and Human Services (HHS)
EXPIRED
MINIMALLY INVASIVE SURGICAL THERAPIES TREATMENT CONSORTIUM FOR BENIGN PROSTATIC HYPERPLASIA Release Date: November 29, 2000 RFA: DK-01-024 National Institute of Diabetes and Digestive and Kidney Diseases Applicant Information Forum Date: January 12, 2001 Letter of Intent Receipt Date: February 23, 2001 Application Receipt Date: March 20, 2001 PURPOSE The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has a substantial and longstanding interest in evaluating the effectiveness of treatment strategies for the symptoms of benign prostatic hyperplasia (BPH). For many years, transurethral resection of the prostate (TURP) has been the standard of surgical therapy for treatment of symptomatic BPH. Over the past decade there have been a number of technical innovations which have allowed the development of new surgical treatments which aim to achieve the same long-term outcomes of TURP but with the advantages of less morbidity, lower costs, shorter length of hospital stay, and more rapid recovery. These new "minimally invasive" surgical approaches include laser therapy, hyperthermia and thermotherapy, transurethral electrovaporization, microwave therapy and transurethral needle ablation, with new techniques appearing regularly. Published reports on the outcomes of these minimally invasive therapies are highly variable in their quality, often suffering from a lack of uniform outcome measurements, variable baseline or study entry criteria, a short period of follow-up, lack of information on the frequency of re-operation, inadequate documentation of adverse events, and absence of information on post- surgical pharmacological treatment. The purpose of this Request for Applications (RFA) is to establish a group of collaborative Prostate Evaluation and Treatment Centers (PETCs) and a Biostatistical Coordinating Center (BCC) to develop and conduct randomized, controlled clinical trials of the long-term efficacy and safety of the major "minimally-invasive" approaches for the treatment of symptomatic BPH. 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, Minimally Invasive Surgical Therapies Treatment Consortium for Benign Prostatic Hyperplasia , is related to one or more of the priority areas. Potential applicants may obtain a copy of Healthy People 2010 at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit and non-profit institutions, public and private organizations, such as universities, colleges, hospitals, units of State and local government, and eligible agencies of the Federal government. Foreign institutions are not eligible to apply. Racial/ethnic minorities, women, and persons with disabilities are encouraged to apply as Principal Investigators. An institution may apply for both a PETC and the BCC, however, separate applications are required and a specific plan of the independent operation (i.e., confidentiality of the study-wide data) of each unit will be maintained is required in each application. MECHANISM OF SUPPORT The administrative and funding instrument to be used for these awards will be the cooperative agreement (U01). The cooperative agreement is an assistance mechanism in which substantial NIDDK scientific and programmatic involvement is anticipated during the performance of the activity. Under the cooperative agreement, the NIDDK"s purpose is to support and encourage the recipient"s activities by working jointly with the awardees in a partnership role, but not to assume direction, prime responsibility, or dominance. Details of the responsibilities, relationships, and governance of a study funded under a cooperative agreement are described under the section entitled "Terms and Conditions of Award." The total project period for applications submitted in response to this RFA must not exceed five years. The anticipated award date is September 30, 2001. At this time, the NIDDK has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The NIDDK plans to make approximately 15 awards for PETCs and a single award for a BCC. Approximately $3,000,000 total cost (direct plus facilities and administrative costs) is expected to be available for the first year of support under this RFA. It is anticipated that the award for each PETC will be about $150,000 total cost per year for the first year of the study. The award to the BCC is anticipated to be $750,000 total costs for each year of the program. Approximately $6,000,000 is expected to be available for years 2 through 5 for this project. Total costs for each PETC will be approximately $350,000 for years 2 through 5. The number of awards to be made is dependent on the receipt of a sufficient number of applications of high scientific merit and availability of funds. Although this program is provided for in the financial plans of the NIDDK, 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. RESEARCH OBJECTIVES A. Background Symptomatic benign prostatic hyperplasia (BPH) is one of the most common disorders for which men seek the care of a physician. The effective treatment of BPH is of importance not only to the patient but also to third party payers, physicians in general, and particularly to urologists. TURP is considered to be the "gold standard" in terms of reducing symptom scores, improving maximum urine flow rates, and decreasing post-void residual urine. The morbidity associated with TURP includes urinary incontinence, erectile dysfunction, retrograde ejaculation, infection, blood loss requiring transfusion, and the long- term effects of bladder neck contracture and the need for reoperation. The potential for adverse outcomes for TURP and their attendant costs has prompted the development and use of both pharmacologic treatment and device-related surgery. Such device-related procedures have become to be known as minimally invasive surgical therapies. These therapies include the use of ultrasound, laser, hyperthermia, microwave, needle ablation, electrovaporization, balloon dilation and intraurethral stents. Manufacturers claim that treatment with these devices reduce the morbidity, obviates the need for hospitalization and thereby reduces overall costs, and achieves a clinical effect similar to that of TURP. However, there are very few well-documented, long- term, multi-center randomized clinical trials comparing subjective and objective outcomes of these minimally invasive surgical therapies. Thus, little is known about the clinical and other characteristics of patients with BPH who achieve successful outcomes, the rate of successful response and its duration, and the frequency of complications. Often the specific enrollment criteria, the diagnostic criteria such as size of the prostate, documentation of subjective and objective symptoms, and use of widely accepted and uniform outcome criteria are lacking in the currently available literature. These reports also do not describe whether adjunctive medical therapy was utilized post-surgery, nor do they report on the outcomes of patients who drop out prior to study completion. Frequently these are not randomized nor do they include sham controls. B. Research Goals and Scope of the Activity The purpose of this RFA is to solicit applications from investigators to serve either as a PETC or a BCC to participate as a consortium to develop and conduct randomized controlled clinical trials to evaluate the long-term efficacy and safety of the most frequently used "minimally-invasive" surgical approaches for the treatment of symptomatic BPH. The major objective of this RFA is to cooperatively develop and carry out clinical trials, singly or concurrently, in order to evaluate the long-term efficacy and safety of these devices. The cooperative group of investigators, to be known as the Minimally Invasive Surgical Therapy (MIST) Study Group, will also develop objective diagnostic and outcome measures. Trials may focus on comparisons of a single surgical technique with a sham control or comparisons of multiple techniques with each other and sham controls. It is expected that PETCs will require expertise in urology and experience in the conduct of multi-center clinical trials related to the treatment of BPH. The BCC must have expertise in biostatistics, data management, database development and computer programming as well as experience in coordinating multi-center clinical trials and/or epidemiological studies. The specific goals of this solicitation are to: 1. establish a group of investigators ( The MIST Study Group ) who will participate in conducting multiple randomized clinical trials, either sequentially or concurrently, of minimally invasive surgical devices for the treatment of symptomatic BPH 2. evaluate the long-term efficacy and safety of the most commonly used minimally invasive surgical devices for the treatment of BPH. 3. determine if baseline clinical characteristics and diagnostic criteria are predictive of successful outcomes of these therapies. 4. assess the need for and if required, whether adjuvant medical therapy improves the long-term outcome of minimally invasive surgery for BPH. 5. determine whether one or more baseline urodynamic measurements are prognostic indicators for surgical success and the feasibility of using selected follow-up urodynamic measurement parameters as secondary outcomes. Applicants are encouraged to collaborate with other investigators via subcontracts to establish satellite centers in order to increase the available pool of potentially eligible participants with the primary goal of enhancing racial and ethnic diversity of the population. PHASES OF STUDY FOR BUDGET CONSIDERATIONS: The timetable for the study may be subdivided into three phases over a five-year period. Phase I (Months 1-12): Protocol Development and Limited Patient Recruitment for Clinical Trial Number 1 This phase will include selecting the devices to be evaluated, planning and developing the protocol for the first clinical trial, establishing inclusion/exclusion criteria, baseline diagnostic criteria, and outcome criteria, including indices for measurement of quality of life and patient satisfaction. Methods to evaluate the safety of these devices will also be developed. The protocol for urodynamic studies will also be developed. Also during this phase, the protocol for the first trial will be written and finalized and a manual of operations and data collection forms will be created. The BCC will develop the database for the trial and implement procedures for data collection by the PETCs. Upon completion of the protocol and manual of operations, centralized training of the study coordinators will be conducted. Subsequently, a small number of participants will be enrolled in the first clinical trial by each PETC during the last two months of Phase I to test recruitment procedures and methods for data collection and transmission. Prior to implementation of the first trial, a Data and Safety Monitoring Board (DSMB), selected by the NIDDK, will review the protocol in terms of its scientific importance, safeguards for participants, and ethical considerations. Phase II (Months 13-54) Implementation of Additional Clinical Trials and Reporting of Results Phase II is a period of patient recruitment, further protocol development and trial implementation, and interim and final data analysis. During the first 12 months of Phase II (months 13-24 of the total project period) recruitment of patients to be enrolled in the first clinical trial will occur. As recruitment proceeds for the first clinical trial, the protocol will be developed for the second trial. Depending upon the sample size, it is expected that at least 3-4 randomized clinical trials will be completed during the five years of this program. This process of developing a protocol for a new trial during the recruitment period of an ongoing trial will continue throughout this Phase of the program. Depending upon the mix of surgical techniques and the number of trial participants that can be recruited by the successful applicants it may be possible to implement two trials concurrently. It is anticipated that the follow-up of patients will be for a minimum of two years post-surgery. As trials are completed final data analysis and reporting in the peer-reviewed literature will occur. Phase III: (Months 55-60) Final Data Analysis and Close-out of Prostate Evaluation and Treatment Centers and the Biostatistical Coordinating Center. Final analysis of results from the trials implemented in the latter stages of Phase II will be completed. Reports of the findings of these trials will be prepared and manuscripts prepared for publication in peer-reviewed scientific journals. The PETCs and the BCC will also be closed out in months 55-60 of the program. STUDY COMPONENTS Prostate Evaluation and Treatment Center A Prostate 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 and a research coordinator and the appropriate support personnel, such data entry and clerical staff. Each PETC which proposes the establishment of a satellite center must specify the working arrangements between parent institution and satellite physicians, describe the potential pool of trial participants and the surgical techniques available at these sites, indicate where baseline and follow-up evaluations will be conducted, and describe how data will be transmitted to the BCC. It is not expected that each PETC will have either the equipment or experience with each type of minimally invasive therapy. Establishment of satellite sites can be used to expand that expertise. It is expected that there will be adequate expertise distributed among the participating PETCs to conduct randomized clinical trials with adequate statistical power to evaluate at least 3-4 of the most frequently used techniques. The purpose of establishing of satellite sites should be not only to expand the types surgical techniques that could be evaluated but also increase recruitment of racial and ethnic minority men. PETC investigators must be capable of recruiting and retaining a sufficient number of men for the proposed clinical trials. PETCs 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 surgical intervention over the 5-year period of the program for each 5- year age range 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 are prior treatment (both medical and surgical) failures. Realistic estimates of the rate of participation of men who are willing to join the trial and be followed at the PETC must be provided. The investigators should describe strategies and techniques that have been found to be effective in patient recruitment for other clinical trials of BPH treatments, with supporting data. Information on the number of patients treated with these devices at their institution during the past 3 years should also be provided. The Principal Investigator and co-investigators should document previous experience in collaborative clinical investigation, including randomized clinical trials. Investigators will be required to submit protocol-specified data to the BCC expeditiously and to collaborate with other investigators in the consortium. PETCs must work in concert with the BCC 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. Biostatistical Coordinating Center The BCC will assist investigators in developing the design and protocol for the clinical trials to be conducted by the consortium, including determination of the final sample size and power calculations. The BCC will also have primary responsibility for collecting, editing, storing, and analyzing data generated by the PETCs. It should be prepared to assume a key role in overseeing implementation and adherence to the trial protocols, and assuring quality control of the data collected. It is expected that a web-based method for data transmission from the PETCs to the BCC will be implemented. Staff required for a BCC should include biostatisticians, a project manager, computer programmers, and a study coordinator. The BCC will also be expected to provide appropriately detailed reports to the Steering and Planning Committee, the Executive Committee, and a group of external advisors at regular intervals, and will be responsible for the logistics and planning of the meetings (including conference calls) of these committees and their subcommittees. The BCC will play a key role in analyzing data to support the efforts of the PETCs in writing manuscripts suitable for publication in peer-reviewed scientific journals. Steering and Planning Committee The primary governing body of the study will be the Steering and Planning Committee comprised of each of the principal investigators of the PETCs and the BCC, the Chairperson of the Steering and Planning Committee, and the NIDDK Project Scientists (described in detail under Terms and Conditions). The Steering and Planning Committee will, in addition to developing the study protocols, propose plans for interim and final data analysis, and along with their staff at the PETCs, recruit, perform surgery and follow-up study participants. The members of the Steering and Planning Committee will serve as chairs of the various subcommittees established to develop the protocols for the trials and to monitor the progress of the consortium. Executive Committee An Executive Committee, including the Chairperson of the Steering and Planing Committee, the Principal Investigator of the BCC, NIDDK Project Scientists, and when necessary, Chairpersons of the various subcommittees of the Steering and Planning Committee, will be established. The purpose of this committee is to handle problems that arise during the interim of regularly scheduled Steering and Planing Committee meetings. Data and Safety Monitoring Board An independent group of experts in urology, biostatistics, clinical trials, and ethics who are not otherwise involved in the study will be recruited by the NIDDK to review periodically the scientific merit of the proposed trial designs (including ethical aspects), and the progress and safety of ongoing trials (described in detail under Terms and Conditions). Project Scientists The NIDDK will identify two Project Scientists for the study. The Project Scientists will assist the Steering and Planning Committee and external advisors in carrying out the study (described in detail under Terms and Conditions). SPECIAL REQUIREMENTS Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to each Principal Investigator as well as to the institutional officials at the time of the award. These terms are in addition to, 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, and other HHS, and NIH Grants Administration policy statements. The participating PETCs will have primary responsibility for recruiting a sufficient number of patients (with a focus on recruiting a sufficient number of racial and ethnic minority participants to permit subgroup analyses), maintaining high rates of follow-up and high quality and complete data collection, and interpreting, presenting, and publishing findings from the trials. It is expected that the PETCs will carry out the protocol agreed upon by the Steering and Planning Committee and approved by the Data and Safety Monitoring Board. The BCC will have the primary responsibility for developing the various trial designs (in concert with the PETCs), coordinating the writing of the study protocol, manual of procedures and data collection forms, and collection, quality control, and analysis of the data. 1) Collaborative Responsibilities 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 the cooperative agreement concept, the dominant role and prime responsibility for the planned activity reside 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 Project Scientists. 2) Awardees Rights and Responsibilities Awardees will have substantial and lead responsibilities in all tasks and activities. These include patient recruitment, performance of the surgery, follow-up, data collection, quality control, final data analysis and interpretation, and preparation of publications. The awardees agree to work cooperatively with the other PETCs and the BCC and agree to follow the common protocols and Manual of Operations developed by the Steering and Planning Committee. The awardees agree also to transmit all study data to the BCC for combination and analysis. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government (e.g., NIDDK, NIH, or PHS) rights or access consistent with current HHS, and NIH policies. 3) NIDDK Staff Responsibilities The NIDDK will name two Project Scientists from within the Division of Kidney, Urologic and Hematologic Diseases whose function will be to assist the Steering and Planning Committee in carrying out the study. One Project Scientist will have clinical expertise in urology and the other will have experience in the development and conduct of multi- center clinical studies. The Project Scientists will be entitled to one vote between them for all key study group subcommittees. The Project Scientists will have substantial scientific-programmatic involvement in 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 Project Scientists. The NIDDK 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. One of the NIDDK Project Scientists will also serve as Executive Secretary of the group of the Data and Safety Monitoring Board. The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of difficulties in recruiting participants to the study, maintaining high rates of patient follow-up and data collection and in timely data transmission, achieving high levels of data quality, working with cooperatively or other major breaches of the protocol, or human subject ethical issues that may dictate a premature termination. 4) Governance a) The Steering and Planning Committee, composed of each of the Principal Investigators of the PETCs, the Principal Investigator of the BCC, the NIDDK 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 common protocol, performing surgery, facilitating the conduct of participant follow-up, monitoring completeness of data collection and timely transmission of data to the BCC, and reporting the study 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 Planing Committee will have one vote (NIDDK Project Scientists will have one vote between them), and all major scientific decisions will be determined by a majority vote of the Steering and Planing Committee. A Chairperson will be chosen from among the Steering and Planing Committee members (but not one of the NIDDK Project Scientist or Biostatistical Coordinating Center Principal Investigator), or alternatively, from among experts in the field of urology and the treatment of BPH who are not participating directly in the study. Subcommittees will be established from among members of the full complement of PETCs and the BCC on topics such as ancillary studies, publications and presentations, quality control, recruitment, protocol adherence, among others. b) An Executive Committee comprised of the Steering and Planning Committee Chairperson, the Principal Investigator of the BCC, and the NIDDK 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 trials. Each member of the Executive Committee will have one vote (the NIDDK Project Scientists are entitled to one vote between them). 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. c) An independent group of external advisors, selected by the Director, NIDDK, known as the Data and Safety Monitoring Board, will review periodically the progress of the trials. This group will include experts in the relevant medical, statistical, and ethics fields that are not otherwise involved in the trials. The Data and Safety Monitoring Board will review the protocols for the various trials and evaluate results, monitor data quality, participant safety, and provide operational and policy advice to the Steering and Planning Committee and to the NIDDK regarding the status of the trials. One of the NIDDK Project Scientists will serve as Executive Secretary of the group of the Data and Safety Monitoring Board. 5) Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between recipients and the NIDDK 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 member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDDK, 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 MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that 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 1003-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research" published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. INFORMATION FOR PROSPECTIVE APPLICANTS Open Forum A one-day open information forum will be held for prospective applicants on January 12, 2001, from 12 p.m. to 3:30 p.m. (EST). The meeting will be held on the NIH Campus, Conference Room B in the Natcher Conference Center located in Building 45 (the Natcher Building), located at 45 Center Drive, Bethesda, Maryland. At this forum NIDDK program staff will address any questions that prospective applicants might have regarding the clinical/scientific concepts of the RFA. Attendance is not required and is not a pre-condition for submission of an application. Applicants planning to attend this meeting should submit their questions in writing (electronic mail is acceptable) to John W. Kusek, Ph.D. at the address listed INQUIRIES at least two weeks in advance of the forum. Information on the Web For those who cannot attend the January 12,2001 forum, a website will contain a summary of that meeting. It will also contain questions of general interest asked by prospective applicants and their answers. Prospective applicants are encouraged to check this website frequently while preparing an application. The website can be reached though the following URL: http://www.niddk.nih.gov/fund/crfo/rfas.htm. LETTER OF INTENT Prospective applicants are asked to submit, by February 23, 2001, 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 a subsequent application, the information that it contains allows the NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard Room 653, MSC 5452 Bethesda, MD 20892-5452 (for express/courier service use 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 Email: [email protected] APPLICATION PROCEDURES Applications must be submitted on the standard research grant application form PHS 398 (rev. 4/98). Application kits are available at most institutional offices of sponsored research and may 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, E-mail: [email protected]. The RFA label in the form PHS 398 (rev. 4/98) must be affixed to the bottom of the face page. 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. For purposes of identification and processing, item 2 of the face page of the application must be marked "YES" and the RFA number and the words Minimally Invasive Surgical Therapies for BPH- Treatment Consortium" must be typed in. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. Failure to use the label could result in delayed processing of the application such that it may not reach the review committee in time for review. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 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: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard Room 653, MSC 5452 Bethesda, MD 20892- 5452 (for express/courier service use 20817) Applications must be received by March 20, 2001. An application that is received after this date 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. Information to be Included in Applications Clinical Trial Design: Applications for a PETC and the BCC must include a proposed design for a single clinical trial to achieve the goals of this RFA. The design must include the surgical technique(s) proposed to be evaluated, entry and exclusion criteria, primary and secondary outcomes, methodological issues surrounding the use of sham controls, frequency and type of measurements during follow-up, and plans for data analysis. Plans for data analysis must be more detailed for applications for a BCC than a PETC. For applications for both the PETC and the BCC sample size estimates and power calculations must be included. Information on Patient Pool (for PETCs only): Detailed information on the number, age, race, ethnicity of men who have been evaluated for symptoms of BPH, and also those who have undergone surgery for BPH during the past three years at the applicant institution and any proposed satellite sites should be provided. The distribution of men who have undergone therapy with minimally invasive surgical techniques over this time period must also be quantified by each technique. Information on the number of cases of new versus repeat surgical procedures in this patient population must also be provided. Previous Experience and Prior Participation in a Collaborative Program: To promote the development of a collaborative program among the awardees, the applicant 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. In the case of the BCC, evidence of coordinating multi-center clinical studies, including clinical trials, should be included in the application. Institutional Support: There should be documentation of strong institutional support for the study, including adequate space in which to conduct clinic activities (PETCs) or in the case of the BCC adequate space to permit data collection, data analysis, and the other activities described for the BCC in this RFA. An organizational structure for the study should be set forth in the application, 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 PETC should include urologists with documented expertise in the treatment of BPH. The PETC 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 guidance. o Physician(s)/clinicians with expertise in the surgical, and pharmacological and management of patients with BPH. o Project Coordinator who can provide full-time attention to administration and management of the trials. o Individual(s) for clerical and technical support, including data entry. The expertise required for the BCC includes statistics, data management, computer programming, data base development, and project management. Clinical consultants with expertise in urology, including familiarity with the major minimally invasive surgical techniques is necessary. The following personnel requirements are suggested for the BCC. 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 group of external advisors, and work with PETC investigators on interim and final publications. Project Coordinator who can provide full-time attention to the administrative and management aspects of the trials. Computer programmers to develop the necessary database. Individuals for clerical and technical support. Part-time medical consultants with expertise in the treatment of BPH, with experience with the most commonly used minimally invasive surgical therapies. Budget Preparation by Year Applicants for the PETCs and the BCC must include an adequately justified year-by-year budget, reflecting the major changes in the proposed activities as the study progresses through its various phases. Note that budgets are NOT to be prepared in modules. Phase I (Months 1-12): The budget should reflect the level of effort necessary to develop the protocol for the first clinical trial. During this phase the BCC will create the data collection forms and computer database necessary for trial number 1. During the last two months of Phase I a small number of participants will be randomized into the first trial. Phase II (Months 13-54): The major activities during this phase are completion of recruitment for trial number 1 (anticipated recruitment period of 12 months) and follow-up data collection. Protocols for subsequent trials will be developed, patients recruited, and followed- up per study protocol. Interim and final data analysis will occur as well as reporting of findings to the group of external advisors. Phase III (Months 55-60): During this phase of the program final reporting of the results of trials implemented during the latter part of Phase II will occur. Computer files of the data for each of the trials will be prepared and submitted to the NIDDK for archiving. The PETCs and the BCC will be closed-out. The project will require meeting approximately every four months in the Washington, D.C. area for each year of the study. The travel budget should be estimated based on travel for the Principal Investigator, a co-investigator and a Study Coordinator. Key personnel from satellite centers may also be included in the travel budget. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for 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 the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review Criteria Applicants are expected to address issues identified under INFORMATION TO BE INCLUDED IN APPLICATIONS. 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. A design for a single clinical trial must be included in the grant applications for both PETCs and the BCC. Review Criteria for Prostate Evaluation and Treatment Centers are as follows. o Significance: The applicant must demonstrate an understanding of the need for conducting randomized controlled clinical trials of the various minimally invasive surgical procedures for BPH. o Proposed Study Design for a Clinical Trial: Is the proposed design for the first clinical trial well-justified and appropriate? Have the sample size and power calculations been presented and the underlying assumptions for treatment effect been adequately described? Have the outcome measures been fully considered and length of follow-up justified? Have the technical issues surrounding the use of sham- controls been adequately discussed? Are the plans for data analysis described? o Recruitment and Retention Capabilities: Applicants must demonstrate the ability to recruit a large number of men who are candidates for surgery for BPH and follow them prospectively post-surgery. Recruitment of racial and ethnic minority men should be described in detail. The importance of complete follow-up of study participants and collection of high quality data 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 surgical procedures for new and repeat procedures for BPH must be described for the past three years. o Investigator: This criterion will focus on the following questions: Is there documented evidence of the investigator"s training and experience relevant to the operation of a PETC for BPH? Is there evidence of successful collaborative interactions with other investigators under a common protocol in a multi-center study? o Environment: Does the clinical environment in which the work will be done contribute to the probability of success? Is there evidence of institutional support and commitment for the proposed program? o Staff Qualifications: Documented specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a PETC and the ability to carry out BPH treatment studies. o Documented experience in surgical treatment with minimally invasive devices for BPH is required. Demonstrated knowledge of clinical aspects of BPH is also necessary. o Resources: Documented adequacy of the proposed facility and space is necessary. Evidence of institutional support and commitment is also required. o Data Management and Transmission: Adequacy of plans to ensure complete, reliable, and timely transmission of the study data to the BCC. 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 trial protocols developed collaboratively by the Steering and Planning Committee must be included in the grant application. o Collaboration between institutions in a single PETC application: For those applications proposing collaborative efforts between one or more applicants from different institutions to form a single PETC additional factors to be considered include the advantages of collaboration in terms of cost, recruitment capabilities, and availability of additional minimally invasive surgical techniques. The organizational and administrative plan for such arrangements needs to be clearly delineated. Review Criteria for the BCC are as follows. o Significance: The applicant must demonstrate an understanding of the need for conducting randomized controlled clinical trials of the various minimally invasive surgical procedures for BPH. o Approach: For the proposed clinical trial, are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the program? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Proposed Study Design for a Clinical Trial: Is the proposed design for the first clinical trial well-justified and appropriate? Are the sample size and power calculations been presented and documentation of the underlying assumptions for treatment effect been described. Have the outcome measures been fully considered and length of follow-up justified? Have the technical issues surrounding the use of sham- controls been adequately discussed? o Proposed Plans for Data Analysis: Have adequate plans been established for analyzing the data from the proposed trial, including plans for interim monitoring of results for the Data and Safety Monitoring Board? The Steering and Planning Committee will collaboratively develop the design for each of the clinical trials to be implemented. Thus, the peer review group will focus on evidence that the applicant has carefully thought about the issues involved and possesses the knowledge necessary to contribute meaningfully to the final designs, including understanding of the scientific, ethical, and practical issues underlying the proposed study. o Environment: Does the clinical environment in which the work will be done contribute to the probability of success? Is there evidence of institutional support and commitment for the proposed program? o Staff Qualifications: Documented specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a BCC. o By means of consultants, documented experience in surgical treatment with minimally invasive devices for BPH is required. Demonstrated knowledge of clinical aspects of BPH is also required. o Resources: Documented adequacy of the proposed facility and space is necessary. Evidence of institutional support and commitment is also required. o Data Management and Quality Control: Adequacy of plans to ensure complete, reliable, and timely transmission of the study data by the PETCs. Have plans been developed to ensure high quality data from the PETCs? o Web-based data transmission: It is expected that the BCC will implement web-based data transmission system between the PETCs and the BCC. A plan for data transmission via the world wide 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 reporting the results of the trials, including adverse events and safety of the interventions? In addition to the above criteria for PETCs and the BCC, in accordance with NIH policy, applications will also be reviewed with respect to the following. o The reasonableness of the proposed budget. o The adequacy of the proposed protection for humans or the environment, to the extent they may be adversely affected by the interventions proposed in the application. The initial review group will also examine the safety of the research environment. 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 Cost o Geographic distribution (for PTECs only) o The frequency and type of surgical procedures available at each PETC o Potential for recruitment of racial and ethnic minorities o Success in the recruitment and retention of trial participants, and the promotion of adherence in other NIDDK funded clinical trials/studies. Schedule Applicant Information Forum Date: January 12,2001 Letter of Intent Receipt Date: February 23, 2001 Application Receipt Date: March 20, 2001 Special Review Committee: July/August 2001 NIDDK Advisory Council: September 20-21, 2001 Anticipated Award Date: September 30, 2001 INQUIRIES Written and telephone inquiries concerning this RFA are strongly encouraged. Direct inquiries regarding programmatic 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 Fax: (301) 480-3510 Email: [email protected] or [email protected] Direct inquiries regarding fiscal and administrative matters to: Trude Hilliard Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Telephone: (301) 594-8859 FAX: (301) 480-3504 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No 93.849. Awards are made under authorization 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 Public Health Service grants policies and Federal Regulations 42 CFR 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 Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free work place 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 Public Health Service mission to protect and advance the physical and mental health of the American people.
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