Full Text AA-97-004 COMBINED BEHAVIORAL/PHARMACOLOGIC TREATMENT OF ALCOHOLISM NIH GUIDE, Volume 26, Number 1, January 10, 1997 RFA: AA-97-004 P.T. 34 Keywords: Alcohol/Alcoholism Treatment, Medical+ Behavioral/Experimental Psychology National Institute on Alcohol Abuse and Alcoholism Letter of Intent Receipt Date: March 21, 1997 Application Receipt Date: April 24, 1997 PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites applications from institutions wishing to participate in a multi-center, cooperative clinical trial to assess the efficacy of combined behavioral and pharmacologic interventions in the treatment of alcohol dependence. The goal of the research is to determine if improvement in treatment outcomes can be achieved by therapeutic strategies that integrate various combinations of pharmacotherapy and behavioral interventions. One of the behavioral therapies should be a less intensive treatment which could be implemented in a managed care setting. This Request for Applications (RFA) solicits applications for both Clinical Research Units (CRUs) and a Coordinating Center (CC). HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), for a multisite study of Combined Behavioral/Pharmacologic Treatment of Alcoholism, is related to the priority area of research on alcoholism treatment. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and 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. This RFA is for both Clinical Research Units (CRUs) and a Coordinating Center (CC). Separate applications are required for each. Awards for Clinical Research Units and the Coordinating Center under this RFA will not be made to the same Principal Investigator, although the same institution may apply for both. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a clinical research cooperative agreement (U10), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial 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 award 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 study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award." The total project period for applications submitted in response to the present RFA may not exceed 6 years. The anticipated award date is September 1997. At this time, the NIAAA has not determined whether or how this solicitation will be continued beyond the present RFA. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the sizes of awards will vary. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is in the financial plans of the NIAAA, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. FUNDS AVAILABLE It is anticipated that up to $2.5 million per year for the first 2 years and up to $5.0 million per year for years 3-6 will be available for direct and facilities and administrative costs under this RFA. It is anticipated that:(a) one award for the Coordinating Center will be made for approximately $375,000 per year in years 1 and 2 and for approximately $750,000 to 1,000,000 per year in years 3-6, (b) 6-8 awards for Clinical Research Units will be made of approximately $250,000 per year in years 1-2, and an average of $500,000 per year in years 3-6, with levels adjusted appropriately for the differing requirements of the activities (e.g., recruitment, intervention, followup, and data analysis) in each of the years. RESEARCH OBJECTIVES Background Important advances have been made in the development of both medications and behavioral interventions to treat alcoholism. Among the medications are naltrexone, nalmefene, and acamprosate. The behavioral interventions include motivationally based, targeted behavioral strategies and interpersonal support treatments. These two types of treatments are not competitive and may enhance each other. Pharmacotherapies may reduce craving for alcohol and/or the reinforcement experienced by drinking alcohol. Behavioral therapies provide skills for patients to maintain sobriety for extended periods of time. Combinations of the two may improve outcome over either modality alone. Recent research is consistent with this and indicates that pharmacologic agents can be combined effectively with behavioral interventions and that their combination enhances treatment outcome. Based on accumulating evidence in the literature, it is appropriate at this time to consider a systematic large scale study of the benefits of combined pharmacologic and behavioral interventions. Relevant literature is summarized below. Promising Pharmacologic Therapies Over the past decade research on medications to treat alcoholism has rapidly expanded (Litten et al., 1996). In particular, advances have been made in understanding the biology underlying drinking behavior, thereby suggesting new possibilities for pharmacologic treatments. For example, it is now known that multiple neurotransmitter systems are involved in problem drinking. These include opioid, serotonin, dopamine, gamma-aminobutyric acid (GABA), and glutamate systems. Several medications that affect these neurotransmitter systems have been tested in humans, including opioid antagonists, selective serotonin reuptake inhibitors, 5-HT3 antagonists, 5-HT2 antagonists, 5-HT1A agonists, dopamine agonists, and GABAergic agents. Currently, the two most promising and reasonably well researched medications are naltrexone and acamprosate. Two landmark clinical trials of naltrexone (Volpicelli et al., 1992 and O'Malley et al., 1992) with alcohol dependent patients produced similar results. Analysis of data combined from the two studies showed that the rate of abstinence for the 12-week trials was 54 percent for the naltrexone group contrasted with 31 percent for the placebo group (O'Malley et al., 1995). If drinking was initiated, the rate of relapse to heavy drinking of the placebo-treated subjects was twice that of the naltrexone group. A possible explanation is that naltrexone blocks the reinforcing effects of alcohol. Naltrexone-treated patients spent 3.1 percent of their days drinking in contrast to 7.5 percent for those on placebo. Finally, craving for alcohol was lower for the naltrexone group than for placebo-treated subjects. In December 1994, naltrexone was approved by the Food and Drug Administration (FDA) for the adjunctive treatment of alcoholism. This is the first medication so designated in over 50 years since the approval of disulfiram. Within the past year, Canada and Austria also approved naltrexone as a treatment for alcoholism. Acamprosate (calcium acetylhomotaurinate) has been studied extensively in Europe. Paille et al., (1995) conducted a 31-site trial of acamprosate in which 538 alcohol dependent patients received either 1.3 g/day or 2.0 g/day or placebo for 1 year. At the end of 6 months, abstinence was sustained in 32 percent of the high dose acamprosate group, in 27 percent of the low dose acamprosate group, and in 19 percent of the placebo group. At the end of 1 year, approximately 19 percent maintained sobriety versus 11 percent of placebo-treated subjects. In addition, treatment retention was significantly higher for both acamprosate groups. Acamprosate produced no major adverse effects. The most common side effect was diarrhea. Whitworth et al., (1996) completed a study with 455 alcohol dependent patients. At the end of the 1 year treatment, 18 percent of acamprosate-treated patients had been abstinent in contrast with 7 percent of placebo-treated subjects. One year after termination of treatment the acamprosate group still demonstrated a significantly higher rate of abstinence than did the placebo group (12 percent versus 5 percent). Sass et al., (1996) reported results from a 12-site study with 272 detoxified alcohol dependent patients. Following 48 weeks of treatment, 43 percent of the acamprosate-treated subjects had sustained sobriety versus 21 percent for the placebo group. The side-effect profiles were identical for acamprosate- and placebo-treated subjects. Mann et al., (1995) analyzed pooled European data consisting of over three thousand alcohol dependent subjects from 11 independent acamprosate studies. The acamprosate group had significantly more sustained abstinence, better treatment retention, and those who drank did so on significantly fewer days than did the placebo-treated subjects. The site of action of acamprosate is different from that of naltrexone, an opioid antagonist. Although the precise mechanism of action is still under investigation, it appears to interact with excitatory amino acids, such as glutamate, and the inhibitory GABA system. Research is needed to determine if the combination of naltrexone and acamprosate will improve treatment outcome. Promising Behavioral Interventions Recently, Project MATCH findings showed marked differences in drinking pre- and post-treatment for three therapies: Cognitive Behavioral Therapy, Motivational Enhancement Treatment, and Twelve Step Facilitation (Project MATCH Research Group, in press). It would be highly desirable to build on these findings and to consider using one or more of the MATCH treatments in the proposed trial. These interventions have demonstrated good retention, patient acceptability and feasibility of implementation. These treatments have been fully described in published therapist manuals which have received wide distribution in the treatment community. Controlled investigations of other behavioral treatments for alcohol problems have been comprehensively reviewed by Hester and Miller (1995). Following review of almost 200 such trials, these commentators identified interventions which offered good evidence for efficacy. Among these were: brief intervention, social skills training, motivational enhancement, and behavior contracting. Social skills training and motivational enhancement techniques were incorporated into the Project MATCH therapies. While other verbal therapies have evidence for their efficacy, none have been studied in a multisite, large sample study as have the three MATCH therapies. Social skills training employs behavioral techniques such as instruction, prompting, practice, and feedback to enhance the patient's general repertoire of interpersonal relationship skills as well as ability to cope with peer pressure that may induce drinking. Motivational enhancement techniques include non-confrontational interviewing of patients, feedback in an attempt to deepen their awareness of need for change, reinforcement of their commitment to and sense of self efficacy for positive change, and establishment of personal goals. Brief intervention is generally undertaken in a primary care setting. While there are many variants of what has been termed "brief intervention," Bien et al., (1993) state that effective brief interventions are characterized by several elements encompassing feedback and patient responsibility for change. Finally, behavior contracting, as the name implies, involves establishing written agreements with the patient to achieve specific goals in treatment or practice a treatment element, such as attend aftercare sessions, complete extra-treatment "homework" assignments, or take disulfiram. Often a significant other also signs the contract. This technique could be utilized as a procedure to enhance compliance with therapy and medications. Research Questions The objective of this study is to conduct a prospective, multi-center cooperative clinical trial to assess the efficacy of combined behavioral and pharmacologic interventions in the treatment of alcohol dependence. It is envisioned that the study will test two behavioral interventions (one of moderate intensity and the other of minimal intensity which would be practical for use in managed care settings and may be either group or individual settings therapy) crossed with two individual pharmacologic agents, the combination of the two agents, and placebo, resulting in an eight cell design. Applicants should address the research questions that flow from this design. Examples of relevant questions include, but are not limited to, the following questions: 1) Can improvement in treatment outcomes be achieved by combining behavioral interventions with pharmacotherapy; 2) Does the relative efficacy of particular combinations of behavioral-pharmacologic therapies differ; 3) Is a moderate intensity behavioral intervention more effective than a more minimal intervention; 4) Does combining two pharmacotherapies lead to greater improvements in outcome than that achieved by use of either of the agents singly; and 5) Are different types of alcoholic patients likely to be more responsive to behavioral or pharmacologic intervention in general as well as to specific types of medicational and behavioral interventions in combination. Outline of Study Design To address the research questions of this program, the application should include, at a minimum, the following major components: 1) A study design which is double blind, placebo controlled, utilizing two medications, such as naltrexone and acamprosate and two behavioral therapies. One behavioral therapy should be a MATCH treatment or one based on a MATCH treatment and the other should be a less intense treatment which could be implemented in a managed care setting. The behavioral interventions may be in either individual or group formats. Strategies should be developed for enhancing compliance with medication and behavioral treatments. Abstinence should be the goal of the interventions. 2) Duration of active treatment should be at least 6 months and minimum follow-up should be at least 1 year post treatment. 3) A comprehensive assessment battery should include as a minimum, instruments to: evaluate patients' drinking history, establish appropriate diagnosis, measure patient variables, e.g., family history likely to be associated with responsivity to current treatment, and assess compliance with treatment, and evaluate drinking outcome. Biochemical markers to validate consumption should be selected. Applicants should strive for practicality and efficiency in their use of markers and collaterals. One of the primary outcomes to be measured is abstinence. 4) Applicants should develop a plan for augmenting the treatment of patients who are nonresponders to the initial medication and psychotherapy combinations, including objective criteria to define nonresponse. 5) The study should be conducted with an outpatient population who meet criteria for alcohol dependence, but who do not meet criteria for current major depression or drug abuse except for nicotine, caffeine, or marijuana. 6) Study duration should be 6 years including the 12 months for a preliminary study. 7) Applicants also should identify and develop a preliminary study to be conducted in months 7-18 related to the study research questions listed above. Examples of such preliminary studies include, but are by no means restricted to, medication compliance management, and issues related to drug administration such as dosing and patient acceptance. The total cost for the preliminary study proposed should not exceed $300,000 including facility and administrative costs, and the duration should not exceed 12 months. Specific hypotheses for the preliminary study, design, and assessment are left to the discretion and creativity of the applicants. Final determinations concerning the nature, scope and timing of the specific preliminary study (or studies) will be made by the Steering Committee during the initial planning period. Elaboration of the Model Study Design Although the outline of a model strategy is given above, applicants should develop and fully elaborate the key elements of the study design such as: 1) Research question and detailed plan for the preliminary study; 2) Nature of the behavioral interventions for the main study; 3) Estimates of sample size for the main study; 4) Details of assessment battery for the main study; 5) Details of the plan for treatment augmentation of nonresponders in the main study; and 6) Data analysis plan. Final Protocol Development In keeping with the goals of the cooperative agreement mechanism, the protocol will be discussed by the Steering Committee, composed of awardees and NIAAA staff. After awards are made the Steering Committee may collaboratively develop a study protocol that differs from the model outlined here (e.g., a different design, alternative drugs, etc)provided the research questions of the RFA are addressed and the Institute agrees that the resultant design is still within the general scope and will serve the purposes described in this RFA. After awards are made participating institutions will collaborate to develop and then follow a mutually acceptable common study protocol with standardized study design, data collection procedures, and intervention approaches. The collaborative protocol will be developed during the first 6 months of the study by the Steering Committee of the study. Coordinating Center In addition to the CRUs, a Coordinating Center will be needed to: (1) organize and provide logistical support for Steering Committee meetings and relevant Executive Secretariat functions; promote communication across sites, including preparation and distribution of meeting minutes and support for the work of trial committees, such as conference call arrangements and distribution of minutes; (2) coordinate the development of trial wide forms, procedures and training exercises; design and maintain a manual of operations; (3) monitor quality control of treatment delivery and data collection; (4) monitor and support enrollment, randomization and follow up activities; (5) design, document, and assemble the data base resulting from the common protocol; (6) perform core trial wide analyses in a centralized manner; (7) coordinate analyses done in a decentralized manner to avoid overlap and assure continuity and quality; (8) procurement, packaging and distribution of the drugs and their matched placebos; (9) application, on behalf of the CRUs, for any necessary IND approval; and (10) establish a centralized and standardized mechanism for performance of bioassays. TIMETABLE Phase 1: The first 6 months of the collaborative effort will be devoted mainly to developing a common protocol, developing the necessary training and implementation procedures, finalizing manuals to ensure cross-site consistency in study execution and identifying the essential preliminary study or studies. Phase 2: In months 7-18 the preliminary study (or studies) will be implemented and completed, based on decisions made by the Steering Committee; in months 18-24 the protocol for the main trial will be finalized. Phase 3: In months 19 through 60 the recruitment for the main study, delivery of treatments, and follow-up will be done. In year 6 data will be analyzed and manuscripts written. SPECIAL REQUIREMENTS This section summarizes special scientific considerations that must be addressed in the applications for Clinical Research Units, in addition to other elements of the research plan. 1. The application should include a proposed protocol that meets the objectives and scope outlined in this RFA and responds to the required major components as stated in the "Research Questions" and "Study Design" sections. Award of the cooperative agreement does not imply that any particular proposed protocol will be implemented. Since the final study will be designed by the Steering Committee, the final protocol may not reflect any single proposal submitted in response to this RFA. 2. Applicants should identify and develop a preliminary study. Specific hypotheses for the preliminary study, details of the study design, and assessment are in the hands of the investigator. This preliminary study should not exceed 12 months in duration. 3. Applicants should develop a plan for augmenting the treatment of patients who are nonresponders to the initial medication and psychotherapy combinations, including objective criteria to define nonresponse. TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official at the time of award. 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, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a clinical research cooperative agreement (U10), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial 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 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 the NIAAA project staff. Details of the roles of the parties are described later in this section. A. Awardee Rights and Responsibilities Awardees will have primary and lead responsibilities for the project as a whole including protocol development, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, as well as collaboration with other awardees and with assistance from NIAAA staff. The Principal Investigator defines the details for the project in accordance with these Terms and Conditions of Award; retains primary responsibility for the performance of the activity; and agrees to close coordination, cooperation, and assistance of NIAAA extramural staff in aspects of scientific and technical management of the project as described herein. 1. Steering Committee Membership and Meeting Attendance Each Principal Investigator (or designee) will be responsible for attending all Steering Committee meetings. The Steering Committee will meet five times in year 1 and four times yearly in subsequent years. The Steering Committee shall be responsible for determining the frequency and scheduling of meetings. Each Principal Investigator (or designee) will be expected to participate in all other Steering Committee activities, e.g., conference calls, special subcommittees as may be necessary, etc. 2. Role of Clinical Research Units Each awardee institution and its corresponding investigators will be responsible for developing and implementing research aims; adjusting research priorities in accordance with current developments and available budget funds; participating in analyses; and accepting the participatory and cooperative nature of the group process and policies relevant to this program. 3. Role of the Coordinating Center In addition to the CRUs, a Coordinating Center will be needed to: (1) organize and provide logistical support for Steering Committee meetings and relevant Executive Secretariat functions; promote communication across sites, including preparation and distribution of meeting minutes and support for the work of trial committees, such as conference call arrangements and distribution of minutes; (2) coordinate the development of trial wide forms, procedures and training exercises; design and maintain a manual of operations; (3) monitor quality control of treatment delivery and data collection; (4) monitor and support enrollment, randomization and follow up activities; (5) design, document, and assemble the data base resulting from the common protocol; (6) perform core trial wide analyses in a centralized manner; (7) coordinate analyses done in a decentralized manner to avoid overlap and assure continuity and quality; (8) procurement, packaging and distribution of the drugs and their matched placebos; (9) application, on behalf of the CRUs, for any necessary IND approval; and (10) establish a centralized and standardized mechanism for performance of bioassays. B. NIAAA Staff Responsibilities The NIAAA staff role in this cooperative agreement will extend beyond the level normally required for stewardship of a grant because of the need for coordination of study protocols among performance sites, technical assistance in the analysis of data, and monitoring and possible reassessment of project objectives as the study proceeds. The NIAAA extramural staff perform different functions in research projects supported under the cooperative agreement mechanism. 1. Program Official The Program Official provides normal stewardship of the award and has overall responsibility for monitoring the conduct, progress, and fiscal management of the program. Progress of the project will be reviewed by the Program Official annually at the time of each continuation application to assure that satisfactory progress is being made in achieving the objectives of the project and that each performance site is following the program goals and procedures recommended for use by all participants in the cooperative program and approved by the Steering Committee. 2. NIAAA Staff Collaborator The NIAAA Staff Collaborator has substantial scientific input in collaboration with award recipients, in both planning and conduct of the research. The NIAAA Staff Collaborator will (1) participate as a voting member on the Steering Committee which oversees this research effort, the Executive Committee and relevant technical subcommittees or working groups as appropriate; (2) participate in the formulation of protocols and other planning related to the completion of the research; and (3) participate in monitoring the progress of the research and quality control, and (4) the analysis and interpretation of data, and possibly in associated publications and presentations. 3. NIAAA Senior Scientific Advisor The NIAAA Senior Scientific Advisor will advise on policy, budget, and technical matters relating to trial conduct. 4. NIAAA Consultants for Behavioral and Pharmacologic Treatments The consultants will advise on technical issues related to these topics, serve on working committees, attend Steering Committee meetings, and participate in analyses and publications. The NIAAA staff will be subject to the same publication/authorship policies governing all participants in the study, as well as to the official NIH Publication Policy governing extramural employees. C. Collaborative Responsibilities 1. Governance/Steering Committee A Steering Committee will be the main governing board of the study and will have primary responsibility for all scientific decisions. The Steering Committee will be composed of the Principal Investigator (or designee) of each Clinical Research Unit, the Coordinating Center, and the NIAAA Staff Collaborator. Each will have one vote, should a vote of the Steering Committee be necessary to make a decision. The functions of the Steering Committee include: defining protocol objectives and approaches; designing and implementing the consensus protocol; developing procedures for data collection and management and quality control; establishing procedures for assessing performance with respect to accrual, timely submission and quality of data, and conscientious observance of protocol requirements; analyzing and interpreting study data; and publishing/presenting study findings. The Steering Committee also approves the preliminary study (studies) based on studies approved during initial peer review. Each member of the Steering Committee will have one vote. The chairperson will be selected by the Steering Committee from among the non-NIAAA members. Subcommittees will be commissioned and monitored by the Steering Committee, as it deems appropriate. Subcommittees will report to the Steering Committee and will function under the direction of the Steering Committee. Additional representatives of NIAAA's Treatment Research Branch may participate as members of subcommittees. A subset of the Steering Committee will be elected by the group to serve as an Executive Committee which will meet via conference call on a regular basis (i.e., weekly or biweekly) between meetings of the full Steering Committee. Both the NIAAA and the Coordinating Center will be represented on the Executive Committee. The collaborative protocols will be developed by the Steering Committee. Data will be submitted centrally according to a specified schedule to the Coordinating Center. Protocols will define rules regarding access to data and publications. By acceptance of this award, awardees will be required to accept and implement the common protocol, procedures and policies approved by the Steering Committee. 2. Data Coordination and Management To insure consistency and timeliness, the content, methods and timetable of core analyses will be stipulated in advance by the Steering Committee and will be performed by the Coordinating Center. No data relating to the core analyses from the trial-wide merged data set will be distributed to individual CRUs until these core analyses are completed. Awardees will retain custody of and primary rights to their data under these awards subject to Institute rights of access, consistent with current HHS, PHS, and NIH policies. Applicants are encouraged to plan to publish their findings in a timely manner and to make the data available to the scientific community in a timely way at the end of the grant period. The trial-wide data set, consisting of the pooled data from all sites, is considered the common data base to which all investigators contribute and have access to. Details of the Publication Policy will be developed by the Steering Committee and will be binding upon members. The Steering Committee will define a key set of publications on the main trial findings which will be authored by the Project Research Group as a whole, with individual investigators precluded from preempting such trial-wide, corporate publications. Review and approval by the Steering Committee will be required for all analyses prior to the publication or presentation according to criteria that will be developed by the Committee. D. Monitoring Study Progress 1. The Steering Committee will establish mechanisms for assessing performance of the CRUs, with particular attention to accrual of adequate numbers of eligible patients, timely submission and quality of required data, and conscientious observance of protocol. 2. The Data and Safety Monitoring Board (DSMB) is an independent board of experts established by the NIAAA which oversees the integrity of data and safety of clients. The Institute convenes the DSMB twice a year. Its major function is to review reports of patient safety and data integrity on a regular basis. The Board is also responsible for reviewing and approving the final protocol prior to the start of the recruitment phase, and for approving the progression from one phase of the trial to the next. E. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIAAA may be brought to arbitration. An arbitration panel will be composed of three members; one selected by the Steering Committee (with the NIAAA member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIAAA, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation 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 subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 21, 1997, a letter of intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and 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 subsequent applications, the information allows the NIAAA staff to estimate the potential review workload and to avoid conflict of interest in the review. A separate letter of intent must be submitted for applications for the Clinical Research Units and the Coordinating Center. The Letter of Intent is to be sent to: RFA-AA-97-004 Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism Willco Building, Room 409 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4375 FAX: (301) 443-6077 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. Applications must address the requirements as outlined in study design, research objectives, special requirements and terms, and conditions. Additional Materials to Include in the Application 1. All costs required for the proposed protocol must be included in the application and must be fully justified. Requested budgets should include travel to the Washington, D.C. area for four 2 day Steering Committee meetings each year during the duration of the trial, except for the first year when five meetings may be required. The acquisition and packaging of the drugs will be handled by the Coordinating Center. Thus CRU applicants need not address this in their application's budget section. The Coordinating Center should include in its budget an estimated cost for drugs of approximately $300,000 per year for years 3, 4 and 5. For budget year 06, applicants should put the 06 budget year on an additional copy of form page 5EE of the PHS 398 application. 2. The applicant institution and each participating institution associated with an applicant consortium must document their experience and capacity to recruit and retain study participants, provide a description of the population currently available for the proposed protocol (including yearly figures on numbers of patients screened, treated, and discharged), and describe proposed mechanisms for recruiting a minimum of 75 patients per year and monitoring accrual performance and criteria for continued participation by each institution contributing patients. 3. The application should discuss the capability of the applicant organization to participate and interact effectively in multi-center clinical trials. 4. The application must include a written commitment to accept the participation and assistance of NIAAA staff in accordance with the guidelines outlines under "NIAAA Staff Responsibilities" as stated above. The application must also include a written commitment to the cooperative organization and willingness to serve on the Steering Committee and adhere to the decisions reached by that Committee, including following a consensus protocol. 5. The application for a CRU must name a single Principal Investigator (PI) who will have scientific responsibility for the application as a whole including all research activities included under it. Applications from a consortia of institutions must name a single senior Investigator for each participating institution (other than the applicant institution) who will be responsible for on-site scientific direction and implementation for the consensus protocol. Senior Investigators in consortia must also document relevant experience in alcoholism treatment research. 6. The application must provide a clear concise plan showing the scientific discipline of the PI and of all key scientific, technical and administrative personnel, and a mechanism for replacing key professional or technical personnel should the need arise. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health 6701 Rockledge Drive, Room 1040-MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817-7710 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to: RFA-AA-97-004 Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism Willco Building, Room 409 6000 Executive Boulevard MSC 7003 Bethesda, Maryland 20892-7003 Rockville, Maryland 20852-7003 (for express/courier service) Applications must be received by April 24, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. REVIEW CONSIDERATIONS All applications will be judged on the basis of the scientific merit of the proposed project and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. Although the scientific and technical merit of the proposed protocol is important, it will not be the sole criterion for evaluation of a study. Other considerations, such as the relevance and importance of the preliminary study proposed, access to patients, and understanding of the nature of a cooperative agreement and the complex requirements of a multisite trial will also be taken into account. Review Method Upon receipt, applications will be reviewed for completeness by the DRG and responsiveness by the NIAAA. Incomplete applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Institute in accordance with the review criteria stated below. As part of the initial merit review, a streamlined review process may be used by the initial review group in which applications may or may not be discussed based on their scientific merit relative to other applications received in response to the RFA. Applications which are fully discussed will be assigned a priority score. Applications which are not discussed will be withdrawn from further considerations and the Principal Investigator and the official signing for the applicant organization will be notified. The second level of review will be provided by the National Advisory Council on Alcohol Abuse and Alcoholism. Review Criteria The major functional units in the trial are the Clinical Research Units (CRUs) and the Coordinating Center (CC). The review criteria for each are described below. Note that an institution may submit an application for a CRU and/or the CC, but no individual PI may serve as both a CRU PI and the CC PI. A separate application is required for each. Factors to be considered in evaluating the scientific and technical merit of applications for Clinical Research Units are: (1) responsiveness to the goals of the RFA and the scientific and technical merit of the approach proposed for the key elements of the main study design, including nature of the behavioral interventions; estimates of sample size; details of the assessment battery; plans for the argumentation of treatment for nonresponders and data analysis. (2) the scientific merit, creativity and relevance of the proposed preliminary study; (3) scientific qualifications and research experience of the principal investigator and other key research personnel to conduct a pharmacologic-behavioral clinical trial and adequacy of their time commitment to the cooperative program; (4) adequacy of facilities and resources, including computer facilities; (5) documented access to a sufficient number of subjects (at least 75 per year) and established treatment sites and ability to retain subjects; (6) understanding of the scientific, logistical, and technical issues underlying a multicenter collaborative agreement and previously demonstrated expertise in closely coordinating with fellow investigators and recruiting sites; (7) adequacy of provisions for the protection of human subjects; (8) adequacy of the plans for the inclusion of both genders and minorities in the project; and (9) appropriateness of budget estimates for the proposed activities. Criteria for scientific merit review of applications for the Coordinating Center include: (1) soundness of the proposed plans for the administrative management and coordination of the trial, including support of the Steering Committee and working committees; (2) adequacy of the plan for administrative structure within the Coordinating Center and methods for coordination with the performance sites; (3) appropriateness of the plans for: collecting and maintaining data; establishing an appropriate database and assuring data integrity; instructing field staff on the correct use of research protocols; and monitoring adherence to research design specifications; (4) appropriateness of plans for: (a) implementation of analyses of trial wide core analyses, based on decisions made by the Steering Committee and (b) distribution of the trialwide data set to CRU's including methods and policy considerations; (5) experience, competence, willingness, and availability of the Principal Investigator and other key personnel to perform the functions of the Coordinating Center, including expertise in statistics, data management, administration of large scale multisite studies, conduct of pharmacologic studies, including drug handling and IND procedures, management of centralized bioassay performance, and training and supervision of therapists; (6) availability and adequacy of facilities relating to data management, data analysis, and other needed resources; (7) reasonableness of budget estimates for the proposed activities; and (8) adequacy of procedures for the protection of human subjects. AWARD CRITERIA Applications recommended by the National Advisory Council on Alcohol Abuse and Alcoholism will be considered for award based upon scientific and technical merit; program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood; and availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcomed. Direct inquiries regarding programmatic issues to: Margaret Mattson, Ph.D. Division of Clinical and Prevention Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard - MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852-7003 (for express/courier service) Telephone: (301) 443-0796 FAX: (301) 443-8774 Email: mmattson@willco.nih.niaaa.gov Direct inquiries regarding fiscal matters to: Linda Hilley Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-0915 FAX: (301) 443-3891 Email: lhilley@willco.niaaa.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.273. Awards are made under the authorization of the Public Health Service Act, Sections 301 and 464H, and administered under the PHS policies and Federal Regulations at Title 42 CFR Part 52 and 45 CFR Part 74. 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. References Bien, T.H., Miller, W.R., and Tonigan, J.S. (1993). Brief interventions for alcohol problems: A review. Addiction, 88, 315-336. Hester, R.K. and Miller, W.R. (1995). Handbook of Alcoholism Treatment Approaches: Effective Alternatives, Hester, R.K. and Miller, W.R. (Eds.). Allyn & Bacon, Needham Heights, MA. Litten, R.Z., Allen, J., and Fertig, J. (1996). Pharmacotherapies for alcohol problems: A review of research with focus on developments since 1991. Alcoholism: Clinical and Experimental Research 20(5):859-876. Mann, K., Chabac, S., Lehert, P., Potgieter, A., and Sass, H. Acamprosate improves treatment outcome in alcoholics: A pooled analysis of 11 randomized placebo controlled trials in 3338 patients. Presented at 34th Annual Meeting of American College of Neuropsychopharmacology, San Juan, Puerto Rico, December 1995. O'Malley, S.S., Jaffe, A.J., Chang, G., Schottenfeld, R.S., and Meyer, R.E. (1992). Naltrexone and coping skills therapy for alcohol dependence: A controlled study. Archives of General Psychiatry 49:881-887. O'Malley, S.S., Croop, R.S., Wroblewski, J.M., Labriola, D.F., Volpicelli, J.R. (1995). Naltrexone in the treatment of alcohol dependence: A combined analysis of two trials. Psychiatric Annuals 25: 681-688. Paille, F.M., Guelfie, J.D., Perkins, A.C., Royer, R., Steru, L. and Parot, P. (1995). Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol and Alcoholism, 30, 239-247. Project MATCH Research Group (in press). Matching Alcoholism Treatments to Client Heterogeneity: Project MATCH Post-treatment Drinking Outcomes. Journal of Studies on Alcohol. Sass, H., Soyka, M., Mann, K., and Zieglgansberger, W. (1996). Relapse Prevention by Acamprosate: Results from a placebo-controlled study on alcohol dependence. Archives General Psychiatry, 53, 673-680. Volpicelli, J.R., Alterman, A.I., Hayashida, M., O'Brien, C.P.(1992). Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry 49: 876-880. Whitworth, A.B., Fischer, F., Lesch, O.M., Nimmerrichter, A., Oberbauer, H., Platz, T., Potgieter, A., Walter, H. and Fleischhacker, W.W. (1996). Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet, 347(9013), 1438-1442. .
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