Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI Table of Contents Part A 1 2 3 Part B 4 5 6 Part C 7 8 9 10 11 Part D 12 13 14 15 16 Part E 17 18 19 Appendices Part D: The Organization of a Clinical Trial 12. The Investigator and Protocol Chair: Roles and Responsibilities 12.1 The Investigator 12.1.1 The FDA Form 1572 12.1.2 Responsibilities of an Investigator for Human Subjects Protection 12.2 The Protocol Chair 12.2.1 Responsibilities 12.2.2 Who May Serve as a Protocol Chair The Organization of a Clinical Trial The following five sections provide a detailed description of NCI policies and procedures for individuals and institutions, including the research base. It includes a discussion of affiliates, accountability and storage of investigational agents, and monitoring and quality assurance. 12. The Investigator and Protocol Chair: Roles and Responsibilities An investigator is any physician who assumes full responsibility for the treatment and evaluation of patients on research protocols, as well as the integrity of the research data. The term distinguishes physicians acting as investigators from those who assume the more limited role of simply administering investigational agents. The investigator is responsible to see that the protocol is followed and the data are collected promptly and accurately, even if he or she delegates the administration of the agent to another physician. Most cancer trials involve collaboration among many investigators, one or more of whom is designated a protocol chair. 12.1 The Investigator There are over ten thousand physicians eligible to receive DCTD-sponsored investigational cancer agents. Most are eligible because they are investigators supported by a peer-reviewed NCI-funded grant, contract, or cooperative agreement. Each investigator agrees to certain essential principles of participation in clinical trials with investigational agents. These principles are contained in an agreement, the FDA Form 1572, http://ctep.cancer.gov/forms/index.html, which is defined by FDA regulation (see Appendix V). 12.1.1 The FDA Form 1572 In signing the FDA Form 1572, the investigator assures CTEP that the clinical trial will be conducted according to ethically and scientifically sound principles. More specifically, a signed FDA Form 1572 commits the investigator to the following obligations or tasks: The investigator provides on the FDA Form 1572 a statement of the education and experience which qualify him or her to perform the study. The investigator assures that a properly constituted IRB will be responsible for the initial and continuing review and approval of the study. Any changes in the research protocol will require IRB approval, and all unanticipated problems involving risks to human subjects must be reported to the IRB. Such changes must also be approved by CTEP (Section 8.6). The investigator is responsible for the proper and secure storage of the investigational agents and is required to maintain adequate agent accountability records (Section 15). The investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to each patient (Section 10). The investigator is required to furnish reports to the CTEP as the investigational agent sponsor (Section 10). In the case of multicenter studies, it is actually the coordinating center and the protocol chair who are responsible for the generation of these reports. The investigator is responsible for submitting data to the coordinating center. The investigator is responsible for promptly reporting any AE reasonably regarded as caused by or probably caused by the agent, and, if the AE is alarming, it shall be reported immediately (according to protocol guidelines). CTEP devised a detailed policy statement that adapts this necessarily ambiguous language to the setting of cancer clinical trials, so that an investigation may more easily determine when a medical event needs to be reported to CTEP (Section 11). The investigator shall maintain agent accountability records and case histories for 2 years following the date an NDA or BLA is approved for that indication or, for at least 2 years after the IND is closed, whichever is longer. CTEP will notify investigators when an IND has been closed. Upon the request of a scientifically trained and properly authorized employee of the DHHS (either FDA or NCI), the investigator will make records available for inspection and copying. The investigator certifies that he or she will personally conduct or supervise the clinical trials. If other physicians administer investigational agents, they will do so only under the direct supervision of the investigator. Each attending physician who meets the DCTD investigator definition is required to be registered with CTEP by submitting a completed FDA Form 1572 to PMB. The investigator certifies that he or she will inform subjects or their representatives that agents are being used for investigational purposes and will obtain the written consent of the subjects or their locally authorized representatives. The investigator assures CTEP that the study will not be initiated until the IRB has reviewed and approved the study. 12.1.2 Responsibilities of an Investigator for Human Subjects Protection The responsibilities of an investigator for IRB review deserve special mention. Each investigator who participates in NCI-sponsored clinical research must have the research approved by an IRB. The procedures followed by the investigator and his or her institution for the protection of human subjects, including IRB composition and function, as well as the basic elements of the informed consent document, are specified in regulations of the DHHS. All clinical research sponsored by DHHS must be in compliance with these regulations (Title 45, Code of Federal Regulations, Part 46 http://www.access.gpo.gov/nara/cfr/waisidx_01/45cfr46_01.html and Title 21, Parts 50 and 56, http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr50_01.html, and http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr56_01.html. Within DHHS, the Office for Human Research Protections (OHRP), http://ohrp.osophs.dhhs.gov/index.html, administers these regulations with each institution. The OHRP negotiates assurances of compliance with DHHS regulations for the protection of human subjects. Under an assurance, the IRB is authorized to review and approve research. Each investigator who participates in NCI-sponsored research must conduct the research at an institution with an OHRP-approved assurance. 12.2 The Protocol Chair 12.2.1 Responsibilities The chair of a clinical trial assumes certain responsibilities in addition to those of the participating investigator. Specifically, these include: Writing the protocol document Assuring that necessary approvals are obtained, including those of the IRB, the sponsor (DCTD), and any others for the protocol and subsequent amendments Monitoring the study during its execution, which includes: Reviewing each case record to confirm eligibility Reviewing each case record to determine compliance with the protocol Reporting adverse events Determining any necessary changes in the protocol and the informed consent documents and submitting them as protocol amendments to the research base and to CTEP Monitoring accrual to the study and stopping the study when the requirements of the study design have been fulfilled Reporting study status changes to CTEP (see Section 8.7). Analyzing Results: By assessing each case to determine eligibility, evaluability, adverse events, protocol compliance, and outcome (this assessment should be independent of that of the treating investigator) Reporting Results to CTEP: Results should be presented in fully analyzed and tabulated form. The protocol chair bears the primary responsibility for this task. In Cooperative Group trials, of course, the statistical center is the protocol chair's most important collaborator in fulfillment of reporting requirements. 12.2.2 Who May Serve as a Protocol Chair Since the protocol chair is responsible for meeting all NCI requirements for IND agent research, as stated in this manual, the protocol chair must be a fully qualified investigator. Trainees may not serve as protocol chairs. Table of Contents Part A 1 2 3 Part B 4 5 7 Part C 7 8 9 10 11 Part D 12 13 14 15 16 Part E 17 18 19 Appendices

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