Full Text CA-97-001 PHASE I TRIALS OF ANTI-CANCER AGENTS NIH GUIDE, Volume 25, Number 40, November 22, 1996 RFA: CA-97-001 P.T. 34 Keywords: Autoimmunity Clinical Trial Chemotherapeutic Agents National Cancer Institute Letter of Intent Receipt Date: January 17, 1997 Application Receipt Date: March 12, 1997 PURPOSE The purpose of this Request for Applications (RFA) is to provide continued funding for a Phase I Clinical Trials Program to support scientifically directed Phase I trials of promising anti-cancer agents available through the National Cancer Institute (NCI) from the NCI's drug screening program or referred to NCI from other sources, (e.g., the pharmaceutical and biotechnology industry and academia); and to conduct pharmacokinetic and 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. The Cancer Therapy Evaluation Program (CTEP) of the Division of Cancer Treatment, Diagnosis and Centers (DCTDC), NCI invites cooperative agreement (U01) applications from institutions wishing to study these anti-cancer agents in Phase I Clinical Trials. Single Institution Phase I studies are preferred, although laboratory studies may be conducted by collaborators at other institutions. Strong justification and evidence of well established collaborations must be supplied for multi-institutional applications. Studies begun under a predecessor cooperative agreement may be completed under this cooperative agreement pending agreement from the NCI Program Director. The increasing number of promising new agents with diverse and novel mechanisms of action makes it desirable to continue NCI support in this area. 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 pharmacokinetics and, where possible, other laboratory correlative studies will be conducted in real-time, throughout the course of the clinical trial to facilitate optimal utilization of the data in the design and coordination of clinical trials with the agent. Applications from any one institution may focus on studies of one or more classes of agents or therapeutic approaches, reflecting the interest, expertise, and experience of the applicant investigators or a more general approach to the pharmacokinetic/pharmacodynamic evaluation of new agents may be developed. 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 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 Summary Report: Stock No. 017-001-00473-1 through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations such as universities, colleges and hospitals, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. 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 and Conditions of Award, NCI Staff Responsibilities. 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 and Conditions of Award. 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. FUNDS AVAILABLE Approximately $5,500,000 in total costs per year for five 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 approximately fifteen awards will be made. The earliest feasible start date for the initial awards will be February 1, 1998. 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. This RFA is a one-time solicitation. At this time the NCI has not determined whether or how this solicitation will be continued beyond the present RFA. If it is determined that there is a sufficient continuing program need, the NCI will either invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review or re-issue the RFA for re-competition. If the NCI does not continue the program, awardees may submit grant applications through the usual investigator-initiated grants program. RESEARCH OBJECTIVES A. Background The NCI currently holds over 200 active INDs for anticancer agents. NCI actively supports the primary development of a diverse array of anticancer therapeutic agents which originate from the NCI's preclinical Developmental Therapeutics Program as well as from academia; in these cases NCI often holds the only IND investigational new drug application). In addition, for agents derived from the pharmaceutical/biotechnology arena where NCI feels that co-development is in the best interest of improving the treatment of cancer patients, NCI may file INDs and participate in collaborative clinical development. In the latter case, NCI often promotes the exploration of important scientific questions which may not be the primary focus of market-driven industry development, either because of limited resources in the case of small companies, the need to perform combination studies with other investigational agents for which NCI holds an IND, or because of small commercial markets due to the relatively low frequency of certain human cancers. NCI support facilitates the development of these important agents and indications. The increasing number of promising new agents with diverse and novel mechanisms of action makes it desirable to continue NCI support for the study of these agents. The NCI will accelerate cancer treatment development by supporting research applications whereby clinicians and laboratory investigators can utilize their extensive experience and expertise to study investigational agents in comprehensive Phase I trials with appropriate laboratory and clinical correlations. 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. Scientific approaches will reflect the scientific interest, creativity and capabilities of participants and the agents available for study. The investigators would bring to the collaboration their specific biological and pharmacological expertise, their ideas concerning clinical investigative strategies unique to each agent, the necessary patient and investigative resources for study of the agent, and their data management and analytical abilities. 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 will sponsor (in accord with Food and Drug Administration requirements) 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, DCTDC 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. An Investigational Drug Branch (IDB) Physician is assigned to each DCTDC IND to assist in the coordination of its development. NCI sponsorship of investigational agents increases the likelihood that agents will be fully developed so that they will ultimately be broadly available for use in cancer treatment and will provide resources to accelerate this process. B. Research Goals and Scope The aims of this initiative are to: (1) provide support for Phase I trials of promising new anti-cancer agents in cancer patients; and (2) provide support for complete pharmacokinetic, pharmacodynamic, and other important laboratory correlative studies in cancer patients receiving these 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 the mediation of anti-cancer effects not only through classical 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 inhibition of tumor angiogenesis and metastasis. In addition, new strategies to overcome resistance to conventional cancer therapeutic approaches are also of interest. 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). The investigators will define scientific objectives and experimental approaches consistent with the goals of Phase I clinical trials. The investigators will select the specific NCI sponsored agents of interest in accord with their areas of scientific interest and expertise, and will develop a series of appropriate phase I trials with supporting protocol documents. The Government will have access to the data generated, will periodically review the data and may perform special analyses of the data. However, the awardees will retain custody and primary rights to their data developed under these awards. Data will be submitted to the NCI's Clinical Trials Monitoring Service at prescribed intervals. Timely publication of findings will be encouraged. Each Phase I awardee institution must have demonstrated experience in conducting Phase I Clinical Trials. Sufficient numbers of patients at the applicant institution should be available in order to allow completion of the trials in a timely manner. 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. 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 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 Phase I investigator data submissions (currently biweekly), 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 Terms of Cooperation These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardee and the NCI Project Scientist. The role of the Cancer Therapy Evaluation Program (CTEP) staff as described throughout these terms and conditions of award is to facilitate and assist 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 DCTDC as a drug sponsor as defined in CFR 21 Part 312. 1. Awardee Rights and Responsibilities It is the responsibility of the Principal Investigator (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. 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 DCTDC investigational agents. a. Protocol Development The PI shall, with CTEP assistance, develop Phase I protocols which define the scientific objectives and experimental approaches for: 1) Anticancer agents identified by the NCI's drug screening program or referred to NCI from other sources, including the pharmaceutical and biotechnology industry; 2) Anticancer agents with novel mechanisms, including but not limited to: inhibitors of angiogenesis and metastasis, differentiating agents, apoptosis-inducing agents, anti-sense oligonucleotides and related gene-specific therapeutic agents, and targeted cytotoxic agents. 3) Existing chemotherapeutic agents which, when administered with colony stimulating factors or other agents to ameliorate dose-limiting toxicities, can be given in doses substantially higher than those previously tested or which on the basis of preclinical studies might have increased anti-tumor effect in combination; and; 4) novel combination pilots of importance to CTEP's drug development program where dose, pharmacokinetic or drug interaction issues must be carefully defined. The protocols shall be conducted in accordance with the instructions in the INVESTIGATOR'S HANDBOOK, A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment, National Cancer Institute, Revised 10/93 (available from the NCI Program Director). The INVESTIGATOR'S HANDBOOK describes the procedures for: o Requirements for Protocol Development and Submission o Ordering Investigational Drugs from NCI o Responsibility for Reporting of Results to CTEP o Adverse Event Reactions o Accountability and Storage of Investigational Drugs o Monitoring and Quality Assurance The PI shall submit the Phase I protocols to CTEP (either to the Letter of Intent (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. The PI shall designate a Protocol Chairperson for each proposed study. The PI will be responsible for communication with the appropriate CTEP staff. The PI is responsible for coordinating protocol development, protocol submission, study conduct, quality control and study monitoring, 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. b. Protocol Submission Communication at the various stages of protocol development is encouraged as necessary to promote protocol development and implementation. It is recommended that protocols be preceded by a written declaration of interest in conducting a particular study from the PI using the suggested format described in the INVESTIGATOR'S HANDBOOK, Appendix VII, GUIDELINES FOR SUBMITTING LOIs - Letter of Intent/ INVESTIGATIONAL DRUG TRIAL. The LOI shall describe the hypothesis to be investigated with appropriate references or supporting data, the general design of the contemplated trial plus relevant information on accrual capabilities to document feasibility. The LOI should be sent to the CTEP LOI Coordinator who receives, logs in and schedules LOIs for review by the PRC. The PI shall submit the Phase I protocols to the CTEP Protocol and Information Office, the receiving office for all protocols sent to CTEP, for review as appropriate prior to their implementation. c. Study Conduct and Monitoring The awardee institution is responsible for ensuring accurate and timely knowledge of the progress of each study through: 1) 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/DCTDC Case Report Form and the individual protocol. 2) 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. 3) registration, tracking and reporting of patient accrual and adherence to defined accrual goals; appropriate attempts to accrue patients who fulfill NIH Guidelines for accrual of women and minorities to clinical trials with appropriate documentation and reporting of accrual as specified by NIH Guidelines; 4) ongoing assessment of case eligibility and evaluability; 5) timely medical review and assessment of patient data; 6) rapid reporting of treatment-related morbidity (adverse event reactions) and measures to ensure communication of this information to all parties; 7) interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice; and 8) timely communication of results of studies. d. Data Management and Analysis The awardee will develop procedures to ensure that data collection and management are: a) adequate for quality control and analysis; and b) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense. f. Investigational Drug Management Investigators performing trials under cooperative agreements involving a Division of Cancer Treatment, Diagnosis and Centers (DCTDC) investigational agent must be NCI registered investigators (Form FDA 1572) and will be expected to implement CTEP requirements described in the INVESTIGATORS' HANDBOOK for storage and accounting for investigational agents, to abide by NCI/HHS Drug Accountability Records (DAR) procedures, and to comply with all FDA requirements for investigational agents. g. Compliance with Federally Mandated Regulatory Requirements The awardee 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: 1) 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. 2) a system for ensuring timely reporting of all serious and unexpected toxicities to the Investigational Drug Branch, (IDB), CTEP according to CTEP guidelines (mailed annually to all registered investigators). This may require reporting Adverse Event Reactions (AERs) by telephone to the responsible IDB Physician within 24 hours of the event and requires a written report to follow within 10 working days. (See 2. NCI Staff Responsibilities for definition of responsible IDB Physician.) 3) a system for ensuring that the required data is provided biweekly to the CTMS. h. Reporting Requirements Reporting requirements will be in agreement with FDA regulations and NCI procedures. Annual progress reports will be submitted to the NCI in a non-competing continuation application 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. I. Publication of Data Timely publication of major findings is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NCI support. The NCI will have access to all data generated under this cooperative agreement, will periodically review the data and may perform special analyses of the data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies. 2. NCI Staff Responsibilities The role of the Cancer Therapy Evaluation Program (CTEP) staff as described throughout these terms and conditions of award is to facilitate and assist 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 DCTDC as a drug sponsor as defined in CFR 21 Part 312. a. Provision of NCI-sponsored Investigational Agents and Responsibilities of IND Sponsor CTEP will supply the investigational agents to be studied and will be the Sponsor for these agents. CTEP will submit Investigational New Drug Applications to the FDA permitting DCTDC to act as a drug sponsor. As a sponsor of an investigational drug, DCTDC, and specifically CTEP, is responsible for seeing that clinical trials proceed safely and rationally from the initial dose-finding studies through the definitive evaluation of the new drug in the treatment of one or more specific cancers. b. CTEP as a Scientific Resource for NCI-supported Phase I Clinical Trials Investigations An Investigational Drug Branch (IDB) Physician is assigned to each DCTDC IND agent to assist in the coordination of its development. The NCI Program Director and the responsible IDB physician 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 and/or responsible IDB Physician will advise the PI of potential studies that will be relevant to new avenues of cancer therapy. The NCI Program Director and/or responsible IDB Physician will assist the PI as appropriate in developing information concerning the scientific basis for specific trials and also will advise the PI of the nature and results of relevant trials being carried out under NCI sponsorship. The NCI Program Director and/or responsible IDB Physician 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 DCTDC. c. CTEP Assistance in Protocol Development The CTEP Protocol Review Committee (PRC), must review and approve every protocol involving DCTDC investigational agents. The PRC, which meets weekly, is chaired by the Associate Director, CTEP, and is comprised of professional staff of the DCTDC including the IDB Physicians, Clinical Investigations Branch disease coordinators, regulatory staff, pharmacy staff and ad hoc reviewers external to NCI when deemed appropriate by the PRC chairperson. The PRC will formally review the LOI. Following LOI review, the responsible IDB physician 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; d) the scientific rationale and value of the proposed study, the design, the statistical requirements; e) the projected accrual rate; f) correlative laboratory studies; and g) the implementation of the study, if indicated. The LOI mechanism is designed for preliminary review and is recommended to expedite protocol development and implementation, to avoid duplication and to facilitate agreement on study priority and design (see the DCTDC Investigator's Handbook, pp 32-35, available on request from the NCI Program Director. d. CTEP Review of Proposed Protocols 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. Following the review of the protocol by the PRC, the responsible IDB physician will provide the PI with a consensus review prepared by the IDB Physician. The consensus review summarizes the PRC review and describes required or recommended modifications and other suggestions, as appropriate. (See the 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 to the PI as a consensus review within 30 days of protocol receipt by the NCI. The NCI Program Director and/or responsible IDB Physician 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. An arbitration system, as detailed below, will be available to resolve disagreements between the NCI and the awardee. 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 below. e. Access to Data The NCI will have access to all data generated under this cooperative agreement and will periodically review the data and may perform special data analyses. Data must also 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. The awardee will retain custody of and primary rights to the data consistent with current HHS, PHS, and NIH policies. f. CTEP Involvement in Protocol Closure The NCI Program Director and/or responsible IDB Physician and the Head, Quality Assurance and Compliance Section (QACS), Clinical Trials Monitoring Branch (CTMB) will monitor protocol progress. The NCI Program Director or the responsible IDB Physician may request that a protocol be closed to accrual for reasons including: a) insufficient accrual rate; b) accrual goal met; c) poor protocol performance; d) patient safety and regulatory concerns; e) study results are already conclusive; f) emergence of new information that diminishes the scientific importance of the study question; and g) 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 to resolve disagreements between the NCI and the awardee. g. CTEP involvement in Investigational New Drug Applications 1) The NCI Program Director and/or the Chief, Regulatory Affairs Branch (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. 2). The NCI Program Director and/or 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). h. CTEP Review of Federally Mandated Regulatory Requirements The Head, QACS, CTMB will review protocols to determine if the awardee's mechanisms for meeting FDA regulatory requirements for studies involving DCTDC-sponsored investigational agents and the Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects are sufficient. These comments are incorporated into the protocol consensus review. (See Awardees Rights and Responsibilities). 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 and to produce periodic routine reports of results and special reports as necessary. For these trials, source documentation will be reviewed on-site three times per year by the CTMS. I. 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, in the study summary reports submitted via the CTEP Data Update reporting system or by CTMS reports. 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 Special Terms and Conditions of Award, may result in a reduction of budget, withholding of support, suspension or termination of the award. 3. Collaborative Responsibilities a. Phase I strategy meetings The NCI Program Director will sponsor semi-annual Phase I strategy meetings with the PIs 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. The PI will be responsible for making scientific reports at these meetings as requested by Program Staff. b. The PI shall, with CTEP assistance as described in the above terms for the NCI staff responsibilities, develop Phase I protocols. The protocols must be mutually acceptable to the PI and to the CTEP Protocol Review Committee (PRC). 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), excluding patient safety issues or regulatory compliance, between award recipients and the NCI may be brought to arbitration. An arbitration panel composed of one awardee 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, DCTDC. The arbitration procedures in no way affect the awardee's right to appeal an adverse determination under the terms of 42 CFR Part 50, Subpart D, and 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Population, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research," which was reprinted in the Federal Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting errors in the earlier publication, and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by January 17, 1997, 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: Michaele C. Christian, M.D. Division of Cancer Treatment, Diagnosis and Centers National Cancer Institute Executive Plaza North, Room 734 6130 Executive Boulevard MSC 7432 BETHESDA, MD 20892-7432 ROCKVILLE, MD 20852 (for express/courier service) Telephone: (301) 496-5223 FAX: (301) 480-4663 APPLICATION PROCEDURES A. PREPARATION OF APPLICATION Applications are to be submitted on the grant application form PHS 398 (rev. 9/96). These forms are available at most institutional offices of sponsored research; from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, E-mail ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed under INQUIRIES. 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 as well as how all of the responsibilities of awardees will be fulfilled. An application from a currently funded program will be a competitive continuation and must include a progress report, which at a minimum consists of a summary of prior Phase I activities/accomplishments, including a clear presentation of pharmacokinetic studies, pharmacodynamic correlations and results, conclusions of correlative laboratory studies and annual accrual over the funding period. A summary of accrual by gender and race and/or ethnicity to all Phase I trials (reported by trial) conducted during the project period must be provided. ALL Applicants 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 AERs 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 Clinical Research Associate/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 RFA label available in the PHS 398 (rev. 5/95) 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. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies, in one package: DIVISION OF RESEARCH GRANTS National INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express mail) At the time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute Executive Plaza North, Room 636 6130 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (for express mail) Applications must be received by March 12, 1997. 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 RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS A. Review Procedure Upon receipt, applications will be reviewed by the Division of Research Grants (DRG) for completeness and by the NCI for responsiveness. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board. The review group will assess the scientific merit of the studies using the following review criteria: 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, equipment and resources to carry out pharmacokinetic and pharmacodynamic analyses in a timely manner. c. adequacy of plans for correlative laboratory studies and evaluation of the data with respect to treatment administration or treatment outcome d. adequacy of statistical approach for correlating research studies with treatment outcomes in Phase I trials. e. adequacy of plans for effective collaboration among laboratory, clinical, and statistical investigators. f. 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 pharmacokinetic/pharmacodynamic 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 pharmacokinetic/pharmacodynamic 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 February 1, 1998. 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. Michaele C. Christian Division of Cancer Treatment, Diagnosis and Centers National Cancer Institute Executive Plaza North, Room 734 6130 Executive Boulevard, MSC 7432 BETHESDA, MD 20892-7432 Telephone: (301) 496-5223 FAX: (301) 480-4663 Email: christim@DCT.NCI.NIH.GOV Direct inquiries regarding fiscal matters to: Crystal Wolfrey National Cancer Institute Executive Plaza South, Room 243 6120 Executive Boulevard MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, ext. 256 FAX: (301) 496-8601 Email: WOLFREYC@GAB.NCI.NIH.GOV 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. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routing education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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. |