CENTERS FOR THE DEVELOPMENT OF MEDICATIONS TO TREAT DRUG AND DRUG ADDICTION Release Date: September 16, 1998 RFA: DA-99-005 P.T. National Institute on Drug Abuse Letter of Intent Receipt Date: November 4, 1998 Application Receipt Date: December 4, 1998 PURPOSE The purpose of this Request for Applications (RFA) is to solicit applications to establish research centers called Medication Development Units (MDU) dedicated to clinical research directed toward the identification, evaluation and development of safe and effective pharmacotherapeutic treatments for cocaine, methamphetamine, opiate, nicotine and cannabis abuse and addiction. Research may focus on currently approved or novel, investigational medications. The treatment of cocaine, methamphetamine, opiate, nicotine or cannabis abuse and addiction disorders necessitates a multidisciplinary approach. Optimal treatments may ultimately require a combined pharmacological and behavioral treatment strategy. Therefore, applications may propose the concurrent evaluation of pharmacotherapy and behavioral treatments in an integrated design, providing that such designs are of adequate size and are well controlled. Applicants may focus on pilot Phase I safety/tolerability or Phase II or III efficacy studies; human laboratory studies on medication interactions with other drugs; pharmacokinetic or pharmacodynamic studies; or, if justified, multisite efficacy studies. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000", a PHS-led national activity for setting priority areas. This RFA, Centers for the Development of Medications to Treat Drug and Drug Addiction, is related to the priority areas of tobacco, alcohol and other drugs, and HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or 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, private and public, such as universities, colleges, hospitals, laboratories, units of State and local governments, pharmaceutical companies, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women and persons with disabilities are encouraged to apply as Principal Investigators. Foreign institutions are not eligible. Prospective investigators are encouraged to consult with the program official listed under INQUIRIES for guidance on current NIDA priorities and how they apply to the planned submission. MECHANISM OF SUPPORT The National Institutes of Health (NIH) specialized research center grant (P50) mechanism will be used under this RFA. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is a one time solicitation. Any applications received after the single receipt date will be returned to the applicant without further review. FUNDS AVAILABLE It is anticipated that approximately $7.3 million in total costs will be available to support the first year of funding. This level of support is dependent on the receipt of a sufficient number and diversity of applications of high scientific merit. It is anticipated that up to eight awards will be made. The total project period for an application submitted in response to this RFA may not exceed 5 years. The anticipated award date is August 1, 1999. The size of individual awards will vary as a function of the nature and scope of the research proposed. However, awards are subject to a first year upper limit of $1.0 million in total costs (direct plus indirect costs) and application acceptability is contingent on this limit. Exception to this budgetary restriction can be made for multisite trials proposed to start in the first year of the award and related to active trial conduct. 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 Cocaine Abuse and Addiction. Cocaine abuse and addiction has devastating personal, social, and public health consequences. National surveys indicate that more than 2.2 million are current cocaine users. Cocaine use is associated with potentially life-threatening cardiovascular effects; sex-for-crack exchanges that are spreading the AIDS virus among both drug-abusing and non-drug-abusing populations; possible damage to infants born to women who abuse cocaine during pregnancy; and violence and neighborhood disintegration related to the cocaine marketplace. To date, no medication has been approved for cocaine or other stimulant abuse and addiction. To address this critical deficiency, NIDA has made the development of an anti- cocaine medication its number one priority. This includes the development of medications to treat a variety of aspects of cocaine abuse and addiction including the short-term (< 3 months) abuse of cocaine, the long-term (>3 months) relapse period intrinsic to cocaine addiction, as well as the long-term inhibition or reversal of neurotoxicity associated with persistent cocaine and/or stimulant (e.g., methamphetamine) abuse and addiction. This priority will also influence funding decisions associated with grant applications. Methamphetamine Abuse and Addiction. Methamphetamine abuse and addiction is an emerging public health problem largely confined to the western portion of the United States. Reflecting this increase is a doubling of emergency room admissions for methamphetamine abuse between 1992 (300 admissions) and 1994 (733 admissions) and a doubling of admissions for treatment of addiction from 1993 (367 admissions) to 1995 (708 admissions) in Los Angeles County. This RFA solicits research on medications to treat methamphetamine abuse and addiction aimed at both its immediate and long-term consequences. Immediate consequences of abuse include serious medical presentations (e.g., convulsion and cardiac arrhythmia) as well as psychiatric problems ranging from panic reactions to psychosis. Management of these problems is usually symptomatic. Strategies to reduce methamphetamine plasma concentrations could possibly serve as a useful adjunct in the management of the acute medical and psychiatric symptomatology of methamphetamine overdose. Moreover, methamphetamine abuse and addiction have been associated with cognitive, affective, and other psychiatric disturbances (e.g., paranoia). There are currently no pharmacotherapies for facilitation of abstinence, relapse prevention, or agents that facilitate restoration of cognitive abilities and reduce lingering paranoia. Concerns about increased HIV risk behaviors are well founded and may pertain especially to certain populations (e.g., gay and bisexual men). Thus, pharmacotherapies that reduce methamphetamine use may reduce HIV risk behaviors and HIV transmission. Opiate Abuse and Addiction. Epidemiological trends suggest that the incidence of heroin abuse and addiction has continued to increase since the 1980s. Some quite effective medications for therapeutic treatment of heroin addiction are currently available. However, these medications are not always appropriate for some patients or under some circumstances. Thus, three areas of opiate pharmacotherapy are of interest to this RFA. They include the use of non-opiate medications for the long-term prevention of relapse, the short-term treatment of symptoms (either acute or protracted) in medically assisted withdrawal and research directed toward pharmacotherapy for dual addiction (opiate and stimulant or opiate and alcohol). Applications for opiate "substitution" pharmacotherapy for opiate maintenance and medically assisted withdrawal approaches using anesthetics are not of interest to this solicitation. Nicotine Addiction. The most preventable cause of premature mortality in American society is cigarette smoking. Nicotine is highly addictive and attempts to quit cigarette smoking often end in failure. The chewing of tobacco is also addictive and may result in cancers of the mouth and throat. The consequences of abuse and addiction to tobacco are grave; over 400,000 premature deaths per year are attributed to chronic smoking. Moreover, chronic lung and cardiac disorders are part of the morbidity associated with smoking. Clearly, pharmacotherapeutic agents which assist in smoking cessation would be a boon to the public health. To this end, NIDA is soliciting novel pharmacotherapeutic approaches to smoking or tobacco chewing cessation. Marijuana Addiction. According to the Treatment Episode Data Set, treatment admissions for marijuana/hashish addiction have risen from 6.2% to 10.8% from 1992 to 1995, respectively. Admissions for marijuana/hashish addiction make up 55% and 47% of the treatment admissions for the under 15 years old and 15-19 year old age groups, respectively. The current treatment of marijuana addiction is a psychosocial-based approach. NIDA is soliciting pharmacotherapeutic approaches to assist marijuana-abusing individuals in eliminating their marijuana use. RESEARCH THEMES. The following are examples of research themes that such Medication Development Units (MDUs) might utilize: (1) Hypothesis driven research leading to Phase I or II medications studies. For example, systematic exploration of medications affecting stress-related hormones of either the hypothalamic-pituitary-adrenal axis or the sympathetic-adrenal axis and the therapeutic effects of these agents on drug abuse and addiction. There should be an integrated emphasis on one or two particular neurochemical approaches -- for example modulation of a specific neurochemical system [e.g., dopamine (DA), norepinephrine (NE), serotonin (5-HT), glutamate and neuromodulators associated with the glutamate cascade, cholecystokinin, opioid peptides], specific mechanistic or receptor sites [e.g., DA, NE, 5-HT, glutamate transporters or particular DA, NE, 5-HT, neuropeptide (including opioid) receptors]. (2) Special populations research defining the influence of medications on a specific group of individuals. For example, studies on the efficacy of medications on individuals with a co-morbid drug abuse disorder (e.g., cocaine and alcohol abuse and addiction), a co-morbid psychiatric disorder (depression, attention deficit disorder, schizophrenia), or other ?subject? factors including the influence of sex, age, or biological/brain markers serving as possible predictors of the efficacy of a medication. For brain imaging, a variety of modalities may be used to define such predictors (e.g., positron emission tomography (PET), simplified dual probe detector PET, functional magnetic resonance imaging). Note: Investigators emphasizing the special populations theme in their MDU should demonstrate their capacity to assess subjects in these categories in sufficient numbers for a 2-3 year period per therapeutic project. (3) Research directed toward the improvement of the quality of clinical trials. This includes the assessment of methods designed to enhance the sensitivity of clinical trials to detect treatment differences over the placebo. SPECIAL REQUIREMENTS An MDU grant is awarded to an institution on behalf of an MDU Director for the support of a broadly based, long term research and development program with a particular major objective or theme. Award duration will not exceed 5 years. The philosophy of MDU center grant application (P50) review requires that each scientific project be assessed within the context of the entire program. Therefore, each application must conform to the following requirements: The MDU and its components must have demonstrated capability to conduct full scale single site clinical trials (placebo-controlled (PC) or active controlled (AC), double-blind (DB)) using the proposed therapeutic approach. Applicants opting to propose multisite trials must have adequately demonstrated efficacy in a single site PC/AC, DB trial. Such applicants must also demonstrate the ability to affiliate rapidly with other sites (through subcontract or collaborative mechanisms) to launch a multi-site Phase II or Phase III PC/AC, DB trial. The MDU Director must possess recognized scientific and administrative competence. The Center Director must show a substantial commitment of time and effort (minimum 25%) to the program and exercise leadership in steering the MDU direction and maintenance of its quality control. Management functions may be accomplished through an administrative core. The MDU provides for administrative and scientific core components such as project management, clinical resources, laboratory equipment and support, statistical support, etc., which are shared by more than one project. An administrative Core provides for central operations, technical support and exercise of leadership for the overall project management, integration, communication and coordination of the MDU. GCP compliance. Each research project, depending on the nature of the program, should also contain documents of GCP (Good Clinical Practice) including assurance of regulatory compliance with respect to submissions of medications protocols to the IRB and to the FDA. 5. The integration of the proposed work should be clearly demonstrated and lead to original and creative contributions related to the objective or theme over and above those which would be obtained if each component of the MDU existed independently. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research", which were published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. NIH POLICY AND GUIDELINES ON THE 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 and 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://www.nih.gov/grants/guide/notice-files/not98-024.html. GUIDELINES FOR THE ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS The National Advisory Council on Drug Abuse recognizes the importance of research involving the administration of drugs to human subjects and has developed guidelines relevant to such research. Potential applicants are encouraged to obtain and review these recommendations before submitting an application that involves the administration of compounds to human subjects. The guidelines are available on the NIDA Home Page at http://www.nida.nih.gov/ or may be obtained by calling (301) 443-2755. LETTER OF INTENT Prospective applicants are asked to submit, by November 4, 1998, a letter of intent that includes a descriptive title of the overall proposed research; the name, address, telephone number, and institution of the Principal Investigator; title of each major project, names of investigators, and their respective institutions; and the number and title of the RFA in response to which the application may be submitted. The letter of intent from the investigator is not binding, nor is it a factor in the peer review of the application. The information they contain is helpful in planning for the review of applications. The letter of intent is to be sent to: Director Office of Extramural Program Review National Institute on Drug Abuse 5600 Fishers Lane, Room 10-42 Rockville, MD 20857 Telephone: (301) 443-2755 APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (rev. 5/95). These forms are available at most institutional offices of sponsored research and may also be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910; telephone 301-710-0267, Email: GrantsInfo@nih.gov. Applications must conform to the SPECIAL REQUIREMENTS described above. Because of the multi-project nature of a Medications Development Unit grant and the special requirements in this RFA, additional instructions regarding format are listed: Applicants are encouraged to organize their application by initially presenting the face page, the abstract page with key personnel, a table of contents, summary budget pages for the entire MDU, and other documentation pertaining to the entire MDU. This should be followed by an Introductory Section of no more than three pages. It should be written for the proposed MDU application describing it as a whole with respect to the overall theme, goals, objectives, and overall research plan. The Introductory Section should contain information on i) the overall research theme, ii) timelines and milestones for each projects in a graphic outline to clearly lay out the sequence of research events and how each project of the MDU relates to each other, iii) the capacity of the MDU to conduct adequately sized clinical trials for the targeted indications within a time frame of 2-3 years per project, and iv) the capability of the proposed Principal Investigator and his/her institution to carry out the scientific and administrative duties required in this RFA. After the introductory section, each core and research project should be presented with its accompanying individual budget, budget justification, biographical sketches, and other support information and research plan. For each core and research project component, there is a 25 page limit for the sections of the research plan (i.e., specific aims, background and significance, preliminary studies/progress report, and research design and methods) as indicated in the form PHS 398. Appendix material limits apply to each component separately; each component's appendix may include up to 10 publications, manuscripts, abstracts, patents, or other printed material directly related to the project. Surveys, questionnaires, data collection instruments, and clinical protocols may also be submitted in the appendix. Original glossy photographs or color images may be included, provided that a photocopy (that may be reduced in size) is included within the 25 pages of the research plan. Applications exceeding page limits, font limits, or appendix limits will be returned to the applicant without review. Appendices should not be placed within the body of the application when submitting, but should be bundled separately, component by component. The RFA label available in the PHS 398 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, to ensure the identification of the application with this RFA the "YES" box must be marked in item 2 of the face page of the application form and the title and number of this RFA typed. Applications that are not received as a single package from the Principal Investigator and that do not conform to the instructions contained in PHS 398 (rev. 5/95) application kit will be judged non-responsive and will be returned to the applicant. The completed original, including the checklist, and three legible copies must be sent or delivered to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC-7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Director Office of Extramural Program Review National Institute on Drug Abuse 5600 Fishers Lane, Room 10-42 Rockville, MD 20857 Telephone: (301) 443-2755 Applications must be received by December 4, 1998. If an application is received after this date, it will be returned to the applicant without review. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. REVIEW CONSIDERATIONS A. Review procedures Applications will be reviewed by the Center for Scientific Review (CSR) for completeness and by NIDA staff to determine programmatic responsiveness to this RFA. Applications deemed to be non-responsive will be returned to the applicant without review. An application with first year total costs (direct and indirect) in excess of $1.0 million will be returned without review, except for those that include active multisite trials in the first year. An appropriate NIDA peer review group convened in accordance with NIH peer review procedures will evaluate applications that are complete and responsive to the RFA for scientific and technical merit. 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 applications under review, will be discussed, assigned priority score, and receive a second level review by the National Advisory Council on Drug Abuse. The review group will review the MDU application as an integrated research effort focused on a central research theme. The review group will assess the scientific and technical merit of the proposal according to the following criteria and assign one overall priority score for the entire MDU application. In addition, each application must meet the Special Requirements identified above. When appropriate, these requirements will also serve as review criteria. B. Review Criteria Scientific Review Group (SRG) review of the scientific and technical merit of MDU grant application will emphasize review of the program as an integrated research effort focused on a medications development theme. The review will also include an assessment of the academic climate and physical environment and special considerations, e.g., compliance with the human subjects and animal welfare regulations. The assessment of the scientific and technical merit will include the following: Significance of the application's impact on pharmacotherapeutic issues in drug addiction treatment and significance of the overall program goals and the development of a well-defined research and development focus of importance and relevance to the goals of this RFA. The application should focus on the timely development of a database of clinical information that will support the advancement of a given pharmacotherapy toward advanced efficacy trials that would themselves support New Drug Applications. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Medication testing and development plan: Clarity of overall medications development research theme supported by a strong rationale; timelines and milestones for each projects in a graphic outline (Gantt and/or Pert charts) is suggested to clearly lay out the sequence of research events and how each project of the MDU relates to each other; and criteria for go/no go decisions at critical points in plan. Plan must indicate that therapeutic trials will be initiated within 6 months of the award date and the results of a particular trial will be completed and analyzed in 2-3 years. Adequacy and feasibility of approach: In view of the overall objectives, is the proposed approach reasonable? Is it likely to be carried out and completed without any major complications or hindrances? Does the applicant recognize and present solutions for potential problems which might arise? The justification for, and usefulness of core facilities (if any) to the research projects: Core unit(s) provide essential facilities or services for the individual projects, including administrative arrangements and organization to facilitate and monitor the attainment of objectives and quality control. For example, these factors will include plans to enhance communication and cooperation among the investigators involved in the program and mechanisms for the allocations of funds for day-to-day management, project management and tracking, contractual agreements and procedures for the replacement of key personnel, such as the Principal Investigators, if required on an interim or permanent basis. Assurance of compound accessibility: The proposal, depending on the nature of the program, must have assurance of the accessibility and availability of the proposed test compounds. A prerequisite for consideration of any study within an application is the demonstrated access to the study compounds as well as necessary formulations as required. This includes necessary placebo forms of the test drug formulation. Assurance of Accessibility to Patient Population and Controls: Each project involving human subjects, depending on the nature of the program, must demonstrate the ability to acquire the specified patients at a rate sufficient to meet the sample size within the 2-3 years study duration, or there must be clear demonstration of target population availability and means to recruit successfully must be provided. Data Management and Statistical Resource: Each project should propose the plan for data management and demonstrate appropriate statistical resources to manage, analyze clinical data and draft summary reports to support IND and possible NDA submissions. Is the general approach to data reduction and analysis clearly presented? G. Integration: The integration of the proposed work should be clearly demonstrated and lead to original and creative contributions related to the objective or theme over and above those which would be obtained if each component of the MDU existed independently. H. For applications that include multisite trials: in addition to appropriateness of proposed methodology and statistical analyses, demonstrate a willingness to work as part of a clinical trials network and use standard methodology and instrumentation as core measures as well as a specific behavioral platform that may be in common or parallel to that used by the Medications Development Division, NIDA. Such trials must also demonstrate well coordinated management plans for subcontracting multisites or coordinating collaborative arrangements. These collaborations cannot be proposed as projects on more than one competing MDU applications to this RFA. Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Investigators: The scientific leadership, ability, stature, experience, and administrative competence of the Project Director and his or her commitment and ability to devote substantial time and effort (at least 25%) to the program. The scientific stature of the Principal Investigators on the research projects and core components and the extent to which each PI contributes to the overall program goals as well as their commitment to the program. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Are test compounds available and are formulations appropriate? Budget: The appropriateness and Reasonableness of the overall budget for the proposed work. Are all items well justified in terms of the aims of the MDU, particularly major and expensive items of equipment, costly supplies and personnel, etc. 6. Adequacy of plans to protect human subjects, animal subjects, and the environment, as appropriate, and adequacy of plans for the inclusion of both genders, minority groups, and children, as appropriate to the goals of the research. AWARD CRITERIA Applications recommended for further consideration by the National Advisory Council on Drug Abuse will be considered for funding based on the following factors: 1. Overall scientific and technical merit of the proposal as determined by peer review. 2. Program priorities (which include cocaine abuse and addiction therapy as the first priority). 3. Availability of funds. Schedule Letter of Intent Receipt Date: November 4, 1998 Application Receipt Date: December 4, 1998 Scientific Review Date: March 1999 Council Meeting Date: May 1999 Earliest Award Date: August 1999 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applications is welcome. Direct inquiries regarding programmatic issues to: Richard Hawks, Ph.D. Medications Development Division National Institute on Drug Abuse 5600 Fishers Lane, Room 11A-55 Rockville, MD 20857 Telephone: (301) 443-3318/9799 FAX: (301) 443-2599 Email: bh78q@nih.gov Direct inquiries regarding fiscal matters to: Gary Fleming, J.D., M.S. Grants Management Branch National Institute on Drug Abuse 5600 Fishers Lane, Room 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 Email: gf6s@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.279. Awards are made under the authority of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 122372 or Health Systems Agency Review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care 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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