Full Text CA-95-017 CANCER THERAPY WITH BIOLOGICAL RESPONSE MODIFIERS NIH GUIDE, Volume 24, Number 33, September 22, 1995 RFA: CA-95-017 P.T. 34 Keywords: Cancer/Carcinogenesis Biological Response Modifiers National Cancer Institute Letter of Intent Receipt Date: October 30, 1995 Application Receipt Date: January 4, 1996 PURPOSE The Division of Cancer Treatment (DCT), National Cancer Institute (NCI), invites applications to establish cooperative agreements for Cancer Therapy with Biological Response Modifiers (CATBRMs), to translate promising preclinical results into innovative clinical approaches to such therapy. 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 Request for Applications (RFA), Cancer Therapy With Biological Response Modifiers (CATBRMs), 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 and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Involvement of intramural NIH personnel is limited as described under the "RESEARCH OBJECTIVES," C, Composition of a CATBRM Group. Women, members of racial/ethnic minority groups and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be 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. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award." This RFA is a reissuance of RFAs CA-92-01 and CA-92-28, which were issued under the title, "Clinical Trials of Cancer Therapy with Biological Response Modifiers (CATBRMs)." Applicants who did not apply under the previous RFAs, who applied but did not receive an award, and those who have received an award, are encouraged to respond to this RFA. However, this reissued RFA is a one-time solicitation. Future unsolicited competing renewal applications will compete as research project applications with all other investigator-initiated applications. Applicants who are past recipients of CATBRM awards must include results of the work supported by those awards, including scientific progress, and how the awardees have met the Terms and Conditions of Award. FUNDS AVAILABLE The NCI plans to make up to four awards for project periods up to four years, and has set aside 1.0 million dollars total costs for the initial year's funding. The total funding level and number of awards to be made is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon continuing availability of funds. The earliest possible starting date for the initial annual period will be July 1, 1996. RESEARCH OBJECTIVES Background Success with biological response modifier (BRM) therapy of cancer has been limited, and the NCI seeks to foster new approaches. Many new BRMs, e.g., growth and differentiation factors; cytokines and colony-stimulating factors; murine, chimeric, and human monoclonal antibodies; and targeting agents such as immunotoxins, fusion proteins, and antibody fragments, have become available for clinical trials. Other agents now under preclinical study may be of interest as BRMs. Development of new technologies (such as gene transfer), and identification of tumor antigens, have led to a resurgent interest in cancer vaccines. Discoveries in cellular immunology are also prompting new approaches to adoptive immunotherapy and bone marrow transplantation, in an attempt to improve the antitumor effects of cytotoxic cells. At the same time, it is clear that much remains to be learned about the relationship between clinical and other biological effects of BRMs, e.g., potential mechanisms of action, appropriate parameters for monitoring of patients, and development of endpoints that may predict clinical benefit. Frequently, attempts to translate promising scientific developments into early clinical trials encounter one or more common obstacles, including lack of availability of clinical-grade agents, difficulties in completing IND-directed studies or preparing an IND, and others. With this RFA, the NCI seeks to assist BRM translational research by teams of clinical and preclinical investigators with the unique technical capabilities to study new agents in innovative clinical trials and to address hypothesis-driven issues of mechanisms of action. The "Research Goals and Scope" of this RFA require a novel plan for clinical study of a given new agent or agents, adequately supported by prior preclinical and, if available, clinical results. The application must describe how its objectives are in accord with the applicant's own interests and experience. The applicant must provide evidence that the investigational agent(s) proposed for study are available for development to a clinical trial. A statement of the type of assistance sought from the NCI and a detailed outline of, or a full protocol for, an initial clinical trial must also be included. The NCI will facilitate the institution of a peer-reviewed, investigator-initiated trial, participating as outlined in the section entitled "SPECIAL REQUIREMENTS," A., Terms and Conditions of Award. Each CATBRM study group will be composed of: a Principal Investigator; one or more laboratory programs, each headed by a Program Leader, with the demonstrated expertise to design and carry out assays for the appropriate patient monitoring and other associated preclinical studies; one or more clinical programs, each headed by a Program Leader, with demonstrated expertise in conducting clinical trials of BRMs; and the NCI Program Director. The application may include investigators from one or more domestic or foreign academic, nonprofit, and/or commercial institutions. Awards under this RFA may also be a way to support the development of agents that have arisen from research supported by the National Cooperative Drug Discovery Groups (NCDDGs), P01s, R01s, R29s, R03s, or other grant mechanisms. For this RFA, a BRM is defined as: An agent or approach intended to modify the relationship between tumor and host by modifying a host's biological response to tumor cells, with resultant therapeutic benefit. This includes: agents or approaches that utilize or modify immunological mechanisms; naturally occurring or recombinantly produced regulatory molecules (e.g., cytokines, growth or differentiation factors); and monoclonal antibodies and their derivatives. (See B below, Definitions.) In responding to this RFA, applicants should propose clinical trials of BRM agents or strategies as so defined, where the focus of study is the testing of a biologic hypothesis. Generally, it is envisioned that this will be done in the context of small pilot clinical trials. Prospective applicants who plan to study agents that are not BRMs as defined, who plan large randomized clinical trials or who plan trials solely to study issues of safety and efficacy apart from any other biologic hypothesis, will be referred to other NCI programs supporting clinical trials for cancer therapy. Definitions STUDY GROUP FOR CLINICAL TRIALS OF CANCER THERAPY WITH BIOLOGICAL RESPONSE MODIFIERS (CATBRM STUDY GROUP) - A group consisting of a single Principal Investigator (who may also be a Program Leader); one or more laboratory programs, each headed by a Program Leader, with the demonstrated expertise to design and carry out assays for the appropriate monitoring of clinical trial subjects; one or more clinical programs, each headed by a Program Leader, with demonstrated expertise in conducting clinical trials of BRMs and the NCI Program Director. Working under the guidance and direction of the Principal Investigator, the CATBRM study group (also referred to simply as a "study group" or a "group" in this RFA) pursues the common goal of the novel clinical development of new agents, regimens, or strategies for therapy of cancer with BRMs. Coordinated through the Principal Investigator, the CATBRM study group will employ a research plan and budget which clearly delineates the clinical and laboratory components of both the plan and the budget. CLINICAL PROGRAM - A research component of the overall group, with the expertise and experience to conduct clinical trials of BRMs based on the latest scientific developments. LABORATORY PROGRAM - A research component of the overall group, with the expertise and experience to carry out assays designed to investigate mechanisms of action of clinical BRM regimens, and other related preclinical studies appropriate to the group's overall scientific plan. PARTICIPATING INSTITUTION (PARTICIPANT)- All institutions and/or individual investigators, both funded and unfunded, who participate in the work of the CATBRM group or collaborate with the group. BIOLOGICAL RESPONSE MODIFIER - An agent or approach intended to modify the relationship between tumor and host by modifying a host's biological response to tumor cells, with resultant therapeutic benefit. This includes: agents or approaches which utilize or modify immunological mechanisms; naturally occurring or recombinantly produced regulatory molecules (e.g., cytokines, growth or differentiation factors); and monoclonal antibodies and their derivatives. CLINICAL INVESTIGATIONS LEADER - An M.D. or D.O., designated on the initial application, who leads the design and conduct of the clinical trial(s) conducted by the group. The Principal Investigator, if an M.D. or D.O., may also be the Clinical Investigations Leader. PROGRAM LEADER - The director of one of the Clinical or Laboratory Programs of the group. The Principal Investigator may also be a Program Leader. NCI PROGRAM DIRECTOR - An extramural Program Director of the Biological Resources Branch, Biological Response Modifiers Program (BRMP), Division of Cancer Treatment (DCT), NCI, designated by NCI, who provides guidance for the overall CATBRM program within the NCI, and who acts as NCI Coordinator for each CATBRM group, facilitating the role of NCI in the group. Composition of a CATBRM Group A Principal Investigator and, if necessary as outlined above, a Clinical Investigations Leader; One or more Clinical Programs, each headed by a Program Leader, each experienced in clinical oncology, clinical immunology and the conduct of clinical trials of BRMs for the treatment of human cancer; One or more Laboratory Programs, each headed by a Program Leader, each with demonstrated expertise in scientific disciplines necessary to design and conduct laboratory monitoring assays and other related preclinical investigations; and The NCI Program Director, who coordinates NCI involvement in the study group. The Principal Investigator, in addition to providing scientific and administrative leadership, may also be a Program Leader. All Program Leaders will be directly responsible to the Principal Investigator. The formation of the group, the application in response to this RFA, the overall management of the group, and the allocation of funds to the various Clinical and Laboratory Programs based on performance and overall group needs at any given time will be the responsibility of the Principal Investigator and the applicant institution in accordance with PHS policies. The specific makeup of the group's Clinical and Laboratory Programs, and the specific disciplines represented, should depend on the talents required to accomplish its scientific and technical objectives as perceived by the Principal Investigator and Program Leaders. The major consideration in structuring a CATBRM group should be the full mobilization of the expertise necessary to accomplish the group's research goals. While the specific makeup of different groups may vary, each group's Clinical and Laboratory Programs, when taken together, must include all necessary expertise for the achievement of its research goals. An individual scientist or clinician may be proposed as a Principal Investigator or a Program Leader in more than one application. If so, the Principal Investigator must demonstrate in the application that there is no scientific or budgetary overlap or proprietary conflict with each individual's proposed activities. Likewise, individuals currently receiving funding via contracts, grants, or cooperative agreements may be funded under this RFA as long as there is no scientific or budgetary overlap or proprietary conflict in funded activities. An NIH intramural scientist may participate in a CATBRM group as a collaborator or consultant, but may not be a Program Leader or receive salary, equipment, supplies, or other remuneration from this program. The intramural scientist must provide a letter of commitment and a current curriculum vitae, and obtain appropriate NIH clearances prior to submission of the application. The Principal Investigator must incorporate into the application, in the usual format, a full description of the collaborative project, including technical details and methodology. The participation of an intramural scientist is independent of and unrelated to the role of the NCI Program Director as described under "SPECIAL REQUIREMENTS," Terms and Conditions of Award. A CATBRM group may include members from a single institution or a number of institutions, depending on the specific goals of the group. While a minimum of one Clinical and one Laboratory Program per group is necessary, there are no limits on the number of Programs in a group. In preparing applications, however, prospective Principal Investigators should keep in mind that effective, efficient cooperation can be difficult in groups with more than a few Clinical and Laboratory Programs. In addition, very large groups may require budgets large enough to be a limiting factor in funding decisions. A CATBRM group may include one or more foreign members or may consist entirely of investigators or programs located outside the United States. Research Goals and Scope The development of novel approaches to the treatment of human cancer with BRMs, employing new agents, concepts, or treatment strategies. The clinical testing of such approaches by the conduct of one or more related, well-designed clinical trials with BRMs. Exploration of mechanisms of antitumor effect and resistance, and of the effects of modifications designed to alter these to clinical and biologic advantage. Observation of clinical effects (e.g., tumor responses) of the treatment regimen, and, where appropriate, correlation of these with other biologic endpoints. SPECIAL REQUIREMENTS The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s), as well as the institutional official at the time of award. Terms and Conditions of Award 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 supports and/or stimulates the recipient's activity by involvement with the awardee as a partner, but does not 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(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Program Staff. A. Awardee Rights and Responsibilities 1. Protocol Development It is anticipated that decisions regarding protocol development will be reached by consensus of the group, under the leadership of the Principal Investigator. The Principal Investigator (or, if required, the Clinical Investigations Leader) shall designate a single Protocol Chairperson for each proposed clinical trial. Group protocols using investigational agents sponsored (i.e., for which the IND is held) by the Division of Cancer Treatment (DCT), NCI must be developed in accordance with the instructions in the NCI INVESTIGATOR'S HANDBOOK. The INVESTIGATOR'S HANDBOOK (available directly from the Cancer Therapy Evaluation Program [CTEP] or through the NCI Coordinator) describes, in accordance with agreements between NCI and the Food and Drug Administration (FDA): o Requirements for Protocol Development and Submission o Ordering Investigational Drugs from NCI o Responsibility for Reporting of Results to NCI o Adverse Event Procedures o Accountability and Storage of Investigational Agents o Monitoring and Quality Assurance 2. Coordination of Group Activities The Principal Investigator is responsible for coordinating all group activities, and for communication with the NCI Coordinator. 3. Protocol Submission The Principal Investigator will submit all group protocols to the NCI Program Director for review and approval. The NCI Program Director will coordinate any required NCI review (e.g., review by CTEP if the protocol is to be conducted under an NCI-held IND), and assure that the results of such review are communicated to the Principal Investigator. The Principal Investigator will be responsible for communicating the results of the protocol review to the group's Program Leaders and participating institutions. 4. Group Compliance with Federally Mandated Regulatory Requirements The awardee institution retains the primary responsibility for ensuring that the group is in compliance with all Food and Drug Administration (FDA) regulatory requirements for studies involving investigational agents and NIH policies applying to the conduct of research involving human subjects. Participants are required to follow group procedures for complying with the federally mandated regulations. a. The group must be able to demonstrate that each participating institution has a current, approved assurance number on file with the NIH Office of Protection from Research Risks (OPRR). b. The group must be able to demonstrate that each protocol and informed consent is approved by the responsible Institutional Review Board(s) (IRBs) prior to patient entry, that each ongoing protocol is reviewed by the IRB(s) at least annually, and that each amendment of a protocol or informed consent is approved by the IRB(s). c. The group must be able to demonstrate that each clinical investigator has provided the IND sponsor with a current FDA form 1572 and a copy of the investigator's current curriculum vitae. d. The group must be able to demonstrate that each patient (or each patient's legal representative) gives written informed consent prior to entry on study. e. The group must assure timely reporting of all serious and unexpected toxicities (adverse drug reactions, also referred to as ADRs) in accordance with FDA requirements, and for informing the NCI Program Director of ADRs. For trials conducted under NCI-held INDs, this includes reporting of ADRs to the Investigational Drug Branch (IDB), CTEP, according to CTEP guidelines. f. For trials conducted under NCI-held INDs, the group must have a method of providing, upon request of the NCI, summaries of toxicity, efficacy, pharmacokinetic, and other laboratory data for inclusion in DCT's annual report to the FDA for each investigational agent it sponsors. g. For trials conducted under NCI-held INDs, the group must have a method for submitting comprehensive study data to CTEP's Clinical Trials Monitoring Service (CTMS) every two weeks, according to CTMS guidelines. The decision to use CTMS monitoring will be NCI's. h. For trials conducted under NCI-held INDs, the group must implement the NCI requirements for storage and accounting for investigational agents. 6. Quality Control and Study Monitoring a. Quality Control The awardee institution is responsible for ensuring that the group establishes mechanisms for quality control of therapeutic and diagnostic modalities employed in its trials. Participants are required to follow group procedures for quality control. These procedures must be reviewed by the NCI Coordinator prior to initiation of clinical trials by the group. b. Study Monitoring The group will establish mechanisms for study monitoring. Participants are required to follow group procedures for study monitoring. The awardee institution is responsible for assuring the group maintains accurate and timely knowledge of the progress of each study through: o Establishing procedures for assigning each new patient to a treatment group at the time of entry to the study; o Assuring that each Clinical and Laboratory Program is maintaining verifiable data, conducting studies in compliance with the approved clinical protocols, and complying with regulatory requirements for the protection of human subjects and investigational agent accountability; o Tracking and reporting of patient accrual and adherence to defined accrual goals; o Ongoing assessment of case eligibility and evaluability; o Timely medical review and assessment of patient data; o Rapid reporting of treatment-related morbidity (adverse drug reactions), in accordance with regulatory requirements and measures to ensure communication of this information to all parties; and o Timely communication of results of studies. c. Quality Assurance and Quality Control of Data The awardee must assure that each Clinical and Laboratory Program maintains accurate, verifiable data. If there is any indication of a pattern of non-compliance with protocol or regulatory requirements, or a finding of possible alteration of data, these findings must be reported immediately by telephone, and before close of business the next business day by FAX, to the NCI Coordinator. 7. Data Management and Analysis The group must establish and implement mechanisms for data management and analysis that ensure that data collection and management are: (1) adequate for quality control and analysis; (2) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (3) sufficiently uniform across the participating institutions. Participants are required to follow group procedures for data management and analysis. Data from protocols conducted under NCI-held INDs must also be available for external monitoring, in accordance with an agreement between the NCI and the FDA governing the NCI's responsibilities as a drug monitor. 8. Protocol Closure If the group wishes to close accrual to a study prior to meeting the initial accrual goal, the Principal Investigator must submit available results and other documentation to the NCI Coordinator for review and concurrence. The NCI Program Director shall submit any NCI request for protocol closure (according to the guidelines given below, under "NCI Staff Responsibilities"), with the reasons for the request, in writing to the Principal Investigator. If the group wishes to continue patient accrual, the Principal Investigator or the Clinical Investigations Leader must submit a written justification to the NCI Program Director for NCI review and approval. Without NCI approval, the group may not expend NCI funds for additional patient accrual to the protocol proposed for closure. Regulatory issues, such as those affecting patient safety, may require suspension of protocol accrual, or changes in the conduct of a protocol. The group must comply fully with any suspension of accrual or other protocol modification mandated by federal regulatory officials. The awardee institution retains the primary responsibility for assuring group compliance with federally-mandated regulatory requirements. 9. Protocol/Progress Reporting Requirements Reporting requirements will be in agreement with FDA regulations and NCI procedures. Annual progress reports shall be submitted to the NCI, and included in the non-competing research application. The report will include summary data on protocol performance by each participating institution, specific data on patient accrual, detailed reports of treatment associated morbidity, and other data deemed relevant by the Principal Investigator. The report must also document the number of women and ethnic minority patients enrolled on the group's clinical trials. In addition, quarterly data summaries must be provided as described above for trials of agents for which NCI holds the IND. 10. Adverse Event Procedures In order to be compliance with FDA regulations, all recipients of NCI support for clinical trials, including groups and institutions responsible for coordinating and monitoring such trials, must promptly notify the NCI and any other sponsors of the trial of adverse events (i.e., adverse drug reactions) according to directions provided in the adverse event reporting section of the protocol. The awardee shall notify all funded or unfunded institutions/investigators participating in this project about the above requirement and about the institutions'/investigators' responsibility to report adverse events as specified in the protocol. The awardee shall promptly notify the NCI Coordinator and, for DCT-sponsored investigational agents, the appropriate Drug Monitor of the Investigational Drug Branch, CTEP of serious or life-threatening events, as instructed in the protocol. 11. Performance Review The group shall establish and follow policies and procedures for assessing performance of its members and collaborators, with particular attention to accrual of adequate number of eligible patients onto CATBRM trials, timely submission of required data, conscientious observance of protocol requirements, preparation of manuscripts for publication, and participation in group leadership. Should the Progress Review process indicate poor performance by a participating institution, the awardee institution may request NCI approval to replace the institution. 12. Procedures in the Event of Scientific Misconduct If a duly authorized governmental or institutional body issues a final determination that scientific misconduct has occurred or if the awardee determines that other events have occurred which have significantly affected the quality or integrity of the group data or patient safety, the awardee is responsible for notifying the NCI Coordinator, the collaborating investigators, the appropriate Institutional Review Boards (IRBs), and other sponsors of the affected work. The awardee is also responsible, if the events described above have occurred, for ensuring that submitted but unpublished abstracts and manuscripts are corrected, if possible. If publication deadlines have passed or if abstracts and/or manuscripts containing the affected data have already been published, the awardee is responsible, within 90 days of learning of the event(s) significantly affecting the quality of the group data or patient safety, for submitting to NCI a re-analysis of the results deleting the false or otherwise unreliable data, and disclosing within the text the reason(s) for the reanalysis. The awardee must submit the reanalysis for publication. The NCI may disseminate information about the reanalysis as broadly as it deems necessary. The awardee must use its best efforts to notify all scientists, research laboratories, and other organizations to which the awardee has sent research materials affected by false or otherwise unreliable data. True copies of data files and other supporting documentation from studies affected by scientific misconduct or other findings affecting the quality or integrity of data or patient safety shall be made available to the NCI in a timely manner upon the request of the Grants Management Officer, NCI. The NCI reserves the right to reanalyze, to publish, or to distribute its analyses of these data when it is in the interest of public health. Prior to release, publication or distribution of such analyses, the NCI will provide such analyses to the awardee. 13. Data Files Available to NCI Upon Request Upon the request of the Grants Management Officer, NCI, true copies of data files and supporting documentation for all NCI- supported protocols that have a major impact on patterns of care, as determined by the NCI, shall be made available to the NCI in a timely manner. 14. Notification of Patients by the Awardee During Patient's Lifetime In order for there to be an appropriate response in the event the NCI determines, either while a protocol is active or (if relevant) during the lifetime of the subjects following protocol closure, that a medically important toxicity or side effect is associated with protocol-directed treatment or that the medical care of one or more subjects may have been compromised by scientific misconduct or other finding affecting the integrity of the data or patient safety at the awardee institution or at a third-party institution, funded or unfunded, the awardee shall assure that the institution(s) responsible for these subject(s') accrual, whether funded or unfunded, will have procedures in place to: (i) contact each subject individually at his or her last known address on file with the institution and which give each subject contact appropriate information and the right to communicate with an appropriate institutional representative and, in the event of misconduct, to meet with a physician not connected with the clinical trial or study in which the subject has participated; and (ii) encourage subjects to notify the institution of any changes of address. The procedure must provide for informing the subjects fully of: the consequences of the toxicity or misconduct for their care and well-being, if any, and the availability of follow-up; and their opportunity to examine any portion of their medical records relevant to the potential effect of the toxicity or side effect upon them or that may be affected by scientific misconduct or other findings affecting the quality or integrity of the data or patient safety. It is understood that under regulations at 45 CFR Section 74.53, NCI has a right of access to research records pertinent to the NCI funding. In exceptional circumstances, such as a public health emergency, the institutions will be required to provide subject names and treatments to the NCI in a format which allows direct notification of the patient by the NCI. 15. Attendance at Meetings The Principal Investigator, Program Leaders, and the NCI Program Director will meet at least once a year, at a site mutually agreed upon by the Principal Investigator and the NCI Program Director. The purpose of this meeting will be to review progress, plan and design research activities, and establish priorities. Because NCI travel funds are limited, the group's budget should assume that the annual meeting will be held at NCI, and should include funds for travel of group members to the meeting. In consultation with the NCI Program Director, the Principal Investigator may call more frequent meetings. The Principal Investigator will be responsible for scheduling the time and place of group meetings. A critical determinant of group success will be the degree of communication among its members. Therefore, additional informal meetings among all participants as well as regular telephone and written communication is encouraged. 16. Publication of Data Timely publication of major findings is encouraged. Publication or oral presentation of results obtained under this Cooperative Agreement will require appropriate acknowledgement of the NCI support. The Government, via the NCI Program Director, shall have access to all data generated under this Cooperative Agreement and may periodically review the data. The awardee shall retain custody of and primary rights to the data, consistent with current HHS, PHS, and NIH policies. B. NCI Staff Responsibilities As described throughout these Terms and Conditions of Award, the role of the NCI will be to assist and facilitate, not to direct, group activities. 1. NCI as a Scientific Resource for CATBRM Group Activities The NCI will designate a Program Director to guide the overall CATBRM program with the NCI. The NCI Program Director will also coordinate and facilitate NCI's role in each group. The NCI Program Director, and other NCI staff at the request of the NCI Program Director, will serve as a resource available to the group for specific scientific information with respect to treatment regimens, clinical trial design, investigational agent management, and regulatory issues. The NCI Program Director will assist the group, as appropriate, in developing information concerning the scientific basis for specific trials. The NCI Program Director will advise the group of potential studies relevant to new approaches to cancer therapy in the area of the group's interest and expertise, and will facilitate interactions between the group and other investigators in the field (e.g., through seminars and conferences). Decisions requiring NCI approval will be obtained through the NCI Program Director, who will also ensure that required approvals from other NCI components are sought in a timely fashion and obtained. 2. Protocol Development While the CATBRM group's initial clinical protocol will have been developed as part of the application submitted to peer review, it is likely that the group will develop subsequent protocols within the objectives approved by peer review. NCI Program Director will assist in developing such protocols by providing, as appropriate: (1) information about concurrent clinical trials in the group's area of research; (2) information about additional investigational agents relevant to the group's research goals; (3) assistance in applying additional government resources; and (4) comments on the scientific rationale, design, statistical requirements, and implementation of the proposed protocol. All group protocols for which government funds from this cooperative agreement are expended will be subject to these Terms and Conditions of Award. 3. Review of Proposed Protocols Awardees will conduct clinical protocols in accordance with the research objectives and methods approved by peer review. All protocols and protocol amendments must be submitted to the NCI Program Director for NCI review and approval. NCI will review protocols to insure they are within the scope of peer review. NCI will also review all protocols for safety considerations, as required by federal regulatory requirements. The NCI Program Director will coordinate and facilitate the review and approval process. The NCI will not provide investigational drugs or permit expenditure of NCI funds for a protocol that has not been approved according to the above procedures. The NCI Program Director will assist the group in developing any protocol revisions necessary to permit NCI approval of the protocol. 4. Review of Quality Control and Study Monitoring The NCI Program Director will coordinate any necessary NCI review and approval of quality control and study monitoring mechanisms. NCI will provide advice, as required, regarding these mechanisms. 5. Review of Data Management and Analysis The NCI Program Director will coordinate any necessary NCI review of the group's mechanisms for data management and analysis. When it deems it appropriate, NCI will make recommendations to ensure that data collection and management procedures are: (1) adequate for quality control and analysis; (2) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (3) sufficiently uniform across the participating institutions. The NCI will have access to all data although they remain the property of the awardee institution. Data from protocols conducted under NCI- held INDs must also be available for external monitoring, in accordance with an agreement between the NCI and the FDA governing the NCI's responsibilities as a drug monitor. 6. Protocol Closure The NCI Program Director may request that a CATBRM protocol be closed to further patient accrual for the following reasons: (a) the protocol's accrual goal has been met; (b) there has been an insufficient accrual rate; (c) there has been poor protocol performance; (d) changes in drug availability make protocol completion unlikely; or (e) for patient safety concerns. The NCI Program Director will submit any such request for protocol closure, with the reasons for the request, in writing to the Principal Investigator. If the group wishes to continue patient accrual, the Principal Investigator or the Clinical Investigations Leader must submit a written justification to the NCI Program Director for NCI review and approval. Without NCI approval, the group may not expend NCI funds for additional patient accrual to the protocol proposed for closure. 7. Involvement in Investigational Drug Management INDs for group trials may be held by the NCI, by a member of the group, or by an appropriate third party (such as the drug manufacturer, if not a member of the group). IND arrangements will be established in discussions between the Principal Investigator and the NCI Program Director, who will make recommendations, as required, regarding IND filing. The NCI must approve in advance any redistribution, outside the group, of biological and chemical materials received from the Government; and any dissemination of research findings resulting from the use of such materials so redistributed. The NCI Program Director will, in such instances, be responsible for assuring that any required approvals from other NCI officials are obtained. When the NCI is to file the initial IND or cross-file to an existing IND for an agent to be studied by a group, the NCI Program Director will coordinate NCI assistance (e.g., facilitating the completion of any necessary agreements between drug suppliers and NCI, or advising the Principal Investigator of FDA-mandated specific requirements and changes in requirements concerning investigational drug management). 8. Review of Compliance with Federally Mandated Regulatory Requirements The NCI Coordinator will review the study group's mechanisms for meeting FDA regulatory requirements for investigational agents, and OPRR requirements for the protection of human subjects, and will determine whether review and approval by the NCI regulatory affairs officials is also required. If so, the NCI Coordinator will facilitate that review and approval. 9. Review of Progress Performance of the group will be reviewed at least annually by the NCI Program Director on the basis of the group's annual reports and other data summaries. In addition, periodic accrual information may be requested from the group by the NCI Program Director for all active protocols when deemed appropriate. Insufficient patient accrual, progress, or noncompliance with the Terms and Conditions of Award, may result in a reduction in budget, withholding of support, suspension, or termination of award. 10. Assistance with cGMP Production of Investigational Agents Upon recommendation of the NCI Program Director, the NCI may produce investigational agents for a group, under current Good Manufacturing Practice (cGMP) conditions, in its Monoclonal Antibody/Recombinant Protein production facility (MARP). Production of investigational agents in the MARP will be contingent upon NCI review of the project's feasibility and costs, and will require approval by the Decision Network Committee (DNC) of the Division of Cancer Treatment, NCI. 11. Use of Other NCI Resources in Support of Group Activities Upon recommendation of the NCI Program Director, the NCI may make limited use of its contract based resources in support of group research activities. Use of such resources may be considered on an occasional basis, at the NCI's discretion, within its budgetary and programmatic constraints. C. Collaborative Responsibilities Membership in the Group Group membership includes the Principal Investigator, the Clinical Investigations Leader, the Program Leaders and the NCI Program Director. The Principal Investigator will be responsible for communication with NCI, through the NCI Program Director. In no case will changes of Principal Investigator, Program Leaders, Clinical or Laboratory Programs, or participating institutions be made without prior approval from the NCI. Such approval may be sought either in the application for continuation (PHS 2590, rev. 9/91) or during the course of the budget period. In the latter case, the procedure for requesting prior approval is described in the "Methods for Grantees to Request Approvals," PHS Grants Policy Statement, page 8-5. Failure of the awardee institution to propose an acceptable replacement for any of the above changes, or to demonstrate to the satisfaction of the NCI that the group's research can be completed in an appropriate and timely fashion, will result in withholding of support, suspension, or termination of this award. D. Arbitration Any disagreement between award recipients and NCI on scientific or programmatic matters (within the scope of the award) may be brought to arbitration. In such instances, an arbitration panel will be formed, consisting of one CATBRM group nominee, one NCI nominee and a third member, chosen by the other two, with expertise in clinical trials of BRMs. The panel will review the NCI 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 CATBRM group will not expend NCI funds to conduct any part of any NCI-disapproved CATBRM study unless the NCI disapproval has been modified by this arbitration process. Drug Information/INDs/Drug Supply A. Patent and license status of agent(s) proposed for study. Since applicants are likely to propose studies with agents in early development, it is essential that each application address the patent/license status of the agent(s) proposed for study. Each applying group is encouraged to employ the specific patenting/licensing arrangement relevant to its application, but must include this information (with any supporting documents) with the application. If a patent/license already exists or is pending for an agent, the application should so state and identify the patent/license holder. A letter, signed by the Principal Investigator and each Program Leader, recognizing the patent/license holder and status, must be submitted to the Scientific Review Administrator, Division of Extramural Activities, NCI prior to peer review. If patent/license coverage does not already exist for a proposed study agent, or if new patents/licenses (e.g., use patents) are to be filed, the application must include a description of procedures for obtaining patent/license coverage for each such agent. This is essential to avoid patent/license disputes from delaying performance of awards by successful applicants. Procedures must also be described for resolution of legal problems within the group, should they arise. A formal agreement to these procedures, signed and dated by the organizational official authorized to enter into patent/license arrangements for each group member and member institution, must be submitted to the Scientific Review Administrator, Division of Extramural Activities, NCI prior to peer review. B. IND status of agent(s) proposed for study. Each application must address the Investigational New Drug (IND) application status for each agent proposed for study. Applicants are encouraged to propose the IND arrangement most appropriate to the goals of their applications. INDs for CATBRM clinical trials may be held by the applicant, or by the supplier of the agent. Alternatively, when desirable to facilitate the conduct of the clinical trial, the NCI may hold the IND or cross-reference an existing IND. In some cases, it may be permissible under federal regulations for group trials to be conducted without an IND. In such cases, primary responsibility for insuring that all applicable federal regulations are met rests with the awardee. If an IND already exists for an agent, the IND number and the identity of the IND holder should be included in the body of the application. For any agent for which an IND does not exist, the application must include enough information to demonstrate that an IND will be obtained in a timely fashion, or to justify proceeding without an IND. This information should include a description of currently available preclinical data for the agent; a list of additional preclinical studies which remain to be done in support of IND filing; and the anticipated date of IND filing. o In addition, the application should demonstrate that INDs for all agents to be used in the initial clinical trial are likely to be available in time to allow patient accrual to begin within 18 months of the date of award. o The application should also demonstrate that INDs for agents to be used in subsequent clinical trials are expected to be available early enough that continuous patient accrual to clinical protocols may be expected throughout the award period. o A group may conduct a trial without an IND only after demonstrating that all applicable FDA requirements will be met, consistent with the above guidelines. C. Supply of agent(s) for clinical trials. Each application must describe the steps the applying group will take to insure adequate supplies of agents for the clinical trials proposed. Depending upon an applicant's particular circumstances, such information may include a discussion of mechanisms of procuring agents, timetables for production of agents, or evidence of industry collaboration. If agents are to be obtained from pharmaceutical companies, individuals, or other outside parties, letters of support from those companies should be included with the application. Applicants who propose obtaining agents from the NCI must discuss their plans with the NCI prior to submitting an application. 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 Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. Investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by October 30, 1995, a short letter of intent that includes a descriptive title of the proposed research, the name, address and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, 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 a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and to avoid conflict of interest in the review. Letters of intent are to be sent directly to: Jon T. Holmlund, M.D. Division of Cancer Treatment National Cancer Institute NCI-FCRDC, Building 1052, Room 253 Frederick, MD 21702-1201 Telephone: (301) 846-1098 FAX: (301) 846-5429 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used. This form is available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3032, Bethesda, MD 20892-7762, telephone 301/710-0267; and from the program administrator listed under INQUIRIES. This RFA requires the submission of a single application for the proposed CATBRM group. Because of the special requirements of this RFA, additional written instructions regarding format will be provided by the program administrator listed under INQUIRIES. Potential applicants are urged to obtain the "Special Instructions to Applicants" to avoid omitting essential information and to expedite review. If required information is not contained within the application, the application will be returned without review. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. 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. On line 2 of the face page of the application form, the YES box must be marked, the RFA number (RFA CA-95-017) must be included, and the Title must be given as Cancer Therapy with Biological Response Modifiers (CATBRMs). Specific titles for the application should be given on line 1. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight service) At the time of submission, two additional copies of the application must be sent to: Toby M. Friedberg Referral Officer National Cancer Institute Executive Plaza North 6130 Executive Boulevard, Room 636 Bethesda, MD 20892-7405 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3428 Applications must be received by January 4, 1996. If an application is received after that date, it will be returned to the applicant without review. 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 Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the NCI. Incomplete applications will be returned to the applicant without further consideration. If an application is not responsive to the RFA, DRG staff will return the application to the applicant. 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 applicants 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. Each Clinical and Laboratory Program will be evaluated on its relevance to the group's objectives as well as its individual scientific merit. Requirements for Responsiveness to RFA To ensure responsiveness to this RFA, applications must include: 1. A primary emphasis on, and plan for, completing a translational research project in the treatment of cancer with BRMs. This must include a clear timeline, which must in turn include at least one clinical trial to begin patient accrual no later than 18 months after award, and to complete all patient treatment and data analysis by the end of the award period. Preclinical work between the time of the award and the initiation of the first clinical trial may be included to support the clinical development of the agent(s) or approach(es) proposed for study. 2. A full protocol, or, at a minimum, an outline for the initial clinical trial, in sufficient detail to permit assessment of the scientific merit of the rationale, proposed clinical treatment and laboratory monitoring approaches and proposed statistical analysis. The description of the initial clinical trial should be commensurate with the proposed timeline; e.g., applications proposing that a trial be initiated within six months of award should include a full protocol. (Protocols or detailed outlines for clinical trials after the first are not necessary for an application to be considered responsive.) 3. A description of the patent/license status of the agent(s) to be studied, and of the group's plans to address patent/license issues. 4. A description of the IND status of the agent(s) proposed for study, including supporting information. 5. A description of the group's plans to ensure the availability of adequate drug supplies for the clinical trial, including supporting material (e.g., letters of support from drug suppliers). 6. A signed statement from the Principal Investigator and from each Program Leader agreeing to accept the Terms and Conditions of Award. 7. A description of the interrelationships among the members of the group and the contribution of each to fulfillment of group objectives. 8. A description of the specific assistance the group believes it will need from NCI to translate its preclinical findings into an initial clinical trial - e.g., assistance with production or procurement of investigational agents, assistance with IND- directed studies, assistance with preparation/filing of an IND, etc. Review Criteria 1. Scientific, technical, or medical significance and originality of the proposed research; 2. Scientific, technical, or medical appropriateness of the overall proposed timeline for the project; 3. Appropriateness and adequacy of the experimental approach and methodology proposed for each Clinical and Laboratory Program, and for the project overall; 4. Qualifications and research experience of the Principal Investigator, Program Leaders and other staff, particularly, but not exclusively, in the area of the proposed research; 5. Availability of the resources necessary to perform the research; 6. Appropriateness of the proposed budget and duration in relation to the proposed research and the proposed project timeline; 7. Quality of supporting data; evidence that studies to date warrant further development of the proposed agents or approaches, and that such development is feasible; 8. Evidence that each component Clinical and Laboratory Program is required for the attainment of the group's objectives, and that each has available the professional and technical personnel to permit efficient and successful conduct of the proposed research; 9. Competence of Principal Investigator to develop, implement, and manage comprehensive research programs, and to coordinate and integrate research activities of diverse clinical and laboratory programs; 10. Adequacy of plans for effective intra-group communication and for ensuring group cohesiveness; 11. Evidence of approval and commitment of institutions represented by group members to group goals. 12. Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA The anticipated date of award is July 1, 1996. In addition to technical merit, the following will be considered in making awards: (1) availability of funds; (2) availability of other resources (including drug supplies for the proposed preclinical studies and clinical trials); (3) program balance, including sufficient compatibility of features to make a successful collaborative program a reasonable likelihood; and (4) NCI program priorities. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Jon Holmlund, M.D. Division of Cancer Treatment National Cancer Institute BRMP, NCI-FCRDC Building 1052, Room 253 Frederick, MD 21701-1201 Telephone: (301) 846-1098 FAX: (301) 846-5429 Direct inquiries regarding fiscal matters to: Eileen Natoli Grants Administration Branch National Cancer Institute Executive Plaza South, Room 242 6120 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7800, Ext. 256 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 authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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 routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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