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| Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI
Part C: The Planning and Execution of a Clinical Trial10. Responsibility for Reporting Results to CTEP
10. Responsibility for Reporting Results to CTEP 10.1 Introduction The timely and accurate reporting of data from investigational agent trials to the sponsor is an important responsibility of investigators testing IND agents. The receipt of these reports in a timely fashion is not an arbitrary requirement. The information contained in them is the material that informs CTEP of the progress of the development of the agent and suggests promising new directions. In addition, the investigator is required by CTEP to meet his/her obligations under FDA regulations to (a) monitor the study and (b) submit reports of current findings to that agency. Failure to comply with these reporting requirements is a serious breach of the agreement that each investigator makes in signing the FDA Form 1572, http://ctep.cancer.gov/forms/index.html, and may result in suspension or termination of investigator privileges. For all trials, it is important to report two types of data: individual patient data and study summaries. Each is briefly discussed in the following paragraphs. Following that, specific reporting requirements for Phase 1 trials are detailed in Section 10.2.1; and for Phase 2 and 3 trials, in Section 10.2.2.
The case report document should not be the same as the patient's primary medical record. The former ultimately serves as the formal and fixed data base on which the study is reported. A well-designed case report form will assist the investigator and assistants in collecting and recording all data called for in the protocol. The patient's chart, although the primary medical record, is generally not organized for purposes of research and does not reliably contain the judgments of the treating physician on the effects of the protocol treatment. For these reasons, a separate research record (i.e., case report form or well-designed clinical trials database) should be maintained on each protocol patient. Case research records are best maintained concurrently with the medical record. A research record should include not only the actual data, but the responsible physician's assessment of the treatment effect (e.g., response category) and judgment as to whether any medical events in the patient's course were treatment-induced (i.e., agent-related adverse events). Unfortunately, adverse events are probably often underreported, particularly if the effect is well described.
In addition to data recording and reporting, investigators and protocol chairs have several other responsibilities for the reporting of pertinent protocol information to CTEP. Procedures for reporting study data vary according to the type of study and category of sponsorship. They are outlined below for the three phases of clinical agent development.
10.2 Report Requirements of Phase 1, 2 and 3 Trials 10.2.1 Clinical Trials Monitoring Service (CTMS) CTMS reporting is required for all early Phase 1 studies. NCI staff determine if a study is early Phase 1. The criteria to determine if a study is early Phase 1 include the first time the agent is utilized in human studies or the first time a new agent combination is used in humans or the first time an agent or combination is utilized in a specific patient group (e.g., children). For each patient on trial, data are recorded on a DCTD Case Report Form or its electronic counterpart, ACES software (described below). This form is specific for early Phase 1 pharmacokinetic trials. All information specified in the protocol should be recorded. It must be maintained prospectively. These forms are submitted biweekly (via mail or electronically) to CTMS of CTEP. The biweekly submission should include case report updates on patients actively on study and data on all new patients entered since the last submission. At the end of each course, the investigator should indicate which medical events in the patient's course were in his/her judgment agent-induced. All evaluations regarding adverse events should be reported using the DCTD Common Toxicity Criteria. These reporting requirements apply to all Phase 1 trials of agents newly entering clinical trial, including both adult and pediatric studies. The protocol chair will periodically receive a full report of his or her study from the CTMS and should review the printout for accuracy and report any discrepancies to CTMS. The CTMS provides CTEP with summary information on all trials in the database for each agent. The CTMS analyzes the data from Phase 1 trials for timeliness of submission and completeness and provides monthly reports of this analysis to CTEP investigators. A computer-based software package (ACES), available from CTMS, emulates the case report form. Data from Phase 1 trials may be entered directly in a PC; the software contains a facility for direct transmission via telephone to CTMS.
10.2.2 Clinical Data Update System The CDUS is the primary clinical trial data resource for DCTD and the Division of Cancer Prevention (DCP). A CDU should be submitted for all DCTD- and DCP-sponsored trials (Phase 1, 2, and 3). This includes all DCTD-sponsored Cooperative Group and CCOP Research Base treatment trials utilizing DCTD-supplied investigational agents; all DCTD-sponsored Cooperative Group and CCOP Research Base treatment trials utilizing non-NCI agents (commercial or investigational); all DCTD-grant funded non-Cooperative Group (Cancer Center or other institution) trials (if CDUS reporting is a grant requirement) utilizing non-NCI agents; all DCTD-sponsored Cooperative Group and CCOP Research Base non-treatment trials (accrual >100 pts.); and all DCP-sponsored CCOP Research Base cancer prevention and control trials. CTEP staff, in conjunction with external participants (e.g., Cooperative Groups, Cancer Centers, FDA, manufacturers), have made every attempt to define the minimum number of data elements needed to fulfill the regulatory, scientific, and administrative needs of the NCI. The type and amount of data required from an investigator depends upon the following:
Abbreviated CDUS
Complete CDUS Summary of the CDUS reporting requirements: Cooperative Groups and CCOP Research-Based Trials:
*CTMS-monitored Phase 1 trials should continue to be reported to CTEP using the CTMS system; these trials will not require CDUS reporting. **Please note that the NCI may choose to "upgrade" a Phase 1 or 2 treatment study from abbreviated to complete CDUS reporting based on the priority of a trial. Investigators will be notified in writing during the consensus review and protocol approval process regarding the reporting requirements for a given study. Non-Cooperative Groups (Cancer Centers and Other Institution) Trials Utilizing DCTD Agents or Grant Funding (If CDUS reporting is a grant requirement):
*CTMS-monitored Phase 1 trials should continue to be reported to CTEP using the CTMS system; these trials will not require CDUS reporting. **Please note that the NCI may choose to "upgrade" a Phase 1 or 2 treatment study from abbreviated to complete CDUS reporting based on the priority of a trial. Investigators will be notified in writing during the consensus review and protocol approval process regarding the reporting requirements for a given study. Additional information regarding the CDUS is available on the CTEP web site, http://ctep.cancer.gov/reporting/cdus.html.
10.2.3 Adverse Events The importance of reporting adverse events (AE) cannot be overstated. Section 11 discusses these requirements in detail. You are reminded that some types of events must be telephoned immediately. IDB maintains a 24-hour line at 301-230-2330 to record these messages. You are urged to call if in doubt concerning the need to report any particular reaction.
10.2.4 Study Status Changes in study status must be promptly communicated in writing to the CTEP PIO (See Section 8.7). Telephone discussions with CTEP physician staff are not considered formal notice of status changes.
10.2.5 Amendments All amendments to a Phase 1 protocol must be submitted and approved by CTEP prior to implementation (see Section 8.6).
10.2.6 Presentations A progress report of the study may be presented by the protocol chair at meetings of the Phase 1 Working Group held at NCI, usually twice a year. Minutes of the meeting are circulated to Phase 1 investigators and other interested parties.
10.2.7 Publications Any publication resulting from a DCTD-sponsored study should be sent to the Protocol and Information Office, CTEP, identifying the protocol by the NCI protocol number.
10.3 Retention of Records FDA regulations require that all research records (including patient charts, case report forms, x-rays and scans that document response, IRB approvals, signed informed consent documents and all agent accountability records) must be kept by the investigator for at least 2 years after an NDA or BLA has been approved for that indication or the CTEP IND has been closed. CTEP will notify investigators when these events occur. This requirement is an explicit part of the FDA Form 1572, http://ctep.cancer.gov/forms/index.html (see Appendix V). 10.4 Reporting to IRBs Each investigator must report to his or her IRB any problems, serious adverse events, or proposed changes in the protocol that may affect the status of the investigation and the willingness of patients to participate in it. The investigator must also give a report to the IRB at intervals appropriate to the degree of risk in the study, but no less frequently than once a year, or at study closure.
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