ALTERNATIVE THERAPIES FOR BENIGN PROSTATE SYMPTOMS – CLINICAL TRIALS CONSORTIUM Release Date: January 16, 2002 RFA: RFA-DK—02-026 Update: The following update relating to this announcement has been issued: September 17, 2009 - This RFA has been reissued as (RFA-DK-09-503). PARTICIPATING INSTITUTES AND CENTERS (ICs): National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) National Center for Complementary and Alternative Medicine (http://www.nccam.nih.gov) Office of Dietary Supplements (http://dietary-supplements.info.nih.gov) Letter of Intent Receipt Date: March 15, 2002 Application Receipt Date: April 15, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to become Principal Investigators o Special Requirements o Where to send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Dietary Supplements (ODS) invite cooperative agreement grant applications to establish a research consortium to conduct a randomized controlled clinical trial of Serenoa repens (Saw palmetto) and Pygeum africanum in men with benign prostatic hyperplasia (BPH). As the population ages the number of men with lower urinary tract symptoms indicative of BPH is expected to increase substantially. The segment of the United States population that utilizes alternative and complementary approaches to disease prevention and management is also increasing rapidly, including the use of phytotherapy to control the symptoms of BPH. The most common phytotherapeutic agent is Serenoa repens or Saw palmetto. Pygeum africanum is also frequently used in this country for the same purpose. Little is known, however, about the long-term effects of these agents on the lower urinary tract symptoms experienced by men with BPH since rigorously conducted clinical trials for these agents have not been conducted. In order to determine the effect of Serenoa repens and Pygeum africanum on the clinical progression of BPH the NIDDK and the NCCAM plan to establish a clinical trial consortium to conduct a large simple placebo controlled clinical trial of these two agents comparing saw palmetto to placebo, and Pygeum to placebo. A secondary analysis will include head-to-head comparison of the two phytotherapy agents. The collaborative research group will consist of Clinical Evaluation and Treatment Centers (CETCs) to design and conduct the clinical trial and a single Data Coordinating Center (DCC) to collect, store, and analyze data generated by the CETCs. RESEARCH OBJECTIVES Background More than one-half of the men 50 years of age or older have lower urinary tract symptoms associated with the development of benign prostatic hyperplasia (BPH). The condition accounts for at least 1.7 million office visits per year in the United States with estimated health care costs exceeding $4 billion a year. In addition, these symptoms have been shown to have a significant negative impact on patient-reported quality of life and psychological well-being. The use of alternative therapeutic agents to relieve the symptoms of BPH is increasing very rapidly. In 1996 extracts of the saw palmetto berry was the 9th most common herbal remedy sold in the U.S increasing to the 5th most common in 1997. It is anticipated that the use of alternative therapies for BPH will continue to increase substantially as the U.S. male population continues to age. Despite the widespread use of phytotherapy for BPH in the United States, most physicians are reluctant to either discuss or recommend their use since only a modest number of published reports have appeared in the peer-reviewed medical literature about their efficacy. Moreover, very few have met rigorous standards for reporting the results of clinical trials. Nonetheless, the available literature supports the hypothesis that these compounds may have some beneficial effects on BPH symptoms. This is supported by a recent meta-analysis that suggests that Saw palmetto improves urinary flow-rate and nocturia in men with symptoms of BPH. However, there are no statistically significant reports of rigorously conducted clinical trials on the long-term effects (both beneficial and adverse) and on patient-reported outcomes. Research Scope The objective of this RFA is to determine if Serenoa repens (Saw palmetto) and Pygeum africanum prevent the clinical progression of BPH, as defined by the development of one of the following: acute urinary retention, renal insufficiency (due to BPH), recurrent urinary tract infections, incontinence, or an increase in the American Urological Association (AUA) symptom score index of four or more points. This definition of the clinical progression of BPH is identical to that used in a soon-to-be-completed clinical trial supported by the NIDDK, the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Results from the MTOPS Trial, in particular the event rate among the placebo group, will be made available to investigators participating in this consortium to assist in refinement of the trial design. The investigators participating in this consortium will design and conduct a large simple clinical trial. It is envisioned that the clinical trial will require a total of approximately 3,100 men with BPH who will be randomized over a two-year period. The clinical trial will be double-masked and placebo controlled. It is expected that each CETC will recruit and follow-up 300 men for the duration of the trial. Men will be followed for a minimum of four (4) years and a maximum of six (6) years post- randomization. Innovative methods will be required to implement this clinical trial including recruitment of a large number of men with symptoms of BPH, use of multiple strategies to promote long-term adherence to these agents, maintenance of high rates for clinic visits, and complete ascertainment of endpoints. Procedures established by NCCAM will be used to select the purveyors of the phytotherapeutic agents prior to beginning these studies. Organization of the Clinical Trial Consortium Clinical Evaluation and Treatment Center A Clinical Evaluation and treatment Center is an institution that is actively involved in the recruitment, evaluation, treatment and follow- up of study participants. It should consist of a team of clinical investigators including physicians with expertise in conducting multicenter clinical trials and with expertise in evaluating and treating patients who desire non-surgical treatment for the lower urinary tract symptoms associated with BPH. It is expected that each CETC will have physicians with clinical expertise in urology, general medicine and other relevant clinical specialties. Data Coordinating Center The DCC will assist investigators in developing the design and protocol for the clinical trial. This includes reconfirmation of the sample size and power calculations. The DCC will also have the primary responsibility for collecting, editing, storing and analyzing data generated by the CETCs. The DCC should be prepared to assume a key role in overseeing implementation and adherence to the trial protocol, and assuring quality control of the data collected. It is expected that a web-based method for data transmission from the CETCs to the DCC will be implemented. The DCC will also be expected to provide appropriately detailed reports to the Steering and Planning Committee, the Executive Committee, and the DSMB at regular intervals, and will be responsible for the logistics and planning of the meetings (including monthly committee conference calls) of these committees and subcommittees. The DCC will play a key role in analyzing data and participating in and supporting the CETC members in preparing and writing abstracts and manuscripts for presentation at meetings and for publication in peer-reviewed scientific journals. The DCC will identify and establish a Phytotherapy Distribution Center to coordinate the supply of Serenoa repens, Pygeum africanum, and placebo to the CETCs. Governance Steering and Planning Committee: The primary governing body of the study will be the Steering and Planning Committee. This committee will be comprised of each of the principal investigators of the CETCs and the DCC, the Chairperson of the Steering and Planning Committee, and the NIDDK and the NCCAM Project Scientists (described under Terms and Conditions). Executive Committee: An Executive Committee will be established to resolve problems and monitor progress, during the interim of regularly scheduled Steering and Planning Committee meetings. The Executive Committee will include the Chairperson of the Steering and Planning Committee, the Principal Investigator of the DCC, the NIDDK and the NCCAM Project Scientists, and when necessary, Chairpersons of the various subcommittees. Data and Safety Monitory Board (DSMB) A independent group of experts in urology and other relevant medical specialties, biostatistics, behavioral medicine, clinical trials and ethics, who are not otherwise involved in the study will be named by the NIDDK and the NCCAM. Prior to implementation of the trial the DSMB will review the scientific rigor of the design and any ethical issues. They will also periodically review outcome data and reports of patient safety including adverse events through pre-planned and any special interim analyses (further detail under Terms and Conditions). NIDDK and NCCAM Project Scientists The NIDDK and the NCCAM will each identify a Project Scientist for the trial. The Project Scientists will assist the Steering and Planning Committee in planning and carrying out the trial (described in detail under Terms and Conditions). MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) cooperative clinical research (U01) agreement award mechanism, an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement is anticipated during the performance of the activity. Under the cooperative agreement, the NIDDK purpose is to support and stimulate the recipients" activity by involvement in the activity and otherwise working jointly with the award recipients in a partner role, but not to assume direction, prime responsibility, or a dominant role in the activity. This is a one-time solicitation to support a Clinical Trials Consortium for seven years. The anticipated award date is September 30, 2002. Modular Grant applications will NOT be accepted for this RFA. However, the standard PHS 398 application instructions apply. The NIH U01 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award" FUNDS AVAILABLE The NIDDK, NCCAM and ODS intend to commit approximately $2 million in total costs (direct plus Facilities and Administrative (F&A)) in Fiscal Year 2002 to fund up to 10 CETCs and one Data Coordinating Center application in response to this RFA. It is anticipated that the award for each CETC will be about $135,000 total cost for the first year, and $ 650,000 total costs for the DCC for the first year of the study. A total of approximately $ 4,500,000 is expected to be available for each year beginning in year 2 of the program. Beginning in year 2 and for each year of the program the total cost for each CETC will be approximately $375,000 per year and $750,000 in total costs for the DCC. Although the financial plans of the NIDDK, NCCAM and ODS provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, or scientific developments. ELIGIBILITY INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. Among the disciplines and expertise that may be appropriate for this program are urology, general medicine, other medical specialties, biostatistics, and clinical trial specialists. SPECIAL REQUIREMENTS A Data Coordinating Center will be part of this clinical trials consortium. In order to ensure that data analysis is done independently of data acquisition, the DCC cannot have the same Principal Investigator as a CETC. Within the Consortium an institution may apply for both a CETC and the DCC, but each must have separate Principal Investigators and submit a separate application with a specific plan of how the independent operation of each unit of the CETC and DCC will be maintained. Cooperative Agreement Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigators as well as to the institutional officials at the time of the award. These special Terms of Award are in addition to and not in lieu of otherwise applicable Office of Management and Budget (OMB) administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part 74 and 92, the NIH Grant Policy statement. The administrative and funding instrument used for this program is the cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardees is anticipated during the 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 awardees for the project as a whole, although specific tasks and activities in carrying out the activity will be shared among the awardees and NIDDK and NCCAM Project Scientists. 1) Awardees Rights and Responsibilities The awardees will have lead responsibilities in all aspects of the protocol, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering and Planning Committee. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights or access consistent with current HHS, PHS, and NIH policies. The collaborative protocol will call for the continued submission of data centrally to the DCC for a collaborative database, procedures for data analysis, reporting and publication, and procedures to protect and ensure the privacy of medical records of individuals. The NIDDK and NCCAM Project Scientists will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering and Planning Committee. The DCC will be involved in collaborations with the NIDDK and the NCCAM and the CETCs during all phases of the trial. The awardee is expected to work cooperatively with CETCs and sponsoring organizations in a multicenter trial and oversee the implementation of and adherence to a common protocol, as well as assure quality control of the data collected. In addition to organizing and attending regular meetings of the Steering and Planning Committee, the DCC will be expected to maintain close communications with the NIDDK and the NCCAM Project Scientists and the Principal Investigators of the CETCs. 2) NIDDK and NCCAM Staff Responsibilities The NIDDK and the NCCAM will each name a Project Scientist whose function will be to assist the Steering and Planning Committee in carrying out the trial. The Project Scientists will have substantial scientific-programmatic involvement in overall quality control, interim data analysis, safety monitoring, and final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The dominant role and prime responsibility for these activities resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK and NCCAM Project Scientists. The NIDDK and the NCCAM Project Scientists will have voting membership on the Steering and Planning Committee and, as determined by that committee, its subcommittees and will have one vote between them. The NIDDK and the NCCAM reserve the right to terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which the NIDDK and the NCCAM cannot concur, (d) reach a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject safety and ethical issues that may dictate a premature termination. 3) Collaborative Responsibilities The Steering and Planning Committee, composed of each of the Principal Investigators of the CETCs and the DCC, the NIDDK and the NCCAM Project Scientists, and the Chairman of the Steering and Planning Committee, will be the main governing board of the study. This committee will have the primary responsibility for developing the final common protocol, facilitating the follow-up of participants, monitoring completeness of data collection and timely transmission of data to the DCC, and reporting the trial results. It will also be responsible for establishing study policies in such areas as access to patient data, ancillary studies, publications and presentations, and performance standards. Each member of the Steering and Planning Committee will have one vote (NIDDK/NCCAM Project Scientists will have one vote between them), and all major scientific decisions will be determined by a majority vote of the Steering and Planning Committee. A Chairperson will be chosen from among the Steering and Planning Committee members (but not one of the Project Scientists or DCC Principal Investigator), or alternatively, from among experts in the field of the treatment of BPH who are not participating directly in the trial. Subcommittees will be established from among members of the full complement of CETCs and the DCC on topics such as ancillary studies, publications and presentations, quality control, recruitment, protocol adherence (including adherence to the intervention), among others. An Executive Committee comprised of the Steering and Planning Committee Chairperson, the Principal Investigator of the DCC, and the NIDDK/NCCAM Project Scientists also will be convened to effect management decisions required between the Steering and Planning Committee meetings, as needed for efficient progress of the trial. The Executive Committee will report its actions to the Steering and Planning Committee on a regular basis. Meetings of the Executive Committee will generally be by conference call. 4) Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between recipients and the NIDDK/NCCAM may be brought to arbitration. An arbitration panel will be composed of three members, one selected by the Steering and Planning Committee (with the NIDDK/NCCAM members not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NIDDK/NCCAM, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardees right to appeal an adverse action that is otherwise subject to appeal in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16, or the rights of NIDDK/NCCAM under applicable statutes, regulations and terms of the award. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: John W. Kusek, Ph.D. Clinical Trials Program Director or Leroy M. Nyberg, Ph.D., M.D. Urology Program Director Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Two Democracy Plaza, Room 617 6707 Democracy Boulevard Bethesda, MD 20892-5458 Telephone: (301) 594-7717 (Dr. Nyberg)/(301) 594-7735 (Dr. Kusek) Fax: (301) 480-3510 Email: firstname.lastname@example.org or email@example.com o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard Room 752, MSC 5452 Bethesda, Maryland 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: firstname.lastname@example.org o Direct your questions about financial or grants management matters to: Trude W. Hilliard Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Room 717 Two Democracy Plaza 6707 Democracy Boulevard Bethesda, Maryland 20892 Telephone: (301) 594-8859 FAX: (301) 480-4237 Email: email@example.com LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Dr. Francisco O. Calvo at the address listed under INQUIRIES, above. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: Applicants must describe plans to accommodate the stated program requirements, criteria, and staff involvement. Applicants must address points discussed in the SPECIAL REQUIREMENTS section of this RFA. Information to be Included in Applications Information Pertaining to Recruitment (CETC applicants only): Each CETC is expected to randomize a total of 300 men with BPH over a two- year period of recruitment. Applications for a CETC must provide convincing evidence that they will be able to achieve this goal given the level of resources provided under this RFA. The CETC application should document the available target population from which study participants can be recruited. This documentation should include, in tabular form, the number of patients anticipated to be eligible for the trial, by five-year age ranges and by race/ethnicity. The investigators must also include in their description of their target population, the sources of referral of their patients, and the estimated percentage who have not received any form of previous therapy (i.e. alternative, pharmacological or surgical). Realistic estimates of the rate of participation of men who are willing to join the trial and be followed at the CETC must be provided. The applicant must describe strategies and techniques that have been found to be effective in patient recruitment for other clinical trials in which they have participated. Applicants who have participated in previous NIH funded trials as Principal Investigator or Co-Investigators must provide the following information for all trials that are included as documentation of previous success in recruitment: name of study, brief description of entry criteria, number of participants recruited, duration of recruitment, percent of study recruitment goal achieved, number/percent of patients who adhered to treatment protocol for duration of study, the number of patients available for evaluation of end of study, and the duration of the study. Information pertaining to NIH-sponsored trials will be reviewed for accuracy by NIDDK program staff. Each CETC that proposes the establishment of a satellite center to increase the pool of eligible participants from which to recruit from must specify the administrative and financial arrangements between the parent institution and the satellite facility. The likely number of participants to be recruited (randomized) from satellite clinics must be specified. The applicant must also indicate where baseline and follow-up evaluations will be conducted and describe how data will be transmitted to the DCC. CETCs must work in concert with the DCC and must be willing to submit to data audits and other data quality control procedures as established by the study protocol and as required by law for government agencies. Applications for the DCC should provide examples of the types of reports on recruitment performance that they will generate and feed back to the CETCs. Clinical Trial Design Issues: Applications for a CETC and the BCC should follow the design for a clinical trial of Serenoa repens (Saw palmetto) and Pygeum africanum as described in this RFA. Serenoa will be compared to placebo and Pygeum will be compared to placebo. Secondary analyses will include a head-to-head comparison of Serenoa and Pygeum. Additional details of the trial design must be described including entry and exclusion criteria, secondary outcomes, and frequency and type of measurements (including validated instruments to assess primary and secondary outcomes) during follow-up. Applications for the DCC must also include a detailed data analysis plan. Applications for a CETC need not include an analysis plan but must comment on the clinical relevance of the primary outcome for the clinical trial (clinical progression of BPH) as described in this RFA. Plans for Establishing and Maintaining Adherence to Assigned Agents: Applicants for a CETC must provide a comprehensive plan to maintain long-term adherence to the randomly assigned agent. The plan must be behaviorally based and include goals for use of their assigned agent, approaches to be used to establish and maintain high rates of adherence and plans to identify barriers for non-adherence and solutions to this problem. Applicants for the DCC must include a description of the type of trial-wide reports they will generate to monitor adherence to the assigned agents and the role they will play in promoting adherence to agent use. Promotion of Clinic Visit Attendance: A goal of follow-up in excess of 90% of the randomized participants at the end of the trial is expected. CETC applications must provide an action-based plan for the long-term follow-up (maintenance of the established clinic visit schedule) of all study participants, including those who choose to discontinue use of their assigned agent, and men recruited from satellite clinics. Previous Experience and Prior Participation in a Collaborative Program: To promote the development of a collaborative program among the awardees, an applicant for a CETC should present evidence of prior experience in working cooperatively with other institutions serving to recruit patients into studies of treatment of BPH and similar multi- center clinical studies and follow them long-term. Applications for the DCC must provide evidence of coordinating multi-center clinical studies, including clinical trials. Institutional Support: There should be documentation of strong institutional support for the program, including adequate space in which to conduct clinic activities (CETCs) or in the case of the DCC adequate space and other resources to permit data collection, data analysis, and the other activities described for the DCC in this RFA. An organizational structure for the study should be set forth in the application for both a CETC and the DCC delineating lines of authority, communication and responsibility for dealing with problems in all general areas as well as stated willingness to follow the commonly agreed upon protocol. Suggested Personnel Requirements: The staff of a CETC must include urologists and general medical physicians with documented expertise in the assessment and non-surgical treatment of BPH. The CETC team is anticipated to include members who perform in roles similar to those cited below. Members may be full or part-time and may serve in more than one capacity, as appropriate. The application must describe the expertise of key scientific, technical and administrative personnel and include a mechanism for replacing key professional or technical personnel should the need arise. The following suggested roles are intended to be illustrative, not prescriptive: o Principal Investigator to provide overall scientific/clinical guidance. This may be a physician of any relevant medical specialty. o Physician(s)/clinicians serving as co-investigators or consultants with expertise in assessment of the symptoms of BPH and the pharmacological management of patients with BPH. o Project Coordinator who can provide full-time attention to administration and management of the trial. o Individual(s) for clerical and technical support, including data entry and culturally competent recruitment/outreach staff. The expertise required for the DCC includes statistics, data management, computer programming, data base development, and project management. Clinical consultants with expertise in the assessment and medical management of persons with lower urinary tract symptoms associated with BPH is advised. The following personnel requirements are suggested for the DCC. Principal investigator to provide overall scientific guidance. Statisticians to perform analysis to support the development of the protocols, provide data for meetings of the Steering and Planning Committee, the DSMB, and work with CETC investigators on interim and final publications. Project Coordinator who can provide full-time attention to the administrative and management aspects of the trial. Computer programmers to develop the necessary database. Individuals for clerical and technical support. Budget To assist in preparation of the budget for each year of the program a timetable in three phases, by calendar time and the tasks to be performed during each phase is presented below: Phase I (Months 1-6) Protocol Development/Centralized Staff Training: The major task during Phase I is refinement of the clinical trial protocol. Uniform entry and exclusion criteria will be established. Baseline data collection will also be agreed upon. The frequency of follow-up and data to be collected post-randomization will be described. The trial protocol and manual of operations will be written. Data collection forms will be produced and the database established. Prior to implementation, the protocol will be reviewed by the Data and Safety Monitoring Board (DSMB). Centralized training of study coordinators and other key personnel will be conducted at the end of Phase I. The purveyors of Serenoa repens and Pygeum africanum will be selected by standard procedures established by the NCCAM and the agents and their matching placebo will be manufactured. A Phytotherapy Distribution Center, to be established by the DCC, will be identified and become operational. It is anticipate that the Steering Committee will meet in the Washington, D.C. area three times in Phase 1. One meeting of the DSMB will be held. Phase II (Months 7 - 79): Patient recruitment, intervention, and follow-up: It is anticipated that there will be a 24-month period of recruitment. Participants will be randomized and follow-up data collection initiated. The minimum period of follow-up for randomized participants will be 48 months. The Steering Committee will meet every 6 months in the Washington, D.C. area during this Phase. The DSMB will meet once per year in Phase II. Phase III (Months 79 – 84): Final Data Analysis and Close-out: The major activities during this phase will be close-out of the CETCs and final data analysis. Results will be presented at major scientific meetings and publications prepared for publication in the peer-reviewed scientific literature. A final meeting of the Steering and Planning Committee will be held in the Washington, D.C. area to review the results of the trial. The DSMB will meet once in Phase III. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At time of submission, two additional copies of the application and any appendix material must be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard Rm. 752 MSC 5452 Bethesda, MD 20892-5452 Telephone: (301) 594-8897 FAX: (301) 480-3505 (for express/courier service: Bethesda, MD 20817) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. 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 NIDDK, NCCAM, and ODS in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the NIDDK National Advisory Council or Board. REVIEW CRITERIA Applicants are expected to address issues identified under SUBMITTING AN APPLICATION/SUPPLEMENTAL INSTRUCTIONS as well as the RESEARCH SCOPE. All applications will be reviewed according to the criteria listed below. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the goals of this solicitation. Each of the criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. Review Criteria for Clinical Evaluation and Treatment Centers (CETC) are as follows. o Significance: The application should address the problem outlined in the RFA. The application should demonstrate how the clinical trial will advance scientific and/or medical knowledge. o Approach: The adequacy of the proposed conceptual framework and details of the trial design. o Recruitment and Retention Capabilities: This is the most critical review criterion. Applicants must demonstrate the ability to recruit a large number of men who are candidates for the non-surgical treatment of BPH and follow them prospectively. Recruitment of racial and ethnic minority men should be described in detail with regards to racial and ethnic make-up of the study population. The importance of complete follow-up of study participants should be considered. Procedures for the maintenance of the long-term participation of study subjects must be provided. Experience and performance in prior NIH-sponsored clinical trials of BPH must be described in detail, including rates of treatment (medication) adherence and follow-up. The number of patients treated with non-surgical therapy over the past three years must be included in the application. o Investigators: The Principal Investigator should be appropriately trained and well suited to carry out this clinical trial. The roles and responsibilities of other key personnel should be identified in the application and their experience in clinical trials clearly noted. o Environment: The environment in which the work will be done should contribute to the probability of success. There should be evidence of institutional support. o Resources: Documented adequacy of the proposed facility and space is necessary. o Data Transmission: Adequacy of plans to ensure complete, reliable, and timely transmission of the study data to the DCC. o Cooperative Experience: Evidence of prior experience in working collaboratively to carry out a developed study protocol. Willingness to work cooperatively in this study is required. An explicit statement of willingness to implement the final protocol developed collaboratively by the Steering and Planning Committee must be included in the grant application. o Collaboration between institutions in a single CETC application: For those applications proposing collaborative efforts between one or more applicants from different institutions to form a single CETC additional factors to be considered include cost, recruitment capabilities, and the utilization of support personnel, and logistics of participant follow-up and adherence promotion. An administrative plan for such arrangements needs to be clearly delineated. Review Criteria for the Data Coordinating Center (DCC) are as follows. o Significance: The application should address the problem outlined in the RFA. The application should demonstrate how the clinical trial will advance scientific and/or medical knowledge. o Approach: The applicant must include the conceptual framework, design, methods, and analyses to support the goals of the program? Potential problem areas and approaches to solve problems must be included in the application. o Potential problems specific to conducting a large simple trial: It is anticipated that there will be few data collection forms and a simple intervention administered to the men participating in this clinical trial (the format of a large simple trial). Applications for the DCC should address potential problems in such a study design. o Proposed Plans for Data Analysis: Plans been established for analyzing (interim and final data analysis) the data from the proposed trial, including plans for interim monitoring of results for the Data and Safety Monitoring Board must be included in the application. o Investigators: The Principal Investigator should be appropriately trained and well suited to carry out this clinical trial. The roles and responsibilities of other key personnel should be identified in the application and their experience in clinical trials clearly noted. o Environment: The environment in which the work will be done should contribute to the probability of success. There should be evidence of institutional support. o Data Management and Quality Control: Adequacy of plans to ensure complete, reliable, and timely transmission of the study data by the CETCs. o Web-based data transmission: It is expected that the DCC will implement a web-based data transmission system. A plan for data transmission via the worldwide web, including maintaining data privacy, must be included in the grant application. Prior experience in the use of a web-based system of data transmission in previous clinical trials/studies should be provided. o Cooperative Experience: Evidence of prior experience in working collaboratively to carry out a developed study protocol. Willingness to work cooperatively in this study is required. o Plans for Reporting to the Data and Safety Monitoring Board: Have adequate plans been proposed for stopping guidelines, reporting the results of the trial, including adverse events and safety of the interventions? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: 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 INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below). o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: March 15, 2002 Application Receipt Date: April 15, 2002 Peer Review Date: June/July 2002 Council Review: September 18-19, 2002 Earliest Anticipated Start Date: September 30, 2002 AWARD CRITERIA Criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities o Geographic distribution (applies only to CETCs) o Potential for recruitment of racial and ethnic minorities (applies to CETCs only) o Success in the recruitment and retention of trial participants, and the promotion of medication adherence in previous NIH funded clinical trials (applies to CETCs only). REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the 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. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.848 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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