EARLY CLINICAL TRIALS OF NEW ANTI-CANCER AGENTS WITH PHASE I EMPHASIS Release Date: November 19, 2001 RFA: RFA-CA-02-011 National Cancer Institute Letter of Intent Receipt Date: February 14, 2002 Application Receipt Date: March 21, 2002 This RFA is a reissue of RFA-CA-97-001 that was published in the NIH Guide on November 22, 1996. PURPOSE The purpose of this Request for Applications (RFA) is to provide funding to assess novel agents available through the NCI in early clinical, dose finding trials. This initiative"s major objective is the timely completion of trials of promising anti-cancer agents and combinations of agents to establish safe and biologically active treatment schedules for patients with cancer and to establish proof of principle for new agents directed at novel molecular targets. Most of these trials will include pharmacokinetic assessment. Many of these trials will include assessment of drug exposure and effect. These assessments may provide an understanding of the relationship between the drug"s doses and schedules and its effects. This RFA invites investigators to form teams of investigators and support staff to propose, develop, perform and analyze the results of early clinical trials. These teams should include clinical investigators with expertise in the performance of early clinical trials, collaborating with researchers with expertise in clinical pharmacology and translational correlative studies as well as support staff. Single Institution Phase I studies are preferred, although laboratory studies may be conducted with collaborators at other institutions. Strong justification, evidence of well-established collaborations and clearly described procedures must be supplied for multi- institutional applications. RESEARCH OBJECTIVES A. Background Increasing numbers of anticancer agents, many of them developed to address newly identified molecular targets, are reaching clinical testing (from a total of 215 agents in trial for cancer in 1995 to 316 in 1997 to 402 in 2000). An effective early clinical trials program must be able to evaluate these new approaches rapidly, conduct trials safely, and establish potentially useful doses and schedules for further evaluation. In addition, early proof of principle trials will be used to assess the validity of the target and optimize drug administration regimens to produce expected effects on the putative targets or downstream processes. The increasing numbers of promising new agents with diverse and novel, but unproven mechanisms of action makes it desirable to continue NCI support in this area. The discovery of specific molecular pathways and their exploitation in cancer drug discovery efforts presents the early clinical trials efforts with striking opportunities as well as challenges. A safe, efficient and scientifically sound clinical trials system to evaluate these new treatment approaches requires rapid development, conduct and reporting of trials. Evaluation of new approaches to phase I studies using appropriate assays, tools or probes to provide early proof of principle, judge the validity of the target and optimize drug administration regimens are additional required elements. Potential agents for early clinical development using NCI support are now evaluated by the Drug Development Group (DDG) with expert review provided by non-NCI scientists. The DDG prioritizes use of NCI resources supporting pre- clinical development by Developmental Therapeutics Program (DTP) as well as clinical development by Cancer Therapy Evaluation program (CTEP). Agents may come to DDG from 1) the Developmental Therapeutics Program, 2) industry, 3) academia, and 4) internal NCI laboratories. For agents approved by the DDG for clinical development, CTEP Senior Clinical Investigators (SCI) prepare a clinical development plan in collaboration with the originator of the agent, and other experts, file the IND and solicit for, review and monitor protocols for phase I (and subsequent) trials. NCI currently holds over 150 active investigational new drug applications (INDs) for anticancer agents. For agents originating from the NCI"s preclinical Developmental Therapeutics Program as well as from academia, NCI often holds the only IND application. NCI may participate in collaborative clinical development of agents derived from pharmaceutical/biotechnology industries when co-development is deemed in the best interest of improving the treatment of cancer patients via advancing the community"s scientific understanding of the approach and extending the possible indications beyond those explored by the sponsor in NDA directed trials. NCI often promotes the exploration of important scientific questions which may not be the primary focus of industry development, either because of limited industry 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 many human cancers. NCI support facilitates the development of these important agents and indications. The changing size and scope of the program is apparent in the existence of collaborative agreements active with approximately 75 industry partners for more than 150 of the 402 cancer agents currently in clinical development worldwide. CTEP files approximately 20 IND applications annually, the majority are for novel agents in early clinical development. Agents under evaluation include small molecules, antibodies, vaccines, targeted toxins, and gene transfer agents. The classes of agents that are being studied include angiogenesis inhibitors, receptor tyrosine kinase inhibitors, signal transduction inhibitors, farnesyl transferase inhibitors, cell cycle inhibitors, histone deacetylase inhibitors and other agents to induce reexpression of critical genes, agents directed at novel targets such as the proteasome, heat shock protein, and vaccines as well as cytotoxic agents directed at cell division and immunotoxins. The phase I cooperative agreement has facilitated the development of phase 1 trial designs allowing evaluation of accelerated dose escalation, designs incorporating biological endpoints, as well as the introduction of tools to assess direct effects on molecular targets or their downstream consequences and dose-determining trials in patients with organ dysfunction. These and other innovations, such as pharmacogenetic studies, and evaluating combinations of investigational agents to improve the phase 1 evaluation of anti-cancer agents will be supported through this RFA. This RFA provides an opportunity for clinicians and laboratory investigators to utilize their extensive experience and expertise to study investigational agents in comprehensive dose finding and proof of principle trials with appropriate laboratory, imaging and anatomic clinical correlations. Scientific approaches will reflect the interest, creativity and capabilities of participants and will frequently be investigator-originated as well as in response to solicitations for trials provided by CTEP. The investigators bring to the collaboration their specific biological and pharmacological expertise, their ideas concerning research strategies unique to each agent, the necessary patient and investigative resources for study of the agent, and their data management and analytical abilities. The investigators will help define the scientific objectives and experimental approaches consistent with the goals of early clinical trials. The Principal Investigators of these awards, the NCI Program Director(s) and CTEP Senior Clinical Investigators (SCI) will be members of an early clinical trials network. This group of investigators has traditionally met at semiannual meetings. Additional activities and responsibilities for a more formalized network may be proposed as part of this application (See Application Procedures). In addition to the funding assistance offered to the investigator(s) by this RFA, NCI will sponsor or co-sponsor the agents under development in accordance with Food and Drug Administration requirements. As sponsor of an investigational drug, DCTD 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. As supplier of the agents and holder of the IND of the investigational agents to be studied, CTEP has very specific and well defined responsibilities in terms of investigational agent development in its role as a drug sponsor as defined in CFR 21 Part 312. An Investigational Drug Branch (IDB) Senior Clinical Investigator (SCI) is assigned to each CTEP IND to assist in the coordination of the agent"s development. To ensure the fulfillment of these responsibilities of sponsorship, participation by NCI in the conduct of the trials is necessary since these agents are in an early stage of development and new information related to the agent must be rapidly communicated between investigators using the agents and the NCI, FDA and other industry partners. The NCI will provide additional coordination by providing information regarding NCI priorities, information on ongoing efforts elsewhere in the scientific community and information on drug toxicities. The NCI will provide technical assistance, through protocol templates and the protocol review and approval process, regarding methodology, feasibility, and adherence to regulatory requirements mandated by NCI"s role as a drug sponsor. The mechanisms for NCI involvement allow for systematic, safe and efficient development of investigational agents. B. Objectives and Scope Institutions responding to this Request for Applications (RFA) should be able to perform dose finding Phase I trials and establish the pharmacological characteristics of these agents, in parallel with assays, tools, or probes to study the biologic effects of these agents on cancer cells and normal tissues. The investigators are expected to design and perform early dose-finding clinical trials of NCI-sponsored anticancer agents, to evaluate the biologic effect of NCI-sponsored anticancer agents on their molecular targets and determine clinically relevant correlates. It is expected that pharmacokinetics and 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 and pharmacodynamic evaluation of new agents may be developed. The objectives of this program are: 1. to safely and efficiently conduct dose ranging clinical trials of single agents and combinations of novel agents to establish dose, schedule and scientific proof of principle for drug effect and establish appropriate doses for activity studies, characterize toxicity and pharmacology, and discover the scientific basis for subsequent prioritization of development plans for NCI sponsored agents of varying classes, many of which are directed at new cancer targets, 2. to characterize the effects of new agents on their targets through integration of suitable biochemical, pathological, immunologic, molecular or imaging methods and correlate those effects with clinically relevant endpoints, 3. to develop new scientific insights into drug mechanisms and determinants of response, and 4. to develop new paradigms suitable for the assessment of novel agents that may not have classical phase 1 endpoints (i.e. toxicity) to guide the selection of doses and schedules and to avoid the futility and expense of carrying ineffective agents into full scale clinical development Over the last 20 years the objectives of dose-finding phase I clinical trials of cancer therapeutics have been the characterization of drug toxicity, maximally tolerated dose and pharmacokinetics of drugs. Recent advances in understanding cancers are leading to the development of a wide range of novel anti-cancer therapeutic agents that will undergo initial dose findings studies. These agents include novel cytotoxic agents, as well as agents designed to affect novel cancer cell targets. The target-directed agents may exert anti-cancer effects not only through classical cytotoxic mechanisms, but also through growth inhibiting mechanisms mediated by interrupting specific oncogene-associated biochemical functions, inhibiting protein synthesis, inducing differentiation and/or apoptosis, and inhibiting tumor angiogenesis and metastasis. Direct assessment of effects on the target, or downstream consequences of drug-target interaction in dose ranging studies may provide biologic endpoints of drug activity that can form the basis for dose and schedule for subsequent studies. These assessments may, in fact, be the only practicable methods of deciding on appropriate doses and schedules for certain drug classes. Thus, the goals of dose finding clinical trials of targeted agents should include studies that lead to a greater understanding of the relationship between drug administration and biological changes in cancer. Appropriate laboratory studies for all dose finding trials of novel agents should include pharmacokinetic studies, including monitoring of relevant metabolites and intracellular products, or other relevant pharmacology correlative studies, when appropriate. It is expected that these measures will be made in real time during the conduct of most dose finding trials. In addition to pharmacokinetic analyses, other laboratory studies may include studies of pharmacogenetic variability in drug metabolism or effect. Novel biochemical, pathological, pharmacologic, immunologic, molecular, or imaging methods should be incorporated, when available, to measure the effect of new target-directed drugs in proof-of-principle clinical trials. These correlative studies should characterize effects on agents on their targets, develop new scientific insights into drug mechanisms and/or characterize the molecular phenotypes of tumors to help identify patients suitable for treatment with specific target- directed agents The investigators will propose scientific objectives and experimental approaches consistent with the goals of dose finding clinical trials. The investigators will identify the specific NCI sponsored agents of interest in accordance with their areas of scientific interest and expertise, and will develop a series of appropriate trials with supporting protocol documents. CTEP will review the protocols and work collaboratively to refine the objectives and experimental approaches, have real time 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. Clinical, pharmacokinetic and pharmacodynamic data will most commonly be submitted to the NCI"s Clinical Trials Monitoring Service every two weeks or, for the minority of trials, to the NCI"s CDUS on a monthly or quarterly basis. Timely publication of findings to make information available to the larger scientific community will be strongly encouraged. Each Phase I awardee must have demonstrated experience in conducting dose finding trials with new agents and associated laboratory evaluations. Applicants must demonstrate that they have expertise in 1) cancer drug development, 2) the clinical management of patients with various cancers, 3) the clinical management of patients on phase 1 clinical trials, 4) phase I clinical trials methodology, 5) pharmacology, 6) pharmacokinetics and 6) pharmacodynamics. They need to provide evidence of their own expertise, or collaborative access to such expertise, in diagnostic and functional imaging, interventional radiology, pathology, and other potentially relevant laboratory methodologies. Sufficient numbers of patients at the applicant institution should be available 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 examples of standards to be met, see Application Procedures. Each applicant is responsible for coordinating the preparation and submission of letters of intent, protocol development and submission, study conduct, quality assurance, 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. C. Related NCI Initiatives A number of interrelated initiatives have recently been developed or implemented to create a cohesive and integrated NCI program in drug discovery and clinical development focused on molecularly targeted new agents. The awards for early clinical trials with Phase I emphasis will provide the major resource for rapid, efficient, systematic evaluation and determination of optimal dose/schedule for specific agents and combinations within the NCI portfolio of investigational agents. The following Web sites present detailed information on other related NCI initiatives in drug discovery for treatment of cancer, clinical trials, and imaging programs that may interact with a phase 1 awardee: Interdisciplinary Research Teams for Molecular Target Assessment: These currently fund 4 teams addressing the discovery, development and validation of research tools that will make mechanism assessment in clinical trials for molecularly targeted agents consistently feasible. These teams currently address agents that inhibit survival signaling, erbB targeted agents, antiangiogenic agents and immunomodulation. Promising assays and research tools will be incorporated in the early phase clinical trials. In vivo Cellular and Molecular Imaging Centers: https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-004.html and the Small- Animal Imaging Resource Program. Imaging initiatives including: small animal imaging, imaging in therapeutic studies, and ICMIC: Critical imaging technologies and tools developed by these initiatives may be used by the phase I cooperative agreement investigators. RFA for imaging in therapeutic studies (https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-98-023.html). QuickTrials Grants (R21): This mechanism is intended to provide an efficient funding mechanism to support hypothesis driven, investigator initiated clinical trials that advance the scientific understanding of cancer treatment. This complementary pathway for clinical trials currently supports only 5 grants with phase I trials of NCI-IND agents. Correlative studies that contribute to elucidation of therapeutic hypotheses may receive support from this mechanism in conjunction with trials performed with support from this U01. This mechanism should be considered for support of complementary laboratory studies for individual phase I trials under this RFA. (https://grants.nih.gov/grants/guide/pa-files/PA-99-070.html). Translational Research Fund (TRF): The TRF provides an acquisition mechanisms (contract) to fund correlative studies characterizing specific effects of new agents on their targets in NCI-sponsored early clinical trials, including pharmacodynamic studies performed by UO1 investigators under this award. The approved correlative studies must be linked to the clinical trials being conducted on NCI-sponsored trials with NCI-IND agents. The TRF will acquire personnel time and procedures directly related to the laboratory correlative investigations, and the laboratory studies. Because the type of assays, probes and tools may vary widely with the agents tested, these costs are not included in the funding under this RFA (see Application Procedures). SPORES. These mechanisms support molecular target discovery and characterization for specific tumor sites, (http://spores.nci.nih.gov/) Cancer Diagnosis Program What"s New (http://www-cdp.ims.nci.nih.gov) SPECIAL REQUIREMENTS 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 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 DCTD as a drug sponsor as defined in CFR 21 Part 312. 1. Awardees Rights and Responsibilities It is the responsibility f 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 DCTD investigational agents. a. Clinical Trial Conduct The clinical trials must 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 and Diagnosis, National Cancer Institute (URL: http://ctep.cancer.gov/handbook/) The Investigator"s Handbook contains information on the following: Protocol Development and Submission Ordering Investigational Drugs from NCI Accountability and Storage of Investigational Drugs Reporting of Results to CTEP [including the Clinical Trials Monitoring Service (CTMS ) and the Clinical Data Update System (CDUS)] Reporting Adverse Drug Reactions [including Adverse Event Expedited Reporting System (AdEERS) and the Common Toxicity Criteria (CTC)] Monitoring and Quality Assurance All Protocols utilizing investigational agents must include the NCI Standard Protocol Language (http://ctep.cancer.gov/industry/industry.html - see bottom of web) and be conducted in accordance with the terms of the Intellectual Property Option to Collaborator (The Intellectual Property Option to Collaborator document may be accessed on the world wide web at http://ctep.cancer.gov/industry/ipo.html or may be obtained from the Regulatory Affairs Branch, CTEP, DCTD, NCI at 301-496-7912. b. Protocol Development The PI should, with CTEP Assistance, develop letters of intent and protocols that define the scientific objectives and experimental approaches for anticancer agents under CTEP INDs, including agents identified by the NCI"s drug screening program or referred to NCI from other sources, including the pharmaceutical and biotechnology industry. These include: a) Anticancer agents with novel mechanisms, including but not limited to: inhibitors of signal transduction, cell cycle, angiogenesis and metastasis, differentiating agents, gene reexpression agents, apoptosis-inducing agents, anti-sense oligonucleotides and related gene-specific therapeutic agents, and targeted cytotoxic agents. b) Combinations of anticancer agents with novel mechanisms and existing chemotherapeutic agents where there is a specific hypothesis and an experimental basis for enhanced effect, where drug potential drug interactions must be carefully defined, and where the hypothesis that combining the agents will produce enhanced effect can be evaluated in dose finding studies or c) Detailed evaluation of doses and schedules of novel agents in unique patient populations, such as those with abnormal elimination of agents due to renal or hepatic injury, those with pharmacogenetic variations in drug metabolism or drug effect, or those with other underlying processes that might be postulated to alter safety and activity. c. Protocol Submission Submission of protocols for review by PRC should be preceded by a written declaration of interest in conducting a particular study from the principal investigator using the suggested format described in the INVESTIGATOR"S HANDBOOK in Appendix VII, GUIDELINES FOR SUBMITTING LOIs - Letter of Intent/ INVESTIGATIONAL DRUG TRIAL. The LOI Submission Form is available at http://ctep.CANCER.GOV/guidelines/index.html. The LOI must 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, competing trials and prioritization of trials to document the feasibility of expeditious completion of the proposed study. The LOI must describe the rationale for correlative studies. If funding for supplemental studies has not been secured by the investigator, the LOI must indicate that funding will be needed through quick trials, TRF or other mechanisms. If TRF support is sought, a tentative budget and brief budget justification must be included in the LOI. The phase 1 awardee must submit a letter of intent (LOI) electronically to the CTEP Protocol and Information Office (who receives, logs in and schedules LOIs for review by the PRC) declaring interest in conducting a particular clinical study (firstname.lastname@example.org.) LOIs may be submitted in response to a CTEP solicitation of proposals to conduct clinical trials with specific NCI-held IND agents or at any time through the investigator"s own initiative. The LOI is reviewed by CTEP Protocol Review Committee for scientific merit and need based on the development plan. The LOI may be rejected, approved with the requirement for recommendations to be incorporated, or fully approved. (See INVESTIGATOR"S HANDBOOK, for a complete description of the LOI process.) If the LOI is approved, the PI must, with CTEP assistance, develop Phase I protocols and submit them for PRC review within 30-45 days of LOI approval (timeline determined at time of LOI approval). For some novel agents, CTEP may provide protocol templates to reduce the effort of multiple investigators duplicating similar efforts in repetitive aspects of protocol development. The protocol should define the scientific objectives and experimental approaches for the specific agent for which CTEP holds an IND. The protocol should define for reference, procedures for pharmacokinetic and other correlative studies. The PI must electronically submit (as .doc or .pdf files) the Phase I protocols to CTEP Protocol and Information Office, the receiving office for all protocols sent to CTEP, for review as appropriate, prior to their implementation. The PI must 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 for reporting serious adverse events and adherence to requirements regarding investigational drug management and federally mandated regulations and protocol and performance reporting. d. Protocol Review, Revision and Implementation Communication between the PI or Protocol Chairperson and CTEP Senior Clinical Investigators (SCI) at the various stages of protocol development and conduct is encouraged as necessary to promote efficient and well informed protocol development and implementation. The PRC will review each protocol (generally within 2 weeks of submission) and the PI will receive electronically a Consensus Review (generally within 3 weeks of submission). Numbered comments may include comments requiring a response, recommendations and/or comments concerning the consent requiring a response, as well as recommendations and/or comments from the industrial co- sponsor, if any. Each numbered comment must be addressed point by point in a cover letter that accompanies the revised protocol. The revised protocol and cover letter must be received by the PIO within 2 -4 weeks of the date on the Consensus Review (which will correspond with the date the Review is sent by e- mail to the PI). The reasonable time to respond to the Consensus Review will be determined by CTEP based on the extent and complexity of required revisions. If the PI has not received the Consensus review within 4 weeks from protocol submission, the PI should contact the PIO. Access to e-mail and ability to attach, send and receive documents (for example, protocols, amendments, and correspondence) via e-mail is required. Protocols can only be activated after review and approval by the Institutional Review Board (an Optional Form 310 must be submitted), the PRC, and the CTEP Coordinator and only after receipt of the protocol approval letter from NCI. The specific requirements of Protocol Submission, Review and Approval are described in the INVESTIGATOR"S HANDBOOK. The PI must notify the Protocol and Information Office in writing of each study status change at the time of status change. (For definition of study status see the INVESTIGATOR"S HANDBOOK). e. Study Conduct and Monitoring The awardee institution is responsible for the ensuring accurate and timely progress of each study and reporting of results to CTEP as the study sponsor through: 1) screening, registering and treating the planned number of patients on study in the time frame agreed to at the time of LOI approval, 2) appropriate patient follow-ups beyond that specified in the protocol e.g. after adverse events, progressive disease or patient withdrawal, 3) establishing data management support capabilities that ensure that clinical, clinical laboratory, imaging and research laboratory 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/DCTD Case Report Form and the individual protocol. 4) 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, and assuring the all the relevant parties (nursing and pharmacy staff) are notified of the current dose level and assigned dose level for an individual patient. 5) 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, 6) ongoing assessment of patient eligibility and evaluability, 7) timely medical review and assessment of patient data, by the study chairperson and PI Investigator, 8) rapid reporting of serious treatment-related morbidity (adverse event reactions) electronically through AdEERS in compliance with FDA regulations and measures to ensure communication of this information to all parties [http://ctep.cancer.gov/reporting/adeers.html], 9) interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice, 10) real-time conduct of pharmacokinetics and other laboratory correlative studies throughout the course of the clinical trial, to facilitate optimal utilization of data generated by such research efforts, and 11) timely communication of interim and final results of studies to CTEP and timely preparation, submission and publication of manuscripts to ensure communication to the scientific community. f. Data Management, Analysis and Reporting The awardee will develop procedures to ensure that data collection and management have: a) acceptable quality assurance standards, and b) procedures that are as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense. Quality assurance at a minimum must consist of: 1) Pathology: Verification of pathologic diagnosis in cases where known variability in the accuracy of histologic diagnosis is a potentially serious problem and where pathology data may provide important prognostic information. 2) Radiation Therapy: Review (either concurrent or retrospective) of port films and compliance with protocol-specified doses for individual patients, where relevant. Determination of adequacy of radiation delivery with the assistance of the Radiological Physics Center (RPC), whose functions usually include equipment dosimetry, periodic institutional visits and other aspects of physics review. 3) Chemotherapy: Review of pharmacy orders, drug administration, flow sheets and drug distribution with determination of protocol compliance in dose administration and dosage modification. 4) Surgery: Assessment of adequacy of protocol-specified surgical procedures (where relevant) through review of operative notes and study-specific surgical forms. 5) Imaging - Assessment of adequacy of protocol-specified imaging procedures. This would include (1) methods for acquisition and display of images, (2) methods for monitoring quality of image interpretation including quantitative measurement of lesions, and (3) methods of data archiving and retrieval as appropriate to specific studies. 6) Laboratory - For pharmacokinetic and correlative studies, quality assurance procedures for the laboratory assays must be established. These may include such elements as assay validation procedures, calibration curves, check samples, standards for accepting or rejecting data such as Shewart charts, positive and negative controls, etc., as well as external quality assurance if it is available. Procedures for ensuring patient privacy and sample tracking must be established by the PI 7) Reporting of pharmacokinetic results - Pharmacokinetic data results must be reported to the Clinical Trials Monitoring Service (CTMS) using case report forms available from Theradex. It is anticipated that most studies will involve assays in (near) real time during the course of the study. The schedule for sample assay should be established in the written protocol (e.g., for each patient in real time, or for a cohort of patients at a particular dose, or after each nth patient as appropriate for a specific study. 8) Reporting of correlative studies results: The performance of correlative studies, including the number of patients studied, the number of samples, imaging studies or other procedures done, the number of samples or other procedures completed with results, and overall conclustions of these studies to date should be reported to the CTMS or CDUS as determined by the written protocol. Reports of study performance to CTMS/CDUS will be the basis for reimbursing invoices under any associated correlative studies funded under contract with the Translational Research Fund (TRF). g. Investigational Drug Management Investigators performing trials under cooperative agreements involving a Division of Cancer Treatment and Diagnosis (DCTD) 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. h. Compliance with Federally Mandated Regulatory Requirements The awardee is responsible for establishing procedures to comply with FDA regulations for studies involving investigational agents and Office for Human Research Protections (OHRP) requirements for the protection of human subjects, and NIH requirements for data and safety monitoring of clinical trials https://grants.nih.gov/grants/guide/notice-files/not98-084.html with additional description at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. These procedures are: 1) Methods for ensuring that the awardee institution has a current, approved assurance on file with the OHRP, that each protocol is reviewed and approved by the responsible Institutional Review Board (IRB) and CTEP PRC 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. In the case of multi-center protocols, the PI must assure that full IRB approval is obtained prior to patient entry at any subcontracted institution, that yearly reapprovals are conducted in a timely fashion and that amendments and serious adverse events are properly reported to each subcontracted institution"s IRB. The PI must maintain documentation of initial approval, yearly reapproval, amendment reviews and reporting of serious adverse events for all participating institutions. 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). http://ctep.cancer.gov/reporting/adeers.html. This will require reporting Adverse Event Reactions (AERs) through AdEERS and/or by telephone to the responsible IDB Senior Clinical Investigator 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 Senior Clinical Investigator Physician.) 3) A system for ensuring that the required data is provided biweekly to the CTMS. 4) A described system for ensuring that data safety monitoring is performed in accordance with NIH requirements i. Reporting Requirements: 1) Routine Protocol Reporting. Reporting requirements will be in agreement with FDA regulations and NCI procedures. The timely and accurate reporting of data from investigational drug trials to the sponsor in a format that is easily integrated is a critical responsibility for Good Clinical Practice and is an important responsibility of investigators doing research with IND drugs. The receipt of these data in a timely fashion is not an arbitrary requirement. The information contained in them is the material which informs CTEP of the progress of the development of the drug, ensures safety and suggests promising new directions. The material is required by CTEP to meet its obligations under FDA regulations to (a) monitor the study and (b) submit regular reports of current findings to that agency. 2) The majority of dose finding trials will require monitoring by the Clinical Trials Monitoring Services (CTMS). Information must be provided to the CTMS at two week intervals and includes: registration of each patient entered onto the protocol within the previous two week period, and all data obtained on each registered patient within the previous two weeks. Investigators are reminded that a course does not need to be complete to submit interval data to CTMS, as this system is designed to accept partial information and additional information for each case report form as it is generated. A fraction of the trials performed will have data submission via the Clinical Data Update System (CDUS), with less frequent reporting requirements (monthly or quarterly rather than biweekly. This reporting system is generally used for studies later in the development of a specific agent (eg, later combination studies) when substantial safety information suggests that frequent oversight by the IND sponsor is less critical for patient safety. 3) Adverse Events Reporting The Contractor must promptly report adverse events (AEs) in accordance with the NCI Guidelines for Adverse Event Reporting found at the following URL: http://ctep.cancer.gov/reporting/adeers.html. Because many antineoplastic agents have a very narrow therapeutic index, and many dose finding studies are done with agents being evaluated for the first time in patients, toxic effects of treatment commonly accompany drug administration. CTEP has developed operational definitions of Adverse Events (AEs) which apply to anticancer drug trials. These definitions are described in the Common Toxicity Criteria, Version 2.0 (CTC v2.0) available at the following URL: http://ctep.cancer.gov/reporting/ctc.html Additional information about reporting adverse events is included in the CTC Manual and other CTC sources at: http://ctep.cancer.gov/reporting/ctc.html. The prompt reporting of AEs to CTEP is the responsibility of each investigator engaged in clinical research with investigational drugs supplied by the NCI and of the PI for the award. It should be noted that verbal/telephone communication of all new adverse events as well as all life-threatening (Grade 4, unless otherwise defined in the specific protocol) or lethal (Grade 5) adverse events is mandated for this process and facilitates discussion and assessment by both sponsor and investigator. See the above referenced URL for specific requirements for Adverse Event Reporting. These should be detailed in the text of the protocols using the CTEP table and additional protocol specific information. All adverse events for NCI-sponsored trials are reported using CTC Version 3.0 as documented in the protocol. 4) Pharmacokinetic/Pharmacodynamic and Correlative Laboratory Study Reports The PI should provide CTEP, via CTMS or CDUS as specified, sample acquisition or procedure performance on a biweekly (or quarterly) basis. The PI must also provide actual data in spreadsheet format for the pd/pk/correlative studies. At the time a protocol with correlative studies is approved, the schedule for delivery of these data will be established. Pharmacokinetic data will be reported as it is generated, biweekly to CTMS. Other data (e.g., imaging data) may also be reported biweekly. For correlative studies analyzed in batches, quarterly reporting may be proposed in the protocol. In special cases where these results will affect the prosecution of the study, data may be required monthly. The PI must provide a descriptive report at the completion of the study summarizing the accrual to correlative studies, the results and conclusions, and problems encountered and recommendations for future studies. Because most correlative studies beyond pharmacokinetics will likely be funded outside of the U01 budget itself, via either R21 grants or Translational Research Fund (TRF) contracts, timely reporting of acquisition of specimens and results will be necessary for reimbursement under a TRF subcontract. 5) Annual Progress Reports: Annual progress reports must be submitted to the NCI in a non-competing continuation application. These reports must also be provided as electronic spreadsheets. The spreadsheet must include at a minimum, a list of LOIs submitted (Identified by NCI LOI number and title, status of LOI (approved/disapproved/on hold), the date the LOI was approved and the date the subsequent protocol was submitted. A second spreadsheet must list the protocols submitted activated and completed (identified by NCI protocol number and title), the initial protocol submission date, the protocol activation date, annual and cumulative accrual to studies and whether the protocol did or did not have correlative laboratory studies, as well as a brief interim narrative on active and completed studies summarizing the findings to date. For trials involving PK and/or correlative studies, the following information by trial should be provided: title of correlative study (test or assay or imaging procedure), number of samples collected/procedures performed, number of samples/procedures analyzed/reported, results, and a progress summary including problems and how the data may affect future studies. Any problems that have arisen related to accrual or prosecution of trials should be addressed in the annual progress report. Copies of the most recent annual report to the IRB for each study should be included. 6) Final Protocol Report: For each protocol, a final protocol report is to be submitted. The draft of a manuscript (or manuscripts) for publication is the preferred format for this report, which should be provided within 3 months of accrual of the last patient for a study. j. On-site Audits: The investigators must be available for on-site audits by the Clinical Trials Monitoring Service (CTMS) three times each year. The examination/audit will require the following resources at the awardee institution: 1) A physician/ administrator to discuss the institution"s overall organizational structure, protocol development, protocol monitoring, patient selection and data collection. 2) The PI who will meet with the audit team leader to discuss the protocol(s) for audit. 3) An institutional staff member to describe the institution"s chart organization, and demonstrate where the auditors would usually find various types of data. 4) A workroom with an x-ray view box. The room must be large enough to accommodate the audit team. 5) Inpatient, outpatient and oncology clinic/research records and any computer generated printouts. 6) Informed consent documents and IRB documents, including those from affiliate sites for patients being reviewed. 7) An inspection of the investigational drug storage area and a responsible individual with whom to discuss inventory control methods, agent storing and dispensing. The NCI Drug Accountability Record Forms must be available for review. k. 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. l. Intellectual Property Awardee agrees to promptly notify the NCI and the commercial Collaborator, if appropriate, in writing of any inventions, discoveries or innovations made by the Awardee"s investigator or any other employees or agents of Awardee, whether patentable or not, which are conceived and/or first actually reduced to practice in the performance of this study using the commercial Collaborator"s Agent (hereinafter "Awardee Inventions"). Awardee agrees to notify NCI and Collaborator in writing upon the filing of any patent applications related to the research with the Agent. Awardee agrees to grant to Collaborator: (i) a paid-up nonexclusive, nontransferable, royalty-free, world-wide license to all Awardee Inventions for research purposes only, and (ii) a time-limited first option to negotiate an exclusive, world-wide royalty-bearing license for all commercial purposes, including the right to grant sub-licenses, to all Awardee Inventions on terms to be negotiated in good faith by Collaborator and Awardee. Collaborator shall notify Awardee, in writing, of its interest in obtaining an exclusive license to any Awardee Invention within six (6) months of Collaborator"s receipt of written notice of such Awardee Invention(s). In the event that Collaborator fails to so notify Awardee, or elects not to obtain an exclusive license, then Collaborator"s option shall expire with respect to that Awardee Invention, and Awardee will be free to dispose of its interests in such Awardee Invention in accordance with Awardee policies. If Awardee and Collaborator fail to reach agreement within ninety (90) days, (or such additional period as Collaborator and Awardee may agree) on the terms for an exclusive license for a particular Awardee Invention, then for a period of six (6) months thereafter Awardee shall not offer to license the Awardee Invention to any third party on materially better terms than those last offered to Collaborator without first offering such terms to Collaborator, in which case Collaborator shall have a period of thirty (30) days in which to accept or reject the offer. Awardee agrees that notwithstanding anything herein to the contrary, any inventions, discoveries or innovations, whether patentable or not, which are not Subject Inventions as defined in 35 USC 201(e),* arising out of any unauthorized use of the Collaborator"s Agent and/or any modifications to the Agent, shall be the property of the Collaborator (hereinafter "Collaborator Inventions"). Awardee will promptly notify the NCI and Collaborator in writing of any such Collaborator Inventions and, at Collaborator"s request and expense, Awardee will request permission from the NIH*, if necessary, to cause to be assigned to Collaborator all right, title and interest in and to any such Collaborator Inventions and provide Collaborator with reasonable assistance to obtain patents (including causing the execution of any invention assignment or other documents). Awardee may also be conducting other more basic research using the Agent under the authority of a separate Material Transfer Agreement (MTA), or other such agreement with the NCI or Collaborator. Inventions arising there under shall be subject to the terms of the separate MTA, and not to this clause. * 35 USC 201 (e): The term ""subject invention"" means any invention of the contractor conceived or first actually reduced to practice in the performance of work under a funding agreement: Provided, That in the case of a variety of plant, the date of determination (as defined in section 41(d) (FOOTNOTE 1) of the Plant Variety Protection Act (7 U.S.C. 2401(d))) must also occur during the period of contract performance. 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 DCTD 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 IND Sponsor for these agents. CTEP will submit Investigational New Drug Applications to the FDA permitting DCTD to act as a drug sponsor. As a sponsor of an investigational drug, DCTD, 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 Investigations and CTEP Assistance in Protocol Development An Investigational Drug Branch (IDB) Senior Clinical Investigator (SCI) is assigned to each DCTD IND agent to assist in the coordination of its development. The NCI Program Director and the responsible IDB SCI 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 SCI will advise the PI of potential studies that will be relevant to new avenues of cancer therapy. The NCI Program Director and/or the IDB SCI will work collaboratively with the PI and Protocol Chairperson to define the objectives and experimental approaches. The NCI Program Director and/or responsible IDB SCI 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 SCI 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 DCTD. CTEP provides each investigator working with agents under CTEP IND with copies of all serious adverse event reports filed with the FDA for that agent. Because several portions of protocols are based on generic information about the agent under study, the IDB SCI will endeavor to provide protocol templates with agent specific information and other generic information to the investigators. This facilitates both protocol writing and protocol review. c. Protocol Review The CTEP Protocol Review Committee (PRC), must review and approve every protocol involving DCTD investigational agents. The PRC, which meets weekly, is chaired by the Associate Director, CTEP, and is comprised of professional staff of the DCTD including the IDB SCIs, Clinical Investigations Branch disease coordinators, biostatisticians, diagnostic experts, regulatory staff, pharmacy staff and ad hoc reviewers external to NCI when deemed appropriate by the PRC chairperson. The PRC will formally review the Letter of Intent (LOI). Following LOI review, the responsible IDB SCI will provide a Program response to the PI and will address the following issues for approved LOI: 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 DCTD Investigator"s Handbook, available at web site http://ctep.cancer.gov/handbook/. The PRC will formally review the protocol. The major considerations relevant to LOI and 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 probability that the trial design will provide a clear answer to the questions posed, d) the avoidance of unnecessary duplication with other ongoing studies, e) the appropriateness of study design with respect to development of the IND agent, f) a satisfactory projected accrual rate and follow-up period, g) patient safety, h) plans for compliance and track record of compliance with federal regulatory requirements, i) adequacy of data management, j) appropriateness of patient selection, evaluation, assessment of toxicity, response to therapy and follow-up k) clarity of methods and quality assurance measures for correlative studies and l) track record of the study chair/site in successfully completing similar trials. Following the review of the protocol by the PRC, the responsible IDB SCI will provide the PI with a consensus review. 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 SCI 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. d. Access to Data The NCI will have real-time access to all data generated under this cooperative agreement, 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. e. CTEP Involvement in Protocol Closure The NCI Program Director and/or responsible IDB SCI and the Chief, Clinical Trials Monitoring Branch (CTMB) will monitor protocol progress. The NCI Program Director or the responsible IDB SCI 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 or transmit 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. f. 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). g. CTEP Review of Federally Mandated Regulatory Requirements The Chief, CTMB will review protocols to determine if the awardee"s mechanisms for meeting FDA regulatory requirements for studies involving DCTD-sponsored investigational agents and the Office Human Research Protection (OHRP) requirements for the protection of human subjects are sufficient. These comments are incorporated into the protocol consensus review. (See Awardees Rights and Responsibilities). As sponsor for investigational agents and the funding agency for cancer clinical trials, FDA regulations require the DCTD to maintain a monitoring program. Furthermore, DHHS regulations require monitoring plans for all clinical trials done under NIH sponsorship. The NCI must ensure that research data generated under its sponsorship are of high quality, reliable and verifiable. On-site monitoring is a requirement for investigators conducting clinical trials under NCI sponsorship. The Clinical Trials Monitoring Branch (CTMB) of CTEP provides direct oversight of the monitoring programs which includes auditing. The purpose of the audit is to document the accuracy of submitted data and to verify investigator"s compliance with protocol and regulatory requirements. 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 (biweekly), and to produce periodic reports of the results and special reports as necessary. A small fraction of dose finding trials, usually those done later in an agent"s development, may use the simplified CDUS reporting system, with monthly or q 3 month reporting. Theradex 7, a Clinical Trials Monitoring Service (CTMS) contractor, administers the site visit audit program on the behalf of CTMB. Theradex7 is a pharmaceutical consulting and development company. The audit teams who conduct the on-site audits are composed of experienced clinical research associates, pharmacists and outside physicians and CTMB staff, as necessary, who have specialized experience and expertise relevant to the types of protocols being reviewed. The awardee institution"s source documentation will be reviewed on-site three times per year by the CTMS. One of the objectives of conducting site visits is to bring the FDA regulatory requirements which affect various aspects of the conduct of clinical studies to the attention of individual investigators. The examination/audit will include, but may not be limited to the following: 1. Full and non-contingent Institutional Review Board (IRB) approvals and reapprovals. 2. Copies of the IRB approval, including approvals for all amendments. 3. Copies of the annual reports on the progress of the study and copies of IRB reapprovals for studies continuing beyond the first anniversary of the IRB approval date. 4. Written informed consent obtained on the form approved by the IRB and the documentation of written informed consent for all the patients entered onto a study. The informed consent form signed by the patient at the time of study entry must be the most current version available from the IRB. 5. Adherence to the protocol details. 6 . Adverse events and medical records to review classification of adverse experiences and the reporting to the IRB and the NCI of unusual or unexpected events, as well as events defined as requiring expedited reporting (serious and unexpected events) and all adverse events reported in case report forms. 7. Record keeping and record retention in accordance with the regulatory requirements. 8. Investigational agent accountability. h. CTEP Review of Progress Progress will be reviewed quarterly 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 CTMS reports (or CDUS 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. The Principal Investigators, the NCI Program Director(s) and CTEP SCI will be members of an early clinical trials network. This group of investigators has traditionally met at semiannual meetings. b. Although it is envisioned that the majority of phase I trials will be performed at a single institution, investigators may collaborate to perform specific pharmacologic and correlative studies. As examples, one site may be identified to do PK assays for 3 trials of an agent that is sufficiently stable to batch and ship samples, to minimize duplication of effort in assay validation and quality assurance procedures, in three planned trials, site A may perform correlative studies on biopsies from site A, B, and C, while site B performs a different correlative study for the same three trials, or several sites may collaborate in phase I trials for unusual populations, such as patients with renal insufficiency. CTEP SCI will assist investigators in the ongoing coordination required for such collaborations. c. Phase I strategy meetings The NCI Program Director(s) 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 and Co- Investigators will be responsible for making scientific reports at these meetings as requested by Program Staff. The PI is expected to attend all of these meetings. 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, DCTD. 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. 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. The total project period for an application submitted in response to this RFA may not exceed 5 years. The anticipated award date is February 1, 2003. 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 continuing program need, the NCI will either invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review or reissue 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. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. FUNDS AVAILABLE The NCI intends to commit in FY2003 approximately $7,200,000 including direct costs and costs for Facilities and Administration to fund 14-15 new and/or competing continuation cooperative agreements in response to this RFA. An applicant may request a project period of up to five years. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. The NCI policy that R01 and U01 applications cannot exceed an increase of 20% over the direct cost award level in the last non-competing (type 5) year does not apply to the applications received in response to this RFA. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from minority individuals, women, and persons with disabilities, are encouraged to apply as principal investigators. 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. Louise B. Grochow Chief, Investigational Drug Branch Cancer Therapy Evaluation Program Division of Cancer Treatment and Diagnosis National Cancer Institute Executive Plaza North, Room 7131 6130 EXECUTIVE BLVD MSC 7426 BETHESDA, MD 20892-7432 Telephone: (301) 496-1196 FAX: (301) 402-0428 E-mail: email@example.com Direct inquiries regarding review issues to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8109, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 Telephone: (301) 496-3428 Fax: (301) 402-0275 Email: firstname.lastname@example.org Direct inquiries regarding fiscal matters to: Ms. Kelli Oster National Cancer Institute Executive Plaza South, Room 243 6120 Executive Boulevard MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-8627 FAX: (301) 496-8601 E-mail: email@example.com Bethesda, MD 20892 LETTER OF INTENT Prospective applicants are asked to submit, by February 14, 2002, a Letter of Intent that includes a descriptive title of the proposed research, the name, address, telephone and fax numbers, and email address of the Principal Investigator, 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, it allows NCI staff to estimate the potential review workload and plan the review. The Letter of Intent is to be sent to Louise B. Grochow, M.D listed under INQUIRIES by the Letter of Intent receipt date. SCHEDULE Letter of Intent Receipt: February 14, 2002 Application Receipt Date: March 21, 2002 Peer Review Date: July/2002 Review by NCAB Advisory Board: September/2002 Earliest Anticipated Start Date: February 1, 2003 APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these cooperative agreements. This version of the PHS 398 is available in an interactive, searchable format. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. An application from a currently funded program will be a competing 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 or other correlative studies 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. An application from a program that is not currently funded should include a similar section in preliminary data, which should consist of a summary of prior dose finding trials performed under other sponsorship, including the same information described in the paragraph above to the extent that it is available. (See PHS 398 (rev 5/2001) Research Plan, section c. Preliminary Studies/Progress Report). A summary of accrual to all cancer treatment trials at the applicant institution (excerpted, for example, from annual progress reports for the Cancer Center) should be included. Tables of the current budget and supported FTEs with a justification for any request for additional resources should be included. ALL Applicants 1. The form PHS 398 should be modified as follows. The number of pages allowed for the "Research Plan" is increased from 25 to 45. 2. Investigators should include in the APPENDIX of the cooperative agreement application. a. Draft copies of some proposed protocol(s) 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. b. Examples of quality assurance procedures for pharmacokinetic and translational endpoints may be included in draft protocols in the Appendix. c. A summary of all publications resulting from prior CTEP phase I support, indicating which publications cited CTEP support with an *, should be included in the appendix. d. A list of early clinical trials that have requested grant support under the Quick Trials mechanism, and indicate which requests were funded. 3. 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. A table listing NCI sponsored and industry or locally sponsored Phase I trials indicating the date of initial IRB approval and annual accrual for a recent 24 month period (split into 1 year accruals). When multiple phase I trials have been performed at a site, evidence of investigators" commitment to timely completion of NCI sponsored phase I trials should be incorporated. b. Laboratory support to perform pharmacokinetic studies of cytotoxic, differentiation-inducing, molecularly targeted, and/or other novel anti-cancer agents, including monitoring of metabolites and intracellular products when appropriate, or other relevant pharmacology correlative studies, documentation of ongoing collaboration with laboratory investigators should be incorporated c. Laboratory support 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, etc), document ongoing collaboration(s) d. Interventional radiology to support the acquisition of CT directed biopsies adequate to perform suitable assays of drug effect when needed, functional imaging with MRI and PET scan facilities to support studies of non- invasive probes of drug effect e. Adequate central data collection and processing capabilities in order to meet FDA requirements for the conduct of research using investigational agents. These specifically include: 1) the capability to transmit patient data to the NCI"s Clinical Trials Monitoring Service (CTMS) on a biweekly basis, and via the Clinical Data Update System (CDUS). 2) the capability of prompt reporting of AERs via AdEERS to CTEP for investigational agents supplied by NCI in accordance with the CTEP guidelines (mailed annually to all registered investigators). f. Adequate pathology support for tumor classification and for banking and distribution of tumor tissues for concurrent and future studies. g. Timely medical review and assessment of patient data, by the study chairperson and PI Investigator. The application should specify how this review will be arranged. h. For pharmacokinetic and correlative studies, quality assurance procedures for the laboratory assays. These may include such elements as assay validation procedures, calibration curves, check samples, standards for accepting or rejecting data such as Shewart charts, positive and negative controls, etc., as well as external quality assurance if it is available. Procedures for ensurng patient privacy and sample tracking must be established by the PI. [As noted above, examples of quality assurance procedures for pharmacokinetic and translational endpoints may be included in the Appendix]. i. Adequate mechanisms in place to ensure that all patients: 1) have histologically confirmed diagnosis of cancer, 2) be staged by conventional methods and found to have locally extensive or disseminated disease not amenable to therapy with curative intent using surgery, chemotherapy, and/or radiotherapy or any other form of known effective therapy, 3) have already received and no longer be receiving benefit from customary systemic or local treatment likely to prolong survival or improve symptoms. For diseases for which curative 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 non-curative therapy of limited benefit to only some patients is available (e.g., carcinomas of the head and neck, hormone-refractory prostatic carcinoma, bladder and stomach cancer, sarcomas, renal cell carcinoma), entry of patients with no prior therapy may be acceptable. 4) have acceptable performance status and acceptable renal, liver, and hematologic function, and 5) 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. j. Evidence of a level of supportive care appropriate for the treatment of patients with advanced malignancies, k. Intensive care, subspecialty consultation in non-oncology fields and blood bank facilities on-site and functioning 24 hours per day. l. Adequate physician and nursing resources to comply with all reporting requirements of NCI-sponsored Phase I trials. m. Appropriate drug accountability procedures as required for utilization of NCI-supplied investigational agents. 4. Additional activities and responsibilities for a clinical trials network may be proposed as part of this application. The early clinical trials network may meet as needed in working groups, either via travel or via teleconferences. Additional experts identified by members of the network may be invited to participate in specific working group meetings to provide expertise in specific agents, targets, and/or trial designs. Members of the early clinical trials network may choose to form agent/class specific study teams to facilitate the identification of appropriate scientists to assist in collaborative studies, evaluate new agents for the need to develop additional research plans addressing aspects of drug metabolism, pharmacogenetics, imaging, novel trial designs and correlative endpoints that are not available at the time of DDG review, arrange for collaborations within the network (or beyond the network) between individual dose finding trials, and provide information to the NCI Program Director(s) and CTEP Senior Clinical Investigators (SCI) to assist in the preparation of solicitations for early clinical trials. Members of the early clinical trials network may also work together to develop policy recommendations for early clinical trials, position papers, agenda for semiannual meetings, etc. For applicants who find participation in an early clinical trials network study team desirable, a description of the process that would be undertaken to form an agent study group and the measures that might be undertaken to evaluate the function and productivity of such study groups should be included in the application. Specific examples of such measures include evaluating the level of effort required to initiate a trial, the quality of the applications received, the speed of trial initiation and completion, the productivity evidenced by publications, and the quality of the trial results. Some agents might be selected for a network study team committee and measures of the development plans for these agents could be compared to agents that are developed with the conventional informal input currently provided to CTEP from extramural scientists. 5. 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 pharmacokinetic studies, quality assurance, data management and data analysis, study monitoring, travel to semiannual early clinical trials meetings and national meetings to present results, and biweekly electronic data submissions to the NCI"s Clinical Trials Monitoring Service as required by the reporting requirements for investigational agents. Costs for the support of translational correlative studies planned in conjunction with phase I trials will not be supported via the U01, but a sample budget for such efforts may be included with the protocol(s) in the appendix to provide evidence of the applicant"s understanding of the scope and planning of such projects. These correlative studies may be funded via other mechanisms (such as R01 or R21 Quick Trials or via acquisition (contract) mechanisms, e.g., as subcontracts via the Translational Research Fund). Decisions to acquire correlative studies will be made at the time of LOI approval, and detailed budgets for correlative studies with budget justifications should be provided at the time of protocol submission to CTEP. 6. The approximate number of patients expected to be accrued annually should be specified. 7. 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). 8. Travel funds for two NCI meetings per year for two representatives from the awardee institution should be included in the budget, as well as travel fund for one representative to two working group meetings and funds for two presenters for major national meetings. 9. Applications must include a description of plans to accommodate the Terms and Conditions of Award, including the NCI staff involvement. 10. All clinical trials supported or performed by NCI require some form of monitoring. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff to a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional Review Board (IRB). For details about the Policy of the NCI for Data Safety Monitoring of Clinical Trials see http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm, For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on Further Guidance on a Data and Safety Monitoring for Phase I and II Trials for additional information: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available to http://www.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive Room 1040 - MSC 7710 Bethesda, MD 20892-7710 (20817 for express service) At the time of submission, two additional copies of the application must also be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8109, MSC-8329 Rockville, MD 20852 (express courier) Bethesda, MD 20892-8329 Applications must be received by March 21, 2002. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must include an Introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the National Cancer Institute. 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 Division of Extramural Activities of the National Cancer Institute in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed assigned a priority score, and receive a second level review by the National Cancer Advisory Board. Review Criteria 1. Significance: 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 novel 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 drug metabolism, elimination, distribution, or effect on specific molecular targets. 2. Approach: appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research including: a. adequacy of plans for the development, implementation, conduct and analysis of Phase I clinical trials. b. adequacy of available patient populations and adequacy of accrual to dose finding trials, demonstrated ability to complete 2-3 phase I trials/year. c. adequacy of plans, equipment and resources to carry out pharmacokinetic and pharmacodynamic analyses in a timely manner. d. adequacy of plans for correlative laboratory studies and evaluation of the data with respect to treatment administration or treatment outcome, availability of interventional and functional imaging teams to collaborate with dose finding trials. e. adequacy of statistical approach for correlating research studies with treatment outcomes in Phase I trials. f. adequacy of plans for effective collaboration among laboratory, imaging, clinical, and statistical investigators. g. adequacy of mechanisms for quality assurance, study monitoring, data management and reporting, data analysis, investigational drug management, and compliance with regulatory requirements h. If additional responsibilities of an early clinical trials network are proposed, reviewers are asked to provide a detailed assessment of their significance to the drug development program, feasibility of the proposed approach, adequacy of the proposal to assess the effect of drug study teams and other proposed elements 3. Innovation: It is understood that dose finding clinical trials per se may not be innovative. However, the potential for proposed correlative studies to use innovative approaches to contribute to a greater understanding of the effect of a specific novel target on cancer control and to a greater understanding of the mechanism of action of a novel agent should be considered under innovation. 4. Investigator: qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research including: a. experience, competence and productivity 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 and productivity 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 e. experience in collaboration with laboratory investigators, including experience in multicenter research efforts if proposed by the applicant 5. Environment: availability of resources necessary to perform the research including: a. adequacy of the available facilities for evaluation and clinical care of patients in dose finding trials b. adequacy of the resources for pharmacokinetic/pharmacodynamic laboratory/correlative studies and for data management resources. c. 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. d. adequacy of patient population to support the completion of at least 2 innovative dose finding trials each year and to support the accrual stated by the applicant e. adequacy of the available facilities for comprehensive multidisciplinary assessment and medical management of patients with advanced malignancies 6. Adequacy of provisions for the protection of human subjects and the humane treatment of animals (if laboratory studies involving animals are proposed). 7. Commitment to accept provisions outlined under the Terms and Conditions of Award. The initial review group will also examine: a. the appropriateness of proposed project budget and duration, b. the adequacy of plans to include both genders, minorities (and their subgroups), and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, c. the provisions for the protection of human and animal subjects, d. the safety of the research environment, e. the adequacy of the proposed plan to share data. AWARD CRITERIA Applications recommended by the National Cancer Advisory Board will be considered for award based upon the following: a. scientific merit (as determined by peer review) b. availability of funds c. programmatic priorities. 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 sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the NIH policy on education in the protection of human research participants now required for all investigators, which is published in the NIH Guide for Grants and Contracts, June 5, 2000 (Revised August 25, 2000), available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research is now available online at http://cme.nci.nih.gov/. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA, Phase I Clinical Trials of New Anti-Cancer Agents, is related to priority area of cancer treatment. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. 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 Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 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 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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