Full Text CA-92-05 NATIONAL COLLABORATIVE RADIATION THERAPY TRIALS: 3-D DOSE ESCALATION STUDY FOR PROSTATE CANCER NIH GUIDE, Volume 21, Number 16, May 1, 1992 RFA: CA-92-05 P.T. 34 Keywords: Cancer/Carcinogenesis Urogenital System Radiotherapy Clinical Trial National Cancer Institute Letter of Intent Receipt Date: June 1, 1992 Application Receipt Date: August 26, 1992 PURPOSE The Radiation Research Program (RRP), Division of Cancer Treatment (DCT), of the National Cancer Institute (NCI) invites applications for cooperative agreements to carry out National Collaborative Radiation Therapy Trials: 3-D Dose Escalation Study for Prostate Cancer. The objectives of the present solicitation are (1) to conduct Phase I, II, and III clinical trials to test the efficacy of using 3-D conformal radiation therapy (3DCRT) in a dose escalation study for the treatment of prostate cancer, and (2) to collect 3-D dose distributions and data on radiation-induced damage to normal tissues. The decade of the 1980s brought unprecedented advances in computer hardware and software for the development and implementation of 3-D techniques in radiation therapy treatment planning and treatment delivery. The new 3-D technology has the potential to deliver higher radiation doses to tumor targets with no increase in normal tissue morbidity. The potential benefit to the cancer patient is improved local control, fewer complications to normal tissues, and longer survival. A potential risk is that tight, conformal fields will underdose occult tumor at the margins of the fields. Multi-institutional trials are supported by the NCI for the conduct of clinical trials to establish the efficacy of new therapies and new approaches for the treatment of cancer. The objective of this Request for Applications (RFA) is to support multicenter cooperative clinical trials carrying out a dose-escalation study in the treatment of prostate cancer. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, National Collaborative Radiation Therapy Trials: 3-D Dose Escalation Study for Prostate Cancer, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from minority individuals and women are encouraged. In order to participate in this program, applicant institutions must demonstrate or meet the following requirements. Requirements for the Operations and Statistical Center o Expertise in the design and coordination of multi-disciplinary, multi-modality cooperative clinical trials. o Capacity to develop and implement a structure for a Cooperative Group, including criteria for membership, and to provide leadership to an Executive Committee (see SPECIAL REQUIREMENTS, Section B2). The Executive Committee will assume responsibility for setting the priorities for the development and coordination of protocol design and implementation, quality control, and formulation of a research strategy. o Expertise in the design of guidelines for statistically valid studies planned for multi-institutional trials. o Availability of facilities and professional personnel with expertise in data management and analysis and the ability to participate in cooperative clinical trials to provide centralized statistical services. o Demonstrated capabilities for monitoring the performance of 3DCRT studies and for providing that information to the Executive Committee for the development of new research strategies. These capabilities shall include availability of facilities and professional personnel with expertise in 3-D treatment planning and 3DCRT treatment delivery and verification techniques for the necessary monitoring of the dose escalation studies for quality control. o Demonstrated capability to exchange magnetic tape of patient data, tumor and treatment volume contours, normal tissue contours, and dose distributions over the volume irradiated between institutions. These data will be the basis for the monitoring of the clinical studies for quality control and provide data for the 3-D database of normal tissue effects. o Demonstrated capability for incorporating 3-D data obtained from dose distributions correlated with anatomical structure (e.g., dose-volume-histograms) into a standard database for the recording of radiation injury as a function of dose and volume. This database will be designed such that it can be made available to other researchers and serve as a resource for developing mathematical models that describe normal tissue complication probabilities as a function of volume irradiated. Requirements for Radiotherapy Centers o Radiotherapy Center applications must demonstrate a commitment to participate in multi-institutional protocols and document the existence and commitment of facilities and professional personnel available to conduct cooperative therapy trials. This includes assignment of appropriate specialists who may be required to carry out the research, including such diverse specialties as, but not necessarily limited to, radiologists, radiotherapists, surgeons, pathologists, physicists, statisticians, dosimetrists, data managers, and radiation therapy technicians, in order to ensure availability of the timely and complete information, expertise, and skills needed for patient treatment planning, radiation therapy treatments and evaluation. o Radiotherapy centers must demonstrate the capability to plan 3-D treatment, deliver treatment, and verify portal in a 3DCRT environment. Specific capabilities will include, as a minimum, 3-D representations of tumor and target/treatment volumes and normal tissues and beam's-eye-view representations for treatment planning, non-conformal beam planning and treatment delivery, and treatment portal verification for each beam. o The presence of expertise for review and evaluation of the treatment plans and treatment delivery for 3DCRT and the existence of procedures for quality control of the radiotherapy treatments must be demonstrated. o The availability of qualified support personnel to ensure timely and accurate data retrieval and reporting is necessary. o Sufficient numbers of patients must be available and enrolled in meaningful trials. Applicants must show the ability to recruit these patients to group studies and to maintain follow-up of the patients after treatment. (see STUDY POPULATIONS.) o The availability of personnel and facilities capable of performing and supporting the administrative functions of a cooperative group member conducting therapy trials in cancer must be demonstrated. o Demonstrated capability of magnetic tape exchange of patient data, tumor and treatment volume contours, normal tissue contours and dose distributions over the volume irradiated with the Operations Center. MECHANISM OF SUPPORT The mechanism for this award is a cooperative agreement (U01). Such assistance programs involve substantial participation of NCI staff during the performance of this project. The nature of NCI staff participation is described under the section "Terms of Cooperation." Applicants will be responsible for the planning, direction, and execution of the proposed project. Except as otherwise stated in this RFA, awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1990. This RFA is a one-time solicitation. Future unsolicited competitive continuation applications will compete as research project applications with all other investigator-initiated applications and be reviewed by the Division of Research Grants (DRG). If the NCI determines that there is sufficient programmatic need, the NCI will invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review according to the procedures described in the section "Terms of Cooperation". FUNDS AVAILABLE Approximately $750,000 in total costs per year for four years will be committed to fund applications that are submitted in response to this RFA. The NCI anticipates a single award for funding an Operations and Statistical Center and up to four to five awards to Radiotherapy Centers for a period of four years. It is estimated that the award for the Operations and Statistical Center will be about $400,000 and the remaining funds will be to the radiotherapy centers. The funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, the award of cooperative agreements in response to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES The objective of this RFA is to support multicenter cooperative clinical trials to conduct disease-specific Phase I and II studies using 3DCRT techniques that will define a new maximum tolerated dose (MTD) beyond standard radiation therapy for prostate cancer treatments. Should the Phase II results be sufficiently convincing that a new MTD has been reached, the Cooperative Group will proceed to Phase III trials, in which 3DCRT will be compared with best standard conventional therapy for prostate cancer. The Cooperative Group, through the Executive Committee, will also define protocols for scoring radiation injury as a function of dose and volume to the normal tissues at risk for this disease, which is to be incorporated into a new three- dimensional (3D) database for future reference and use by scientific investigators. The design, structure, and maintenance of the 3D database is a research objective of this RFA. The Division of Cancer Treatment, NCI, intends to support these trials by awarding cooperative agreements to selected institutions that have the capability to plan and deliver 3D conformal radiation therapy, and to a single organization or institution that is capable of coordinating the multi-institutional studies and serving as a data management and analysis center. Background There are approximately 122,000 new cases of prostate cancer in this country each year. It is the second-most common cancer among men and results in about 32,000 deaths annually. Radiation therapy is commonly used in the curative management of the disease, and it is estimated that approximately 40-50 percent of the cases are treated with radiation therapy. The Patterns of Care studies funded by the National Cancer Institute in 1973, 1978 and 1983 (1516 patients) showed that excellent 5- and 10-year survival for patients treated with radiation therapy is achieved for T1 or early stage B patients (1). Patterns of Care 10-year survival data showed that Stage A of the disease is locally controlled with radiation therapy at the 97-98 percent level. Stages A2 and B patients with negative lymph node dissections show freedom from recurrence that is equal to those results from radical surgery. Local control is less effective for more advanced disease, however, with a 67-69 percent 10-year survival rate found for Stage C. Approximately 40 percent of the prostate cancer cases diagnosed each year are Stage C. The Patterns of Care analyses demonstrated a dose-response effect in the recurrence-free outcome for the Stage C patients that was not shown in Stage A and B patients. Doses of greater than 70 Gy (or 7000 centigray) reduce the recurrence of disease in Stage C patients to 24 percent from a rate of 36 percent for patients receiving doses of 65 Gy or less. There was no dose-response effect observed for Stage B or Stage A. Complication rates, however, increase when doses of greater than 70 Gy are delivered. The Patterns analyses showed a doubling of complication rates from 3.5 percent to about 7 percent when doses of 70 Gy are used. A retrospective study of patients treated in the Netherlands without field blocking showed a 60 percent complication rate for doses greater than 75 Gy (2). Such treatment techniques without the use of field blocks treats normal tissues to the same dose as the tumor target, which resulted in a high complication rate in the Netherlands study. The use of 3DCRT "conforms" the radiation field precisely to the treatment volume and thereby focuses the radiation on the target, sparing normal tissues. Failure of Local Control The objective of this RFA is to focus on two factors that are recognized as the causes of local failure with radiation therapy: (1) failure to appreciate the true anatomical extent of the tumor; and (2) failure to deliver tumoricidal doses due to the limitations of the radiation tolerance of the normal tissues involved. The limitations of conventional treatment planning, as practiced routinely during the last decade, are generally recognized to be the following: o Definitions of the tumor target volume are incomplete. o Tumor and normal tissue boundaries are only approximated. (For example, treatment planning is generally carried out on only a few representative CT slices: the mid-field plane slice and one or two other slices. The superior and inferior boundaries of the treatment field are typically determined from the x-ray simulation film.) o Beam apertures or radiation field boundaries are simplified. o Treatment planning isodose displays may not display dose throughout the entire volume. o Plan evaluation and optimization are often based on a limited number of planar isodose displays without full dose-volume information. 3-D Treatment Planning Research Since 1982, the Radiation Research Program of the National Cancer Institute has supported multi-institutional collaborative working groups in treatment planning that have focused research efforts on 3-D treatment planning evaluation, beginning with the Collaborative Working Group for the Evaluation of Treatment Planning for Particle Beam Radiotherapy from 1982-86. The work of this group of contractors was then modified, improved and expanded by the Collaborative Working Group on the Evaluation of Treatment Planning for External Photon Beam Radiotherapy, funded from 1984-87 (3). The Collaborative Working Group for High Energy Electron External Beam Treatment Planning was funded from 1986-89. All of these collaborative working groups in 3-D treatment planning advanced the field dramatically, and the result has been the development of a new technology. Embraced by the leading radiotherapy departments and institutions in the country as a major technological advance for the treatment of cancer, 3-DCRT is now ready to be tested in a clinical environment. 3DCRT Characteristics The basic characteristics of a 3-D planning system have been described elsewhere (3). The application of a 3-D planning system, coupled with the necessary modifications and enhancements to traditional conventional methods for treatment delivery and verification, constitutes a 3DCRT environment. Its basic characteristics can generally be described as follows: o Tumor or treatment targets are defined as volumes, showing the full extent in all slices in three dimensions. Typically, they are generated by a radiotherapist drawing or outlining the two-dimensional contours on each CT slice throughout the tumor region. Depending on the thickness of the CT slice for the treatment planning scan, the study may contain contours on 10-20 or more CT slices. o Normal structures are defined as volumes; they are not limited to single points or a single contour on one CT slice. In 3-D conformal therapy, tumor contours, treatment volumes and normal tissue anatomical structures, particularly those at risk during the radiation therapy treatment, are entered on the entire set of CT slices that comprise the study--up to as many as 50 CT slices. o Treatment planning then proceeds in a 3-D environment---namely the manipulation of the target and anatomical structures as volumes. An important advance with this technology is the development of the beam's-eye-view, which shows the projection of the tumor from a particular beam direction, allowing for the precise shaping of the treatment portal from any arbitrary beam angle, thereby enabling the planner to minimize radiation damage to local adjacent structures. o Radiation dose calculations are modeled in three dimensions, taking into account the effect of inhomogeneities. Dose- volume-histograms are calculated that show the dose as a function of volume, either as an integral plot or a differential plot, in both the target volumes and in the organs and normal tissues at risk. Using theoretical models that predict complication probabilities, it is possible to use the dose-volume-histogram to assist in the evaluation of competing plans. o 3-D conformal therapy requires accurate and precise positioning of the patient and immobilization during treatment. The task of reproducibility becomes much more important when the treatment technique reduces the volume of normal tissues at risk. Over a six to seven week course of treatment, reproducibility of the patient treatment position must be verified through careful portal imaging and verification techniques. SPECIAL REQUIREMENTS Terms of Cooperation A. Nature of Participation by NCI Staff The role of the NCI staff is to assist and facilitate, but not to direct the research activities. 1. RRP as a Scientific Resource for NCI-supported Clinical Investigations The Associate Director of the RRP, or his/her designee Program Director (RRP/PD), will serve as a resource available to awardees for specific scientific information with respect to clinical trial design and advise the group of the nature and results of relevant national and international studies. The collective group of participating institutions in this RFA, including the Operations and Statistical Center, will be referred to as the Cooperative Group and the Principal Investigator (PI) of the Operations and Statistical Center will be the Group Chairperson. The Executive Committee will consist of the PI's of the Operations and Statistical Center and the Radiotherapy Centers. Similar types of studies have found it beneficial to authorize an Executive Committee to direct the research in accordance with the goals and objectives of this initiative. The RRP/PD will participate in planning and strategy meetings of the Executive Committee when indicated. 2. RRP Assistance in Protocol Development a. Protocol Design The Associate Director, RRP, or his/her RRP/PD will participate in the design of new studies and the development of protocols as needed, assisting the awardees and facilitating the process, rather than directing it, to assure that the proposed studies are in accord with NCI and PHS research requirements and regulations. The RRP/PD will serve as a resource available to the Group for specific scientific information with respect to protocol design and advise the group of the nature and results of relevant national and international clinical studies. b. Protocol Approval Protocols will be submitted under the leadership of the Group Chairperson to the Protocol Review Committee of the Clinical Therapy Evaluation Program (CTEP) Protocol and Information office in a timely fashion for review and approval by NCI. Protocols will be developed and submitted and studies will be conducted in accordance with established DCT Clinical Trials Cooperative Group Guidelines. The major considerations relevant to protocol review by NCI include: (a) strength of the scientific rationale supporting the study; (b) the medical importance of the question being posed; (c) the avoidance of undesirable duplication with other ongoing studies; (d) the appropriateness of study design; (e) a satisfactory projected accrual rate and follow-up period; (f) patient safety; (g) compliance with Federal regulatory requirements; (h) adequacy of date management; (i) appropriateness of patient selection and follow-up; and (j) evaluation and assessment of complications/toxicity. c. Arbitration Process If a proposed protocol is not approved by the RRP Program Director or the Protocol Review Committee, the specific reasons for the disapproval will be communicated to the Group Chairperson within 45 days of receipt by the NCI. The NCI will not permit expenditure of NCI funds for a protocol that has not been approved. Disagreements arising pursuant to protocol disapproval and/or other scientific programmatic matters may be submitted to an arbitration panel to determine the suitability of a protocol that has been disapproved. An arbitration panel composed of one Group designee, one NCI designee, and a third member with clinical trials expertise chosen by the other two designees will be formed to review the contested decision(s). The arbitration panel will recommend an appropriate course of action to the Director, DCT. These special arbitration procedures in no way affect the awardees' rights to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. The Group will not expend NCI funds to conduct any study that has been disapproved by the NCI, unless the disapproval has been modified by the arbitration process outlined above. d. Protocol Closure The RRP/PD may request that a protocol study be closed to accrual for reasons including: (a) insufficient accrual rate; (b) achievement of the original accrual goals; (c) patient safety; (e) conclusive study results; (f) unacceptable toxicity; (g) further accrual will not add information of scientific value; and (h) emergence of new information that diminishes the scientific importance of the study in question. Protocols shall not be terminated by the Group before reaching the projected accrual target without the approval of the RRP/PD. Such approval will be based on a submission of an interim results report and written justification for closing the study. Unresolved disagreements between NCI staff and the awardee institutions regarding the appropriateness of early study closure will be arbitrated by the process outlined in item 2.c. above. 3. Review of Progress Performance of the Group will be reviewed at least annually by the RRP/PD on the basis of information provided at Group meetings, annual progress reports, and interim reports. The content of these reports is described in the next section, Responsibilities of Awardees, Reporting Requirements. Support recommended for the remaining project period will be contingent upon annual favorable review by the RRP/PD of the progress of the project and sufficient patient accrual to complete the studies within the allotted time. Insufficient patient accrual or noncompliance with the terms of award, including these Terms of Cooperation, may result in a reduction of the budget, withholding of support, suspension or termination of the award. Future support recommended for the entire Group will be contingent upon favorable review by NCI program staff of the progress of the Group as manifested in part by sufficient patient accrual of the Group as a whole. NCI funding is contingent upon an awardee institution remaining as a member of the Group. 4. Access to Data The NCI via the RRP/PD shall have access to all data generated under this cooperative agreement and may periodically review the data. The awardee will retain custody of and primary rights to the data consistent with current HHS, PHS, and NIH policies. B. Responsibilities of Awardees It is the responsibility of the awardees to develop the details of the research design, including definition of objectives and approaches, planning, implementation, analysis and publication of results, interpretations, and conclusions of the clinical studies. 1. Group Chairperson The PI of the Operations and Statistical Center will serve as Chairperson of the Cooperative Group and will oversee the management and direction of the Executive Committee. The Group Chairperson will be responsible for the logistics of Group meetings, for the coordination of protocol development and protocol submission to NCI, for communicating the results of NCI protocol reviews to the awardee institutions, for the management and conduct of the clinical studies, for quality control of the studies, for data management, for coordinating group-related scientific and administrative decisions, and for providing leadership to the Executive Committee. The Group Chairperson will be the principal point of contact for the RRP/PD in the conduct of this clinical trial. 2. Executive Committee The PI of the Operations and Statistical Center, the PI's of each of the awardee institutions, and the RRP/PD constitute the Executive Committee. The Executive Committee will have the authority to create committees it deems necessary for protocol design, for defining and maintaining quality assurance, for collection and dissemination of the data, and for the design, structure, and implementation of the 3-D database (see 9 below). The Executive Committee will have the responsibility of implementing methods of assuring quality research that is carefully monitored and controlled. Such methods may include, but not be limited to, the following: setting standards for a minimum number of evaluable cases submitted by awardee institutions, maintaining quality control of the studies, termination of current members whenever indicated, and defining principles governing admission of new group members. 3. Executive Committee Meetings It is anticipated that all decisions of the Group will be reached by Group consensus under the leadership of the Group Chairperson. It is required that the PI (or designee) of each awardee institution attend all Executive Committee meetings. Members of the Executive Committee will meet at least twice a year at Group Headquarters to review progress, establish priorities, and plan future activities. For purposes of developing a budget in response to this RFA, applicants should assume a city in the Midwest. At the time of award, travel costs will be negotiated with awardees on the basis of actual location of the Group Headquarters. 4. Clinical Studies a. Protocol Development and Submission It shall be the responsibility of the Group Chairperson to coordinate protocol development and submit protocols to the NCI for approval as described in the previous section, A. Nature of Participation by NCI Staff. The Group Chairperson may authorize meetings of the Executive Committee for the purpose of discussions of protocol design, monitoring of the studies, and quality assurance. The Group Chairperson shall be responsible for the logistics of Group meetings, for submitting protocols to the NCI for approval, for communicating the results of NCI protocol reviews to the awardee institutions, and for providing leadership to the Executive Committee in the development of new protocols. Protocols will be submitted by the Group Chairperson to the Protocol Review Committee of the CTEP Protocol and Information office in a timely fashion for review and approval by NCI. Protocols will be developed and submitted and studies will be conducted in accordance with the "DCT Guidelines for Multicenter Investigational Agent Studies" (available upon request from the RRP Program Director at the address below) or in accordance with established DCT Clinical Trials Cooperative Group Guidelines. The major considerations relevant to protocol review by NCI are contained under 2.b., Protocol Approval. b. Quality Assurance and Control The Executive Committee will be responsible for overseeing and monitoring data collections to ensure the highest possible quality control of the clinical studies. Such quality control issues may include, but not be limited to, adequacy of tumor delineation and target definition in three dimensions; portal image verification; compliance with treatment planning protocols, specifically with respect to treatment volume, including adequate margins in three dimensions; adequacy of tumor coverage in three dimensions to the isodose line prescribed in the protocol; adequacy of dose-volume-histogram calculations; and adequacy of the documentation provided. Non-compliance on the part of awardee institutions of quality control standards as defined by the Executive Committee may be the basis for excluding that institution from the Group. Any disagreements between the awardee institutions and the Executive Committee relating to data management and analysis that cannot be resolved by bilateral discussions will be submitted to the same arbitration process previously outlined in Section 2.c, Arbitration Process under the Terms of Cooperation. c. Protection of Human Subjects It will be the responsibility of the PI of each awardee institution to submit new and revised protocols to each appropriate Institutional Review Board (IRB) within 30 days of the date of written notification of NCI approval. Each institution is responsible for ensuring that each protocol is reviewed and approved prior to patient entry, in accordance with 45 CFR, Part 46, Protection of Human Subjects. Written informed consent must be obtained prior to entry on the studies. Each protocol must be reviewed and approved at least annually by the appropriate IRB while the protocol is active. 5. Conduct of Research and Patient Accrual Awardees are expected to provide timely results from a sufficient number of patients as required by the NCI approved protocols and the Executive Committee recommendations. 6. Study Monitoring The Operations and Statistical Center, under the leadership of the Group Chairperson, is responsible for establishing a mechanism for study monitoring to ensure quality control of the studies and accurate and timely knowledge of the progress of each study through: a. Tracking and reporting of patient accrual and adherence to defined accrual goals and protocol requirements. b. Ongoing assessment of case eligibility and evaluability. c. Assuring that each participating institution's IRB has reviewed and approved each new and revised protocol prior to patient entry. d. Timely review and assessment of patient data. e. Rapid reporting of treatment-related morbidity and measures to ensure communication of this information to all parties. f. Interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice. g. Timely communication of results of studies. 7. Reporting Requirements Annual progress reports will be submitted by the PI of each awardee institution to the NCI through the Group Chairperson describing their participation in the study, the accomplishments at that institution, and the number of patients entered into the study. Each awardee institution must submit to the Group Chairperson a biannual report of patient accrual and treatment-associated morbidity. Determination of adequate patient accrual will be based on plans developed by the PI's in their Executive Committee roles (see B.2., Executive Committee, and B.4.b., Quality Assurance and Control). The Group Chairperson shall submit an annual report summarizing the accomplishments of the Cooperative Group and the Executive Committee. The report shall contain (1) highlights of progress made during the period regarding the important issues of this study, such as protocol development, 3-D database design, magnetic tape exchange; (2) documentation of patient accrual to the studies; and (3) reports of treatment-associated toxicity. Minutes of the Executive Committee meetings, protocols developed, and other supplementary material as deemed appropriate, will be included as appendices. 8. Publication of Data Timely publication of major findings is encouraged. Topics of publications and authorship will be decided upon by the Executive Committee under the leadership of the Group Chairperson. Data generated in these studies remains the property of the awardee institution, consistent with current HHS, PHS, and NIH policies, but publication and oral presentation of work done under this agreement will require appropriate acknowledgement of NCI support. The NCI, through the RRP/PD, will have access to all data generated under this cooperative agreement and may periodically review the data. 9. 3-D Database It is the responsibility of the Operations and Statistical Center, in collaboration with the Executive Committee, to design and implement a database for the incorporation of 3-D dose/volume data that will be maintained and made available to scientific researchers. One of the potential uses of such a database is the development of models that can predict normal tissue complication probabilities on the basis of the partial irradiation of an organ. The maintenance of the database beyond the lifetime of this award will be based on sufficient programmatic need as determined by the NCI (see MECHANISM OF SUPPORT). C. The Terms of Cooperation described in this section are in addition to, and not in lieu of, otherwise applicable Office of Management and Budget administrative guidelines, HHS Grant Administration regulations at 45 CFR, Part 74, and other HHS, PHS and NIH grant administration policy statements. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS (Considerations of women in the NIH and ADAMHA policy do not apply for this RFA.) NIH and ADAMHA policy is that applications for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males of all ages. If minorities are excluded or inadequately represented in the clinical research of this RFA, a clear and compelling rationale should be provided. The composition of the proposed study population must be described in terms of the racial/ethnic group, together with a rationale for its choice. In addition, racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 (rev. 9/91) in the Research Plan, 1-4, and summarized in 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissue from racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of minorities in the study design is inadequate to answer the scientific question addressed and the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit, by June 1, 1992, a letter of intent that includes a descriptive title of the proposed research, the name and address of the PI, the names of other key personnel, the participating institutions, and the number and title of the RFA in response to which the application is being submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, it is requested in order to provide an indication of the number and scope of applications to be reviewed. The letter of intent is to be sent to Dr. Sandra Zink at the address noted below. APPLICATION PROCEDURES Application for Public Health Service cooperative agreements must be submitted on form PHS 398 (rev. 9/91). Application kits are available from most institutional business offices, and may be obtained from the Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Bethesda, MD 20892, telephone (301) 496-7441. The RFA label available in the application form PHS 398 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. In addition, the RFA number and title must be typed on line 2a of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies, in one package to the address below. The photocopies must be legible and single-sided. Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, send two additional copies of the application to: Referral Officer Division of Extramural Activities National Cancer Institute Westwood Building, Room 838 5333 Westbard Avenue Bethesda, MD 20892 Applications must be received by August 26, 1992. If an application is received after that date, it will be returned. Also, the DRG will not accept any application in response to this announcement that is the same as one currently being considered by any other NIH review group or awarding unit. Special Instructions For Preparation of Cooperative Agreement Applications General instructions for the preparation of the cooperative agreement application are contained in the grant application form PHS 398 (rev. 9/91). The applicant organizations for the Operations and Statistical Center may propose a consortium arrangement for operations of the Center if necessary. The Operations and Statistical Center and the Radiotherapy Centers will constitute a single Cooperative Group to conduct the clinical trials. The PI of the Operations and Statistical Center will serve as the Chairperson of the Cooperative Group. Because the Terms of Cooperation discussed above will be included in all awards issued as a result of this RFA, it is critical that each applicant include specific plans for responding to these terms. Plans must describe how the applicant will comply with the program staff involvement and how all the responsibilities of awardees will be fulfilled. REVIEW CONSIDERATIONS Review Procedure Upon receipt, applications will be reviewed by the DRG for completeness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the program requirements and criteria stated in the RFA is an NCI program staff function. Applications that are judged non-responsive will be returned to the applicant by the NCI, but may be submitted as investigator-initiated research grants. Questions concerning the responsiveness of proposed research to the RFA should be directed to program staff. If the number of applications submitted is large compared to the number of awards to be made, the NCI may conduct a preliminary scientific peer review (triage) to eliminate those that are clearly not competitive. The NCI will remove from competition those applications judged to be noncompetitive for award and notify the applicant and institutional business official. Those applications judged to be both competitive and responsive will be further evaluated according to the review criteria stated below for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review will be by the National Cancer Advisory Board. Review Criteria Review criteria for the Operations and Statistical Center include: (1) the leadership ability of the PI and documented experience in dealing with the problems of cooperative clinical research; (2) proposed methodology for the conduct of the clinical trials to attain the research objectives; (3) ability of the Operations and Statistical Center staff to monitor clinical trials for quality assurance; (4) adequacy of statistical support necessary for the design, monitoring, analysis, and reporting of the 3DCRT cooperative multi-center clinical trials; and (5) capability to design and develop a database documenting dose and irradiated volume with normal tissue response. For the Radiation Center applicants, review criteria include: (1) documented experience in the development and conduct of clinical trials at their institution; (2) documented evidence that their institution has the potential to accrue the necessary patients through patterns of referral, previous experience, and accession; (3) proposed methodology for the conduct of the clinical trials; (4) availability of appropriate facilities, treatment planning capabilities, appropriate staff, and appropriate hardware to treat patients and perform clinical trials in a 3DCRT environment; and (5) adequacy of provisions for the protection of human subjects. The review group will critically evaluate the submitted budgets and will recommend an appropriate budget and period of support for each approved application. AWARD CRITERIA The earliest feasible start date for the initial awards will be April 1, 1993. Awards will be made solely on the basis of peer review and only the most meritorious will be considered, contingent upon the availability of funds. Although this program is provided for in the financial plans of the NCI, the award of cooperative agreements pursuant to this RFA is contingent upon the availability of funds for this purpose. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA and inquires about whether or not specific proposed research would be responsive are encouraged and should be directed to Dr. Zink at the address below. Dr. Zink welcomes the opportunity to clarify any issues or questions from potential applicants. For technical information: Dr. Sandra Zink Program Director Radiation Research Program National Cancer Institute Executive Plaza North, Suite 800 Bethesda, MD 20892 Telephone: (301) 496-9360 FAX: (301) 480-5785 For business information: Ms. Barbara Fisher Grants Management Specialist Grants Administration Branch National Cancer Institute Executive Plaza South, Room 242 6120 Executive Blvd. Rockville, MD 20852 Telephone: (301) 496-7800, Ext. 29 FAX: (301) 496-8601 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395, Cancer Treatment Research. Awards are made under the authorization of Public Health Service Act, Title IV, Sections 301, 410 and 411, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285 (a.)) and administered under the PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. REFERENCES 1. Leibel, SA, GE Hanks, S Kramer, Int J Rad Oncol Biol Phys <10>, pp 401-409 (1984). 2. Smith, WGJM, PA Helle, WLJ van Putten, AJ Wijnmaalen, JJ Seldenrath, BHP van der Werf-Messing, Int. J Rad Oncol Biol Phys <18>, pp 23-29 (1990). 3. Special Supplement, Int J Rad Oncol Biol Phys, <21, No. 1>, May 15, 1991. .
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Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
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