPs 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 are and will be determined by the Steering Committee based on input from the Nodes and subject to the approval of the external Ad Hoc Oversight Board and NIDA. Future research must be within and consistent with the scientific objectives of the RFA. The Steering Committee uses both established and ad hoc subcommittees and workgroups to assist it in carrying out its functions. The Steering Committee meets no more than six times per year, usually in the Washington, D.C., area. Applicants should include costs 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, Node personnel 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 reviews 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 oversees and monitors the conduct of the clinical trials to ensure the safety of participants and the validity and integrity of data for each study. The DSMB also makes an independent assessment of the interventions under study and whether or not any trial undertaken in the CTN will continue. One or more NIDA staff serves as non-voting members on the DSMB. CTN Ad Hoc Oversight Board. An independent expert board, appointed and reporting to the Director of NIDA, that oversees all activities conducted under the CTN. The Board advises the NIDA Director regarding the programmatic advisability of proceeding with studies proposed by the Network Steering Committee and assists the Institute in prioritizing and approving protocols for implementation in the CTN. Protocols are implemented with the approval of the NIDA Director. Central Data Management Center (CDMC). Clinical data information systems provided by each Node are required to implement standards established by NIDA and the CTN Steering Committee. Such standards guide development and implementation of the protocol-specific electronic case report form (eCRF) applications that each Node must implement at participating CTP sites. The CDMC reports directly to NIDA, although it 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 Support Center (ASC). NIDA provides via contracts certain resources providing common services for CTN clinical trials, including support for administrative requirements and oversight functions mandated by NIH. Specifically; 1) Regulatory affairs and Investigational New Drug (IND) filing; 2) Monitoring for clinical study sites; 3) Administrative support for protocol development; 4) Project management; 5) Training in Good Clinical Practice (GCP) etc.; In addition, central pharmacy services for medication packaging and shipping as well as clinical laboratory support are provided by NIDA as central resources for the CTN. Logistic Support Center (LSC). A contract awarded by NIDA to support many of the administrative and logistic functions of the CTN including: 1) Coordinating logistic and operational support for a variety of CTN meetings with up to 250 attendees; 2) Handling all logistics and costs with coordinating over 400 conference calls on an as needed basis per year; 3) Support for consultants providing NIDA and the CTN grantees with expert advice on a variety of topics regarding the Network; 4) Preparing publicity, meeting, and protocol related materials as required; 5) Providing scientific writers/editors to prepare reports, take minutes of meetings and conference calls, edit documents; 6) Reproducing and distributing research materials, protocol related documents, and educational materials; 7) Creating and maintaining administrative records to support the CTN activities; 8) Providing translation services for CTN materials in languages other than English; 9) Maintaining a CTN web site; and 10) Miscellaneous support services. [NOTE: Funds to support Node personnel travel to meetings will not be disbursed by the LSC. Applicants should make adequate provision for these funds in the budgets submitted under the present RFA. See the Subsection "Budget" in the "APPLICATION PACKAGE" section below for more guidance on this issue.] Center for the Clinical Trials Network (CCTN). An organization 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 rigorous, multi-site clinical trials of efficacious behavioral, pharmacological, and combined behavioral and pharmacological treatment interventions in community-based treatment programs to determine effectiveness across a broad range of treatment settings and patient populations. -- Encouraging research on effective strategies for transporting science-based, treatment interventions into clinical practice. -- Furthering the development of effective treatments by integrating behavioral and pharmacological interventions. -- Ensuring that treatment research in drug abuse and addiction is extended to the wider community, such as minorities, women, children, adolescents, and underserved populations. -- Ensuring that treatment research in drug abuse and addiction addresses the needs of special populations within the wider community, including court-involved patients and patients with co-morbid psychiatric or medical conditions. -- Fostering the collaboration between community practitioners and treatment researchers by providing opportunities for bi-directional education, exchange of ideas, information, and values. -- Investigating the impact of community-based treatment research on community treatment practices. -- Determining whether transport of novel, effective treatments to the community impacts 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 with a stable and broadly representative platform for drug abuse treatment research through regional Nodes distributed throughout the country. Each Node will encompass a substantial geographical area and a variety of treatment settings, patient populations, and drug abuse problems. The RRTC of each Node must have demonstrated expertise in conducting drug abuse clinical trials and in research and clinical training. Through its associated CTPs, each Node must demonstrate the capacity to recruit and treat a broad range of patients, including adolescent, women, patients with co-occurring mental disorders, those at high risk for HIV infection, members of racial/ethnic groups, and those abusing or addicted to various drugs of abuse. All Nodes must demonstrate the capacity to deliver and test a variety of both pharmacological and behavioral therapies. 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. For the CTN to be maximally effective, the CTPs must be partners in the research enterprise by participating in research decisions, including selection of trials to be implemented and decisions concerning protocol design. Current CTN Research The CTN has implemented the following studies, which are provided as examples of the type of research appropriate for the CTN: -- Buprenorphine/Naloxone versus Clonidine for Inpatient Opiate Detoxification -- Buprenorphine/Naloxone versus Clonidine for Outpatient Opiate Detoxification -- Buprenorphine/Naloxone: Comparison of Three Taper Schedules for Opiate Detoxification -- Motivational Enhancement Treatment to Improve Treatment Engagement and Outcome in Subjects Seeking Treatment for Substance Abuse -- Motivational Interviewing to Improve Treatment Engagement and Outcome in Subjects Seeking Treatment for Substance Abuse -- Motivational Incentives for Enhanced Drug Abuse Recovery: Methadone Clinics -- Motivational Incentives for Enhanced Drug Abuse Recovery: Drug Free Clinics In addition to the above studies that are underway, the following protocols and concepts have been approved: -- Characteristics of and practices among community-based providers -- Smoking cessation treatment in substance abuse rehabilitation programs -- Enhancing continuing care engagement to reduce relapse following residential treatment -- Buprenorphine/Naloxone in the treatment of adolescent heroin addicts -- Infections screening in substance abuse treatment programs -- Gender-specific intervention to reduce HIV risk behavior in drug abuse treatment -- Treating trauma and substance abuse in women -- Brief Strategic Family Therapy for adolescents -- Performance monitoring and feedback to counselors to improve drug abuse treatment -outcome -- Job seekers skills training -- Motivational Interviewing for pregnant women -- HIV intervention in drug treatment settings As the CTN continues to develop, it is anticipated that other topics could be studied such as: -- 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. -- Optimizing 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. -- 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. -- Models for integrating new behavioral interventions into existing clinical practices. -- 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 CTPs participating in the CTN must provide HIV risk reduction counseling and offer HIV testing. -- Efficacy of drug abuse treatment on AIDS related outcomes, such as rate of progression to AIDS. Studies could examine the effects of: 1) the early treatment of HIV, Hepatitis B and C and Sexually Transmitted Diseases, or 2) the prevention and early treatment of co-morbid medical and mental health conditions associated with HIV/AIDS infection. Such 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. CTN Platform for Other Funded Research The CTN, with its core of CTPs engaging diverse populations, is also designed to provide a much needed vehicle to recruit study subjects for such related topics as the medical consequences of long-term drug use and the genetics of vulnerability to addiction, which would 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 permits rapid and concurrent multi-site testing of a wide range of promising science-based therapies in statistically sound 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 are 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 Center for Clinical Trials Network (CCTN) and the Principal Investigators of the CTN Nodes. The NIDA CCTN will assist in coordinating 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: Grantees must participate in The National Drug Abuse Treatment Clinical Trials Network (CTN) Steering Committee that serves as the governing body of the CTN. The voting membership of the Steering Committee consists of the The Principal Investigator and a CTP representative of each RRTC, and two representatives from NIDA, one of which is the NIDA CCTN Director. The Steering Committee reviews and approves the research agenda, formulates and monitors policies and procedures guiding the research activities, and oversees communications within the CTN as well as with the greater scientific community and the public. All major scientific decisions are 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 undertaken within the CTN is 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 policies and standard operating procedures 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 also has established CTN performance goals and standards, and it monitors progress throughout the life of the CTN and its research projects. Standard operating procedures and policies governing the CTN are available at http://www.drugabuse.gov/CTN/policies.html. Subcommittees and Workgroups have been and will continue to be established to assist the Steering Committee in carrying out its function. b. Policies/Operating Procedures The Steering Committee 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, project initiation, conduct, and closure, data collection and management, 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 operating center for a Node, has primary responsibility for 1) establishing an infrastructure for core functions, 2) generating a research agenda, 3) providing the 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, with possibility for expansion 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/implementation - 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 concept, a protocol specific project team will be established to develop and implement the research project. It is expected that a Lead Investigator will come from the Node where the research concept and protocol originate. NIDA Staff will be designated as scientific and programmatic collaborators on the project team. The Lead Investigator 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. -- Partnership with 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 must provide 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. a. Protocol Development: The Principal Investigator of a RRTC shall initiate the development of a trial concept/protocol and expeditiously draft a research 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. Data Management and Analysis: Each CTN RRTC is required to provide clinical data acquisition and management systems within their Node to gather, manage, and if serving as a Lead Investigator, analyze data collected as part of CTN multi- site studies. The RRTC data systems will directly support data management activities within their Node at affiliated Community Treatment Programs. A Node may elect to operate its data management center directly or arrange these services through contract with an outside organization or by arranging with another CTN Node data management operation. Data information systems operated by each Node are required to implement standards established by NIDA and 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, and define a Node's responsibility and procedures for providing data to NIDA's Central Data Management Center. NIDA maintains a Central Data Management Center (CDMC) to support its program oversight role and to provide a repository of clinical 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 NIDA and the CTN Steering Committee. Each research project proposed under the CTN must include a data management plan that defines specific data acquisition requirements and identifies responsibility for data management throughout the research project life cycle. The NIDA CDMC will review, approve, and certify data acquisition and data management systems used in CTN research projects prior to the enrollment of any participants in CTN research projects. 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, accurate, and complete data for purposes of monitoring the safety and progress of research projects 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. c. 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. d. Quality Control and Monitoring: All behavioral and medication trials are subject to quality control and monitoring as stated in the policies and procedures established by the Steering Committee. The Lead Investigator of each trial is primarily responsible for study control and monitoring as defined by FDA rules and regulations. In addition, NIDA or its representative will provide periodic oversight monitoring of all clinical trial sites. The Awardee agrees to permit on site monitoring for all of its community treatment provider sites. For Laboratory Quality Control and Data Management, the RRTCs agree to follow protocol-defined measures to ensure methodological and analytic guidelines established by NIDA through the Steering Committee. 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 standards across Nodes. 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. Although behavioral therapy trials are not bound to FDA regulations, NIDA, through the Steering Committee, may implement quality control and monitoring procedures for behavioral trials with the same rigor defined by FDA rules and regulations. e. Training: The RRTC will be responsible for providing regional training to node personnel involved in the conduct of clinical trials. The training should support the implementation of protocols in which their affiliated CTPs will participate. Training will include, but is not limited to, adhering to GCP guidelines, research ethics training, biological specimens handling, data management, quality control and regulatory procedures. The RRTC may also be responsible for providing training for delivering the medications and behavioral therapies, and conducting assessments that are specific to each protocol, in accordance with protocol training plan specifications. RRTCs are responsible for following the policies and procedures approved by the Steering Committee for conducting training in the CTN. 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, and other research projects, 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 are not limited to, Title 21 CFR Parts 11, 50, 56, 312, and Title 45 CFR 46. The RRTC must be able to demonstrate that each institution and CTP has a current, approved, Institutional Assurance of Protection for Human Subjects on file with the Department of Health and Human Services Office for Human Research Protections; that each protocol and informed consent is approved by the recognized Institutional Review Board (IRB) prior to the 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 necessary 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 operated by NIDA and adopted 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: CTN Node Operations Reports: Awardees are required and agree to provide quarterly reports of program activities to NIDA by the 10th day of the month following the end of programmatic quarters (90 days from the date of award). These reports include a quarterly progress report of the activities of the Node within the reporting period and quarterly financial reports showing a breakdown of the costs incurred for both the RRTC and CTPs for the reporting period. The quarterly financial report shall include a total of all costs spent in previous quarters for that year as well as the current reporting period. This report is in addition to the yearly Federal Status Report (FSR) required by NIH. The CTN Steering Committee will define a recommended format and specify minimum content for these Program Operations Reports. CTN Research Project Reports: Awardees are required and agree to provide periodic reports of the research projects undertaken in the CTN. At minimum the Lead Investigator must provide timely information on the tasks, schedule, and costs associated with the development and implementation of a CTN research project. Enrollment information in a format and according to a schedule defined by NIDA and the Steering Committee are required for each CTN clinical research project. 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 has established and will continue to elaborate 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 have been 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 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 has developed policies on Conflict of Interest and monitors compliance to that policy. The Conflict of Interest Policy addresses issues that may arise through financial ties between RRTC and CTP participants and the private sectors. Awardees will abide by the Conflict of Interest Policy. m. Protocol Closure: Throughout the term of the cooperative agreement NIDA may request that a research project be terminated 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 project closure, except that funds may remain available for patients already enrolled in the study. 3. RRTC and CTPs: a. The RRTC agrees to negotiate and establish subcontracts with at least five 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 least 100/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 access to HIV testing; -- Maintain patient records and other source documents 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 research concepts and protocols for trials to be conducted 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 appropriate 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. CTPs are not expected to participate in every CTN research project, but must adhere to the above terms when they choose to participate in a CTN research project. 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 do have and 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 in these terms and conditions. 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 CCTN 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 CCTN Director will be substantially involved as described in these terms and conditions. NIDA maintains a separate Administrative Services Center (ASC) and a Logistic Support Center (LSC) through contract. These central resources support certain administrative coordinating functions of the CTN. These include: 1) Logistical support for meetings of the Network, e.g., CTN Steering Committee, subcommittees, workgroups and other Boards (the Advisory Board, the DSMB, etc.), 2) Reproduction and distribution of research and educational materials, including treatment protocols, training manuals, and instrumentation, 3) Development, reproduction, and distribution of materials publicizing the activities of the CTN, 4) Provision of trial medications and clinical laboratory services and 5) Support for other operational needs, such as protocol development, regulatory affairs, monitoring/quality assurance, project management, etc. 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 CCTN 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. The following Boards will have approval authorities as indicated: 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 review study plans and 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 the effectiveness of interventions under investigation and whether a trial will continue. One or more NIDA staff will serve as non-voting members on the DSMB. CTN Ad hoc Oversight 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 the NIDA Director. b. NIDA's Role in Protocol Review and Approval In order for a CTN research project 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 clinical 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 personnel will estimate required resources associated with the proposed clinical protocol and provide the CCTN Director with advice on proposed resource requirements. In the event a protocol is disapproved, the NIDA CCTN 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 to implement the research project 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 Approval to Enroll Study Participants CTN research projects may proceed upon the Lead Investigator receiving approval from the NIDA CCTN Director that enrollment may begin. The Lead Investigator is responsible for providing all necessary documentation of the readiness of each participating site to initiate participant enrollment. Such documentation will include evidence of IRB approval for each clinical site, evidence of participating Node data system readiness based on successful test and certification by NIDA's Central Data Management Center, evidence that all participating project personnel have received the training needed to conduct the research according to the protocol, and evidence that Node quality assurance plans are in place to monitor the research project at participating clinical sites. d. NIDA's Role During Protocol Conduct For ongoing research projects NIDA personnel and its contractors will monitor the safety of study participants through review of incremental case report form data collected by Node data acquisition systems, and data gathered through other means, including NIDA clinical monitoring activities. For all clinical trials, NIDA will assign a Medical Officer who will be responsible for the review and disposition of adverse events that may arise in the course of a study. NIDA will prepare periodic reports profiling the conduct of the study including the safety of study participants for review by the CTN Data and Safety Monitoring Board (DSMB). e. NIDA's Role in Protocol Closure The NIDA CCTN 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 or study performance issues. 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. f. NIDA Access to Data The NIDA CCTN Director, and/or designated 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. g. 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. h. 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 DHHS Office for Human Research Protections regulations for the protection of human volunteers in clinical research studies. i. Review of Performance The NIDA CCTN Director 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 the performance standards established by NIDA and the Steering Committee. The annual review will be based 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 clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS 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. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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 RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Director, Office of Extramural Affairs National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD 20852(for express/courier services) APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable format. For further assistance contact Grants Info, 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 addresses the fundamental goals and collaborative nature of the CTN. The use of tables, diagrams, and organizational and flow charts is strongly encouraged. Application Package The application should conform to the general instructions and requirements (e.g., for font size and page limits) of the PHS 398 (rev. 5/2001) with the exceptions noted below. Sections a-d need not be organized according to Specific Aims, Background and Significance, etc. as stated in the PHS 398 application kit. It is suggested that sections a-d be replaced with the following six sections. 1. Understanding of and Ability to Contribute to the Mission of the CTN: This section should consist of a few pages to establish the applicant's understanding of the CTN. 2. Administrative and Management Plans: 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. Evidence of participation in multi-site clinical trials is desirable. It is important to demonstrate the Principal Investigator's ability to contribute to the scientific agenda and commit a minimum of 50 percent of time 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 communications and data management operations encompassing all of the Node's CTPs should be specified. Diagrams and descriptions of proposed intra-Node committee structures should be given. Each applicant must demonstrate the ability to train and maintain the proficiency of RRTC and CTP personnel to successfully manage treatment and clinical trials research. This will include training in project management, data collection and data management, clinical trial design and analysis, clinical trial monitoring, and implementation of research protocols. 3. Research and Clinical Infrastructures: The plans should document the availability of appropriate expertise within the RRTC to design, implement, and analyze the results of proposed trials. Description of the infrastructure for core functions, which include but are not limited to managing the participation of five CTPs in the first year, staffing technical personnel for protocol design, development and implementation, and providing resources for and coordination of intra- Node activities. That plan should also elaborate on the infrastructure capabilities in research administration, project management, protocol design and development, clinical data information systems, and regulatory affairs. In order to reduce redundancy in functions among various CTN Nodes, NIDA advises that applicants utilize existent data center resources at currently funded CTN Nodes. Therefore, the descriptions of local data information systems must clearly state the applicant's intention and arrangements to provide for intra-Node data acquisition, data management, and statistical analysis. The appendix should contain letter(s) of agreement from CTN Principal Investigators, or existing CTN data management providers the applicant intends to contract with to provide data acquisition and data management services. Applicants may obtain a list of current CTN data management providers from the CTN CCTN Director. 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. Applicants must demonstrate access to diverse racial and ethnic populations through the aggregate of their proposed community treatment providers. 4. Collaborations between the RRTC and CTPs: The application should describe the relationships between the CTPs and RRTC. It should provide detailed descriptions of five CTPs that will participate in the first year, with detailed descriptions of each CTP's characteristics, including patient population characteristics, patient throughput, types of treatment currently delivered, and staff number, characteristics, and structure. Each CTP's description is limited to two pages of text. It will be critical for the Node to recruit and retain sufficient CTPs to participate in multiple simultaneous trials. The possibility of expanding the number of CTPs should be addressed. The appendix should contain letters of agreement from CTP directors and tables, as needed, to describe the CTPs. An organizational chart to describe the functional structure of RRTC and CTP personnel in the design and implementation of a variety of clinical research projects should be provided in the body of the application (i.e., within the 45 pages). An organizational chart and a description of the RRTC operation should describe the relationship between the research and administrative functional units within the Node. Evidence of current or previous successful collaborations with the community treatment programs would be desirable. 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 research concept origination, protocol design, research project implementation, and administrative support services. 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. 5. Research Concepts: Applicants should not propose detailed research protocols, but should provide 2 or 3 specific examples of research concepts and abbreviated plans that could be undertaken and are consistent with the RFA to take advantage of the unique capabilities of the CTN, including collaboration across Nodes. The concepts should present 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 emphasis 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. The research plans for the proposed controlled clinical trials should include descriptions of research study design, interventions, outcome measures, and statistical considerations; access to appropriate patients; procedures for data management, quality control and follow- up; procedures for monitoring and reporting adverse events; and information on human subjects protections. Each concept is limited to 3 pages. 6. Other: There should be information on literature cited, contractual arrangements, etc. as specified in the PHS 398. NOTE: Human Subjects Research (research plan section e) instructions have been revised and must be addressed in the application; no specific page limits apply, but be complete and concise. The application should describe plans on human subject protections, data safety monitoring and patient populations for the CTN Node as a whole. Budget The budget and accompanying justification are not part of the 45 page limit. 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. 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 costs, logistic support, travel, etc.) and; 2) research project specific costs such as training of therapists, research assistants, or data acquisition personnel, data management and analysis staff, clinical expenses related to the research (excluding costs of routine ongoing clinic treatment), laboratory costs, monitoring costs, publications costs; and 3) CTP support to conduct the clinical trials. As noted elsewhere in this RFA, funds for Node travel should be included to provide for participation in CTN related meetings. In general, no more than $1 million in direct costs should be allocated to support first year operations. Most CTN participants have found that the initial year requires intensive developmental activities and that research is not actually undertaken until late in the first year or in the second year. Therefore, the budgets for ensuing years (year two through year five) should be increased to reflect anticipated costs associated with maintaining the Node infrastructure and performing research projects. The "lead Node," or Node that has primary responsibility for leading a research project, will support costs related to that project either through their award, or with CTN central resources provided by NIDA contracts. Such costs may include: 1) Reproducing and distributing research materials (including treatment protocols, training manuals, and instrumentation) and educational materials; 2) Monitoring and managing clinical supplies for medication trials; and 3) Supporting other operational needs, such as protocol development, regulatory assistance, monitoring/quality assurance, trial material distribution, central resources for analysis of biological fluids, etc. The Applicant should prepare a budget request for each year (Year one through Year five) to include costs for Node infrastructure and three concepts proposed. Page Limits To summarize the guidance above, the total length of the Research Plan, including the CTP descriptions and research concepts and administrative and management plan 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. Literature Cited and Consortium/Contractual Arrangements sections should be provided following the 45 pages and in total should not exceed 15 pages. 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. 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 Affairs 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 February 22, 2002. 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 (IC). 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 the NIDA in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and 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, 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. As part of the review process, the review panel will conduct an initial review to select the most meritorious applications for a site visit prior to final scoring. It is expected that these site visits will occur early during the summer of 2002 and be followed by a final review meeting, at which time scoring will occur. REVIEW CRITERIA 1. UNDERSTANDING THE CTN o How well does the proposed Node (i.e., the applicant RRTC and its affiliated community treatment programs) demonstrate an understanding of the scientific agenda of the Clinical Trials Network (CTN)? o To what extent would the proposed Node likely contribute to the goals and enhance the capability of a nationwide CTN? 2. ADMINISTRATIVE AND MANAGEMENT PLANS o How strong are the plans for overall Node management and operations, including the structure and mechanisms for effective intra-Node communication and collaboration? o How well documented are the applicant's previous experience and plans for training RRTC personnel, including therapists and research associates in implementing multi-site clinical trials? o How well developed are intra-node data management plans, including plans for incorporating CTN-wide standards, data collection, analysis, and site-specific training? o How strong are the plans for effective interaction and coordination with other Nodes and NIDA? 3. RESEARCH AND CLINICAL INFRASTRUCTURE o To what degree is the proposed Principal Investigator (PI) able to devote adequate time to carry out the work of the CTN? o How strong are the previous research experience and other qualifications of the PI and other named staff in design, administration, and management of multi-center clinical trials? o How strong are the qualifications of key personnel and scientific staff in the areas of the proposed research concepts? o How strong are the qualifications of staff in providing statistical and data management expertise for multi-site clinical trials? o How adequate are the available resources and proposed personnel for administering Node activities? o How strong is the evidence of infrastructure capabilities in project management, protocol development, clinical data information systems, and management of regulatory affairs? 4. COLLABORATION BETWEEN RRTC AND CTPs o Is there a record of previous RRTC-CTP collaboration? o What is the quality of plans for involving CTPs in the research and organizational activities of the CTN? o How well developed are the RRTC's criteria for selecting CTPs with diverse geographic and population representation (as balanced by constraints of reasonable management)? o What are the quality of the proposed CTPs and the experience of their program directors? o To what extent do the proposed CTPs vary programmatically? To what extent are they able to accrue a demographically diverse patient population? o How feasible are CTP plans for patient enrollment and retention? How well do the CTPs demonstrate their ability to accrue patients at an adequate rate to support multi-site clinical trials? 5. RESEARCH PLANS o How significant are the proposed research concepts? o How well do the proposed research concepts demonstrate knowledge of state-of-the-art research designs, methodologies, and operations? 6. OTHER In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o The adequacy of the proposed plan to share data. o The plans for data safety monitoring will be assessed. 7. BUDGET o The reasonableness of the proposed budget and duration in relation to the proposed research. o How appropriate are the budget estimates for infrastructure to enable the RRTC to provide core functions for the Node (e.g., personnel, facilities, equipment, supplies, training costs, logistic support, travel, etc.)? o How appropriate are budget estimates of protocol-specific costs, such as training, clinical expenses, laboratory costs, monitoring costs, and publication costs? o How appropriate are budget estimates for CTP support to conduct the clinical trials? o How adequate are plans for budgetary control and oversight? SCHEDULE Letter of Intent Receipt Date: January 22, 2002 Application Receipt Date: February 22, 2002 Scientific Review Date: May/June, 2002 Council Meeting Date: September 2002 Earliest Award Date: September 30, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: 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; and c) availability of funds. In addition, in order to heighten the generalizability and utility of findings, very high priority will be given to applications in geographic regions where the CTN is not currently well represented. 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. Center for the Clinical Trials Network National Institute on Drug Abuse 6001 Executive Boulevard, Room 4234, MSC 9557 Bethesda, MD 20892-9557 Telephone: (301) 443-2397 FAX: (301) 443-2317 Email: btai@nida.nih.gov Jack D. Blaine, M.D. Center for the Clinical Trials Network National Institute on Drug Abuse 6001 Executive Boulevard, Room 4234, MSC 9557 Bethesda, MD 20892-9557 Telephone: (301) 443-2246 FAX: (301) 443-2317 Email: jb167n@nih.gov Direct inquiries regarding peer review issues to: Teresa Levitin, Ph.D. Office of Extramural Affairs 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 authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS 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, 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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