Full Text CA-93-07 PHASE I TRIALS OF NEW ANTI-CANCER AGENTS NIH GUIDE, Volume 21, Number 45, December 18, 1992 RFA: CA-93-07 P.T. 34 Keywords: Clinical Trial Cancer/Carcinogenesis Chemotherapeutic Agents Pharmacology National Cancer Institute Letter of Intent Receipt Date: January 22, 1993 Application Receipt Date: March 23, 1993 PURPOSE The Division of Cancer Treatment (DCT), National Cancer Institute (NCI) invites cooperative agreement (U01) applications from single institutions wishing to perform Phase I trials of promising anti-cancer agents in patients with cancer refractory to currently available therapy and to conduct laboratory studies in support of the clinical trials such that their conduct leads to a greater understanding of the relationship between drug administration and biological changes in patients. Patients should be treated only at the applicant institution, although support for laboratory studies may be conducted by collaborators at other institutions. The increasing numbers of promising new agents with novel mechanisms of action and the large number of institutions both capable of and interested in conducting Phase I clinical trials of cancer therapies makes it desirable to expand NCI grant support in this area. The need for increased resources for clinical development of a wide range of novel anti-cancer agents has led to this request for cooperative agreement applications to establish the pharmacological and initial clinical characteristics of these agents. Institutions responding to this Request for Applications (RFA) should be able to perform Phase I trials and establish the pharmacological characteristics, in parallel with biochemical and other appropriate biological studies, of the effects of these agents on cancer cells and normal tissues. It is expected that the application from any one institution will focus on studies of one or more classes of agents, reflecting the interest, expertise, and experience of the applicant investigators. 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, Phase I Trials of New Anti-Cancer Agents, 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 "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/783-3238). ELIGIBILITY REQUIREMENTS Domestic for-profit and non-profit organizations such as universities, colleges and hospitals and governments and their agencies are eligible to apply. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT Support of this program will be through the cooperative agreement (U01), an assistance mechanism in which substantial NCI programmatic involvement with the recipient during performance of the planned activity is anticipated. The nature of NCI staff involvement is described in the section SPECIAL REQUIREMENTS, Terms of Cooperation, Nature of Participation by NCI Staff. Applicants will be responsible for the planning, direction, and execution of the proposed project. There is no intent, real or implied, for NCI staff to direct awardee activities or to limit the freedom of investigators. Under the cooperative agreement, a relationship exits between the recipient of the award and the NCI, in which the recipient is responsive to the requirements and conditions set forth in the RFA. Specifically, the Principal Investigator defines the details for the project within the quidelines of the RFA, retains primary responsibility for the performance of the activity, and agrees to accept close coordination, cooperation and assistance of the NCI extramural staff (through the NCI Program Director - see INQUIRIES) in all aspects of scientific and technical management of the project in accordance with the Terms of Cooperation. 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. However, if it is determined that there is a sufficient continuing program 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 Review Considerations, Part A. FUNDS AVAILABLE Approximately $2,000,000 in total costs per year for four years will be committed to specifically fund applications submitted in response to this RFA. This funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. It is anticipated that six to eight awards will be made. The total project period for applications submitted in response to the present RFA may not exceed four years. The earliest feasible start date for the initial awards will be December 1, 1994. 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. RESEARCH OBJECTIVES A. Background The purpose of this RFA is to provide support for single institution Phase I clinical trials with investigational anti-cancer agents. Phase I clinical trials have as their objectives the characterization of drug toxicity, maximally tolerated dose, pharmacokinetics, and biological effects (pharmacodynamics) of drugs. These anti-cancer agents have traditionally been obtained either from the NCI drug development program or through collaborative drug development agreements with the pharmaceutical industry. Recent advances in understanding of the pathobiology of malignancy are leading to the development of a wide range of novel anti-cancer therapeutic agents that require Phase I testing. These agents include, but are not limited to, new classes of cytotoxic agents derived from natural products, as well as rationally designed anti-cancer agents targeted specifically to novel cancer cell targets, including surface receptors, signal transduction molecules, transcriptional factors, and particular DNA and RNA sequences. Furthermore, mechanisms of action of these new anti-cancer agents available for clinical study include not only the mediation of anti-cancer effects through cytotoxic mechanisms, but also through growth inhibition by interruption of specific oncogene-associated biochemical functions, inhibition of protein synthesis through targeted toxins, induction of differentiation and/or programmed cell death (apoptosis), and through anti-tumor angiogenesis. In addition, new strategies to overcome resistance to conventional cancer therapeutic approaches are also of interest. In an attempt to reduce the time period between new drug discovery and the general introduction of an effective new therapy to patients, the NCI offers assistance at many levels to investigators attempting to develop active new cancer therapies. In addition to the funding assistance offered to the investigator(s) by this RFA, NCI may sponsor (in the Food and Drug Administration sense) or co-sponsor the agents under development. An organization or individual who assumes legal responsibilities for supervising or overseeing clinical trials with investigational agents is termed a sponsor. As sponsor of an investigational drug, DCT and specifically, CTEP, is responsible for ensuring that clinical trials proceed safely and rationally from the initial dose-finding studies to a definitive evaluation of the role of the new drug in the treatment of one or more specific cancer(s). Fulfillment of this goal obviously requires the active participation of CTEP staff throughout the entire process. NCI sponsorship of investigational agents increases the likelihood that agents will be further developed so that they will ultimately be broadly available for use in cancer treatment and will accelerate the time frame in which this process would occur. B. Research Goals and Scope The aims of this initiative are: (1) to provide support for Phase I trials of promising new anti-cancer agents in cancer patients; and (2) to provide support for complete pharmacokinetic, pharmacodynamic, and other important laboratory correlative studies in cancer patients receiving these anti-cancer agents. The laboratory studies should be in support of the clinical trial, such that their conduct leads to a greater understanding of the relationship between drug administration and biological changes in patients. Laboratory studies would include pharmacokinetic studies of cytotoxic, differentiation-inducing, targeted and/or other novel anti-cancer agents, including monitoring of metabolites and intracellular products when appropriate, or other relevant pharmacology correlative studies; and the measurement of relevant indicators of pharmacodynamic or biologic response (e.g., changes in signal transduction pathways, induction or suppression of specific gene function, other indications of differentiation induction, or induction of apoptosis). Specific objectives and scientific approaches will be investigator-originated and should reflect the creativity and capability of the investigators. This RFA provides an opportunity for clinical and laboratory investigators within an institution to develop a program in drug development that utilizes the strengths of pre-existing basic scientific expertise and available clinical resources. The Principal Investigator will select the specific agents to be tested in accord with their area of scientific interest and expertise and will develop a series of appropriate Phase I trials with supporting protocol documents. The NCI may provide NCI-sponsored IND agents or provide assistance to the awardee institution by sponsoring or co-sponsoring other selected agents. Each Phase I awardee institution will be expected to complete on average two to three Phase I trials per year, with each trial encompassing 20-40 patients. In all categories of diseases, the Principal Investigator must select those patients for trial with the best performance status and with the minimum amount of prior treatment consistent with ethical medical practice. Sufficient numbers of patients at the applicant institution should be available in order to allow completion of the trials in a timely manner. The Principal Investigator will ensure that these Phase I trials conform to accepted standards of patient care. For example, patients should: a. have a microscopically confirmed diagnosis of cancer; b. be staged by conventional methods and found to have disseminated disease not amenable to curative intent therapy with surgery and/or radiotherapy; c. have already received and failed appropriate initial systemic treatment. For diseases for which systemic treatment exists (e.g., the acute leukemias, diffuse non-Hodgkin's lymphomas, Hodgkin's disease, testicular cancer, limited small cell lung cancer, ovarian carcinoma), patients should have received the minimum extent of prior treatment compatible with current ethical standards of care, and should have a high performance status. For other diseases in which only partially effective non-curative therapy is available (e.g., carcinomas of the head and neck, hormone-refractory prostatic carcinoma, bladder and stomach cancer, sarcomas), entry of patients with no prior therapy may be appropriate. d. receive appropriate initial and follow-up, hematologic, biochemical, radiologic, and immunologic investigations; and e. have given a signed informed consent indicating that they are aware of the investigational nature of the studies involved. Each applicant institution is responsible for coordination of protocol development and submission, study conduct, quality control, data management and analysis, adherence to NCI requirements for investigational agents, adherence to FDA/DHHS regulations, and performance reporting of data from the Phase I trials. For Phase I trials with NCI-sponsored investigational agents, the NCI has contracted for a Clinical Trials Monitoring Service (CTMS) to document regulatory compliance, to maintain a computerized data base of the biweekly Phase I investigator data submissions, and to produce periodic routine reports of the results and special reports as necessary. The awardee institution's source documentation will be reviewed on-site three times per year by the CTMS. SPECIAL REQUIREMENTS A. MINIMAL REQUIREMENTS FOR APPLICATIONS 1. Investigators should include in the APPENDIX of the cooperative agreement application draft copies of proposed protocols that might be undertaken in the first year and should identify the particular areas of laboratory expertise that would be utilized in the performance of these trials. 2. The applicant must demonstrate in the application the ability to meet the following requirements: a. documented numbers of eligible patients with a history of adequate accrual at the applicant institution to complete on average two to three Phase I trials annually. b. laboratory support within the institution to perform pharmacokinetic studies of cytotoxic, differentiation-inducing, targeted, and/or other novel anti-cancer agents, including monitoring of metabolites and intracellular products when appropriate, or other relevant pharmacology correlative studies; c. laboratory support within the institution to measure relevant indicators of pharmacodynamic or biologic response (e.g., changes in signal transduction pathways, induction or suppression of specific gene function, other indications of differentiation induction, or induction of apoptosis); d. adequate central data collection and processing capabilities in order to meet FDA requirements for the conduct of research using investigational agents. These specifically include: e. the capability to transmit patient data to the NCI's Clinical Trials Monitoring Service (CTMS) on a biweekly basis. f. the capability of prompt reporting of ADRs to CTEP for investigational agents supplied by NCI in accordance with the CTEP guidelines (mailed annually to all registered investigators). g. adequate pathology support for tumor classification and for banking and distribution of tumor tissues for concurrent and future studies. h. adequate mechanisms in place to ensure that all patients: (1) have histologically confirmed diagnosis of cancer; (2) have refractory disease not amenable to therapy with curative intent using surgery, chemotherapy, and/or radiotherapy or any other form of known effective therapy; (3) have acceptable performance status and acceptable renal, liver, and hematologic function; and (4) have given signed informed consent in accordance with 45 CFR Part 46, Protection of Human Subjects, indicating that they are aware of the investigational nature of the studies involved. i. Evidence of a level of supportive care appropriate for the treatment of patients with advanced malignancies; j. Intensive care and blood bank facilities on-site and functioning 24 hours per day. k. Adequate physician and nursing resources to comply with all reporting requirements of NCI-sponsored Phase I trials. l. Appropriate drug accountability procedures as required for utilization of NCI-supplied investigational agents. 3. All costs required for these studies must be included in the application and must be fully justified. These costs include the additional costs of clinical research associated with Phase I studies including costs related to patient accrual, data collection, sample handling, additional staff time, specific supply needs related to required laboratory studies, quality assurance, data management and data analysis, study monitoring, travel, and biweekly electronic data submissions to the NCI's Clinical Trials Monitoring Service as required by the reporting requirements for investigational agents. 4. If capitation costs are requested as reimbursement for patient accruals, the cost per patient must be broken down and justified, e.g.: a. estimate of physician time spent on research (e.g., to obtain informed consent, to fill out data forms, and others) and the resultant cost. Time spent delivering standard medical care is not allowable. b. estimate of data manager or nurse time to meet research requirements (e.g., compiling and mailing data, specimens) and the resultant cost. c. cost of mailing or handling research-related patient specimens, forms, materials (e.g., slides, X-ray) d. other consultant costs (e.g., pathology, radiology). 5. Travel funds for two meetings per year for two representatives from the awardee institution should be included in the budget. The applicant should also request funding for the initial Phase I strategy meeting. B. Terms of Cooperation The following Terms of Cooperation are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Part 74 and 92, and other HHS, PHS and NIH grant administration policy statements. The NCI arbitration process for the cooperative agreement in no way affects the rights of awardees to appeal selected post award administrative decisions in accordance with PHS regulations at 42 CFR part 50, subpart D and HHS regulations at 45 CFR part 16. Nature of Participation by NCI Staff The role of the Cancer Therapy Evaluation Program (CTEP) staff as described throughout these terms of cooperation is to assist and facilitate but not to direct research activities. This cooperative agreement is part of a larger program of investigational agent development in the NCI. Each of the CTEP staff listed below has very specific and well defined responsibilities in terms of investigational agent development and the role of DCT as a drug sponsor as defined in CFR 21 Part 312. 1. CTEP as a Scientific Resource for NCI-supported Phase I Clinical Trials Investigations The NCI Program Director (see INQUIRIES) will serve as a resource available to the Principal Investigator (PI) for specific scientific information with respect to treatment regimens and clinical trial design. The NCI Program Director will assist the PI as appropriate in developing information concerning the scientific basis for specific trials and also will be responsible for advising the PI of the nature and results of relevant trials being carried out nationally or internationally. The NCI Program Director will also provide updated information on the efficacy and toxicity of investigational new agents supplied to the PI under an Investigational New Drug (IND) Application sponsored by the DCT. The NCI Program Director will sponsor an initial Phase I strategy meeting with the PIs to review the research plans proposed by each individual research group to ensure that they are compatible with the overall goals of the RFA, to ensure avoidance of duplication of effort with other ongoing clinical trials and to ensure the most effective use of available resources including investigational agents. An arbitration system, as detailed below, will be available to resolve disagreements between the NCI and the awardee institution. The NCI Program Director will sponsor semi-annual Phase I meetings to review relevant scientific information, to review progress in the clinical trials, and to review the status of newly available investigational agents in order to plan future activities. 2. CTEP Assistance in Protocol Development A protocol is the detailed written plan of a clinical experiment. The protocol must be mutually acceptable to the PI and to the CTEP Protocol Review Committee (PRC), which must review and approve every protocol involving DCT investigational agents. The PRC is chaired by the Associate Director, CTEP, and is comprised of professional staff of the DCT including drug monitors, disease coordinators, regulatory staff, pharmacy staff and ad hoc reviewers external to NCI when deemed appropriate by the PRC chairperson. Communication at the various stages of protocol development is encouraged as necessary to promote protocol development and implementation. All protocols should be preceded by a written declaration of interest in conducting a particular study from the PI using the format described in the Guidelines for Submitting LOIs - Letter of Intent/Investigational Drug Trial (available upon request from Dr. David Parkinson at the address listed under INQUIRIES). The LOI should be sent to the CTEP LOI Coordinator who receives, logs in and schedules LOIs for review by the PRC (see Responsibilities of Awardees). The PRC will formally review the LOI. Following LOI review, the NCI Program Director will provide a Program response to the PI and will address the following issues: a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort; b) information including relevant pharmacokinetic and pharmacodynamic data concerning investigational agents; c) availability of investigational agents, including biologic response modifiers; d) the scientific rationale and value of the proposed study, the design, the statistical requirements; and e) the implementation of the study, if indicated. The LOI mechanism is designed for preliminary review and is recommended to expedite protocol development and implementation and to facilitate agreement on study priority and design (see the DCT Investigator's Handbook, pp 32-35, available on request from Dr. David Parkinson at the address below, for further discussion of these mechanisms). 3. CTEP Review of Proposed Protocols The awardee protocols will be reviewed by the PRC which meets weekly. The major considerations relevant to Protocol Review by CTEP include: (a) the strength of the scientific rationale supporting the study; (b) the medical importance of the question being posed; (c) the avoidance of unnecessary duplication with other ongoing studies; (d) the appropriateness of study design with respect to development of the IND agent; (e) a satisfactory projected accrual rate and follow-up period; (f) patient safety; (g) compliance with federal regulatory requirements; (h) adequacy of data management; and (i) appropriateness of patient selection, evaluation, assessment of toxicity, response to therapy and follow-up. An Investigational Drug Branch (IDB) Physician (Drug Monitor) is assigned to each DCT IND agent to assist in the coordination of its development. Following the review of the protocol by the PRC, the NCI Program Director will provide the PI with a consensus review prepared by the IDB Drug Monitor. The consensus review describes required or recommended modifications and other suggestions, as appropriate. The NCI Program Director will not serve as the consensus reviewer. (See the DCT Investigator's Handbook, for further information regarding protocol review at CTEP). If a proposed protocol is disapproved, the specific reasons for lack of approval will be communicated by the NCI Program Director to the PI as a consensus review within 30 days of protocol receipt by the NCI. The NCI Program Director will be available to assist the PI in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the PI and of the NCI. Disagreements arising pursuant to protocol approval will be submitted to an arbitration panel to determine the suitability of a protocol that has been disapproved. An arbitration panel composed of one awardee institution nominee, one NCI nominee, and a third member with clinical trials expertise chosen by the other two nominees will be formed to review the CTEP decision and recommend an appropriate course of action to the Director, DCT. These special arbitration procedures in no way affect the awardee's right to appeal an adverse determination in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. The NCI will not provide investigational agents or permit expenditure of NCI funds for a protocol that it has not approved unless CTEP's disapproval has been modified by the arbitration process outlined above. 4. Access to Data The NCI will have access to all data generated under this cooperative agreement and will periodically review the data. Data must be available for external monitoring as required by NCI's Drug Master File Agreement with the FDA relative to the responsibility of the NCI as an IND agent sponsor. Source documentation will be reviewed on-site three times per year by the NCI's Clinical Trials Monitoring Service (CTMS). The awardee institution will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies. 5. CTEP Involvement in Protocol Closure The NCI Program Director will monitor protocol progress. When a study involves a DCT IND agent, the Head, Quality Assurance and Compliance Section, (QACS), Regulatory Affairs Branch (RAB), CTEP and the IDB Drug Monitor and well as the NCI Program Director will monitor protocol progress. The NCI Program Director or the IDB Drug Monitor may request that a protocol be closed to accrual for reasons including: (1) insufficient accrual rate; (2) accrual goal met; (3) poor protocol performance; (4) patient safety and regulatory concerns; (5) study results are already conclusive; (6) emergence of new information that diminishes the scientific importance of the study question; and (7) failure to collect data in a timely manner. NCI will not provide investigational agents or permit expenditures of NCI funds for a study after requesting closure (except for patients already on-study). If disagreements develop over NCI-recommended study closure for reasons other than patient safety or regulatory concerns, NCI will establish an arbitration process identical to that described above for protocol disapproval. 6. CTEP involvement in Investigational New Drug Applications a. The NCI will have the option to cross file or independently file an IND on investigational agents evaluated in the Phase I Clinical Trials. This would apply to agents not primarily developed in the NCI drug development program. b. The NCI Program Director assisted by the Chief, RAB, CTEP, will advise investigators of specific requirements and changes in requirements concerning IND sponsorship that the FDA may mandate. Investigators performing trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents. c. Investigators performing NCI funded Phase I Clinical Trials will be advised by the NCI Program Director of potential studies that will be relevant to new avenues of cancer therapy. When this involves investigational agents, the NCI Program Director assisted by the Chief, RAB, CTEP will advise the investigators of the specific clinical information that will be needed from the clinical trials for that information to be acceptable to the FDA for inclusion in a new drug application (NDA). 7. CTEP Review of Federally Mandated Regulatory Requirements The Head, QACS, through the NCI Program Director, will advise the PI regarding mechanisms to meet FDA regulatory requirements for studies involving DCT-sponsored investigational agents and the Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects by the awardee institution. See Responsibilities of Awardees. For Phase I trials with NCI-sponsored investigational agents, the NCI has contracted for a Clinical Trials Monitoring Service (CTMS) to document regulatory compliance, to maintain a computerized data base of the biweekly Phase I investigator data submissions, and to produce periodic routine reports of the results and special reports as necessary. Source documentation will be reviewed on-site three times per year by the CTMS. 8. CTEP Review of Progress Progress will be reviewed at least annually by the NCI Program Director on the basis of the information provided at the semi-annual Phase I meetings, in the continuation application, and in reports provided to the NCI Program Director by the CTMS. In addition, periodic accrual information may be requested from the PI by the NCI Program Director for all active studies when deemed appropriate. Insufficient patient accrual or progress, or noncompliance with the terms of award, including these Terms of Cooperation, may result in a reduction of budget, withholding of support, suspension or termination of the award. Responsibilities of Awardees It is the responsibility of the PI 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 studies. The PI shall, with CTEP assistance, develop Phase I protocols for clinical cancer research in accord with its research interests, abilities and goals and in accord with research goals established at the Phase I strategy meetings and submit them to CTEP (either to the LOI Coordinator or to the CTEP Protocol and Information Office, the receiving office for all protocols sent to CTEP) for review as appropriate prior to their implementation. 1. Protocol Development The PI will designate a Protocol Chairperson for each proposed study. The PI will be responsible for communication with the appropriate CTEP staff. The PI, with CTEP assistance, is responsible for coordinating protocol development, protocol submission, study conduct, quality control, drug ordering, data management and analysis, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations and protocol and performance reporting. 2. Protocol Submission The PI will submit protocols to the CTEP Protocol and Information Office in a timely fashion for review and approval by NCI. All protocols should be preceded by a written Letter of Intent (LOI) from the PI to the CTEP LOI Coordinator declaring interest in conducting a particular study. The LOI will describe the hypothesis to be investigated, the general design of the contemplated trial plus relevant information on accrual capabilities to document feasibility. 3. Study Conduct and Monitoring The awardee institution is responsible for ensuring accurate and timely knowledge of the progress of each study through: a. establishing data management support capabilities that ensure that data will be submitted via electronic transfer biweekly to NCI's Clinical Trials Monitoring Service (CTMS). This data includes: registration of each patient entered onto a Phase I protocol within the previous two week period, and all data obtained on each registered patient within the previous two weeks as specified by the NCI/DCT Standard Case Report Form and the individual protocol. b. establishing procedures for assigning dose level at the time a new patient is entered, and assuring that the required observation period has elapsed before beginning a higher dose level. c. registration, tracking and reporting of patient accrual and adherence to defined accrual goals; d. ongoing assessment of case eligibility and evaluability; e. timely medical review and assessment of patient data; f. rapid reporting of treatment-related morbidity (adverse drug reactions) and measures to ensure communication of this information to all parties; g. interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice; and h. timely communication of results of studies. 4. Data Management and Analysis The awardee institution will develop procedures to ensure that data collection and management are: (1) adequate for quality control and analysis and (2) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense. 5. Investigational Drug Management Investigators performing trials under this cooperative agreement must be NCI registered investigators (Form 1572) and will be expected to implement CTEP requirements described in the DCT Investigators' Handbook for storage and accounting for investigational agents, to abide by NCI/DHHS Drug Accountability Records (DAR) procedures, and to comply with all FDA requirements for investigational agents. 6. Compliance with Federally Mandated Regulatory Requirements The awardee institution is responsible for establishing procedures to comply with FDA regulations for studies involving investigational agents and OPRR requirements for the protection of human subjects. These procedures are: a. methods for ensuring that the awardee institution has a current, approved assurance on file with the OPRR; that each protocol is reviewed and approved by the responsible Institutional Review Board (IRB) prior to patient entry; that each protocol is reviewed at least annually by the IRB so long as the protocol is active; that amendments are approved by the IRB; that each investigator is registered with the Drug Management and Authorization Section (DMAS), CTEP with a current 1572 form on file; and that each patient (or legal representative) gives written informed consent prior to entry on study. b. a system for ensuring timely reporting of all serious and unexpected toxicities to the IDB, CTEP according to CTEP guidelines (mailed annually to all registered investigators). This may require reporting Adverse Drug Reactions (ADRs) by telephone to the IDB Drug Monitor within 24 hours of the event and requires a written report to follow within 10 working days. c. a system for ensuring that the required data is provided biweekly to the CTMS. 7. Attendance at Meetings The PI or appropriate representative(s) of the awardee institution, will attend the initial Phase I strategy meeting At the initial strategy meeting, the investigators and the NCI Program Director, assisted by other CTEP staff, will review the research plans proposed by each individual research group to ensure that they are compatible with the overall goals of the RFA, to ensure avoidance of duplication of effort and to ensure the most effective use of available resources including investigational agents. The PI or appropriate representative shall attend the semi-annual Phase I meetings to review relevant scientific information, to review progress in the clinical trials, and to review the status of newly available investigational agents in order to plan future activities. 8. Reporting Requirements Reporting requirements will be in agreement with FDA regulations and NCI procedures. Annual progress reports will be submitted to the NCI and will include at a minimum summary data on protocol performance by the awardee institution, interim reports of each activated study including specific data on patient accrual, as well as detailed reports of treatment-associated morbidity and other relevant data. 9. Publication of Data Timely publication of major findings is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgement of NCI support. The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women 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 should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and women of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, gender and 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 in the Research Plan, 1-4, AND summarized in Section 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 tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. 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 women or minorities in a study design is inadequate to answer the scientific question(s) 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 January 22, 1993, a letter of intent that includes a descriptive title of the proposed research, the name and address of the Principal Investigator, the names of other key personnel, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, 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: David R. Parkinson, M.D. Chief, Investigational Drug Branch Cancer Therapy Evaluation Program National Cancer Institute Executive Plaza North, Room 734 Bethesda, MD 20892 Telephone: (301) 496-5223 FAX: (301) 480-4663 Applicants who use express mail or a courier service are advised to follow the carrier's requirements for showing a street address. The address for the Executive Plaza North is: 6130 Executive Boulevard Rockville, MD 20852 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for cooperative agreements. These forms are available at most institutional offices of sponsored research; from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, 5333 Westbard Avenue, Bethesda, MD 20892, telephone (301) 496-7441; and from the NCI Program Director named below. The RFA label available in the application form 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 and the YES box must be marked. 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 staff involvement. 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 clear and single sided. Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Referral Officer Division of Extramural Activities National Cancer Institute Westwood Building, Room 838 Bethesda, MD 20892 Applications must be received by March 23, 1993. If an application is received after that date, it will be returned. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS A. Review Procedure Upon receipt, applications will be reviewed for completeness by the DRG and responsiveness by the NCI. Incomplete applications will be returned to the applicant without further consideration. Applications that are judged to be non-responsive will be returned by the NCI. Applications judged to be non-responsive to this RFA may be submitted as an investigator-initiated regular research grant (R01) or program project grant (P01) at the next receipt date. The application would require modification in accordance with R01 or P01 guidelines. The revised application would not be considered an application for a cooperative agreement nor would it be considered a response to an RFA. Questions concerning the responsiveness of proposed research to the RFA may be directed to program staff listed under INQUIRIES. Applications may be triaged by an NCI peer review group on the basis of relative competitiveness. The NIH will withdraw from further competition those applications judged to be non-competitive for award and notify the applicant Principal Investigator and institutional official. Those applications judged to be competitive will undergo further scientific merit review. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical review by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review will be provided by the National Cancer Advisory Board. B. Review Criteria The factors considered in evaluating the scientific merit of each application will be: 1. scientific, technical, medical significance and originality of proposed research as reflected in the protocols, research plans and strategies that address the clinical and laboratory considerations for Phase I studies using cytotoxic and biologic agents alone or in combination; evidence that the proposed scientific studies would contribute to a greater understanding of the nature of the therapeutic agent which may include but are not limited to an understanding of its mechanism of action, mechanisms of resistance, or differences among patients with respect to pharmacology or metabolism. 2. appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research including: a. adequacy of plans for the development, implementation and analysis of Phase I clinical trials b. adequacy of plans for correlative laboratory studies and evaluation of the data with respect to treatment administration or treatment outcome c. adequacy of statistical approach for correlating research studies with treatment outcomes in Phase I trials. d. adequacy of plans for effective collaboration among laboratory, clinical, and statistical investigators. e. adequacy of mechanisms for quality control, study monitoring, data management and reporting, data analysis, investigational drug management, and compliance with regulatory requirements 3. qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research including: a. experience and competence of the Principal Investigator and clinical investigators in the development, implementation and analysis of Phase I trials. b. experience in the daily management and treatment of patients with various malignant tumors and assessment of eligibility/evaluability of these patients in cancer clinical trials. c. experience of the investigators in obtaining blood and/or tissue specimens for research purposes from patients entered onto clinical trials and the evaluation of those data with respect to treatment administered or treatment outcome. d. experience in performance of laboratory/correlative studies relevant to the development of a class of anticancer therapeutic agents and evaluation of the data with respect to treatment administration or treatment outcome 4. availability of resources necessary to perform the research including: a. adequacy of the available facilities for clinical and laboratory/correlative studies, data management resources, and patient population. b. demonstration of availability of and access to appropriate numbers of patients eligible to receive defined treatments on phase I clinical trials and/or to human tissue with the associated pathological data and clinical follow-up. 5. adequacy of provisions for the protection of human subjects and the humane treatment of animals (if laboratory studies involving animals are proposed). 6. Adequacy of the plans for inclusion of women and minorities. 7. Commitment to accept provisions outlined under Terms of Cooperation. The reviewers will also judge the appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is December 1, 1994. In addition to the technical merit of the application, NCI will consider how well the applicant institution meets the goals and objectives of the program as described in the RFA, availability of resources, and balance of study populations. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA and inquiries about whether or not specific proposed research would be responsive are strongly encouraged and may be directed to the program staff listed below. The program staff welcome the opportunity to clarify any issues or questions from potential applicants. Direct inquiries regarding programmatic issues to: Dr. David Parkinson Chief, Investigational Drug Branch Cancer Therapy Evaluation Program National Cancer Institute Executive Plaza North, Room 734 Bethesda, MD 20892 Telephone: (301) 496-5223 FAX: (301) 480-4663 Direct inquiries regarding fiscal matters to: Barbara A. Fisher National Cancer Institute Executive Plaza South, Room 242 Bethesda, MD 20892 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 the Public Health Service Act, Title IV Sections 301, 410, and 411, Part A (Public Law 78-410, 42 USC 241 as amended, Public Law 99-158, 42 USC 285a) and administered under PHS grants policies and Federal Regulations at 42 CFR Part 52 and 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |