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| Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI
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Part C: The Planning and Execution of a Clinical TrialThe following five sections provide a detailed description of the responsibilities of the investigator for the implementation of a clinical trial, from the drafting of the protocol to completion of the study. They are intended to guide both the protocol chair and the participating investigator and outline NCI policies on the responsibilities of each in the execution of a clinical trial.
7. The Drafting of a Protocol
The Planning and Execution of a Clinical Trial The following five sections provide a detailed description of the responsibilities of the investigator for the implementation of a clinical trial, from the drafting of the protocol to completion of the study. They are intended to guide both the protocol chair and the participating investigator and outline NCI policies on the responsibilities of each in the execution of a clinical trial. 7. The Drafting of a Protocol A protocol is the detailed written plan of a clinical experiment. This section details the essential features of a protocol. Careful attention to the following material will expedite the review of your protocol by CTEP. 7.1 Title Page The face sheet of the protocol is the primary source of identifying information for the Protocol and Information Office (PIO) of CTEP, for the agent distribution system, for the IND file at the FDA, and for the listing of the protocol in the Physician Data Query (PDQ) system. Each protocol submitted to CTEP, therefore, must have a title page or face sheet that contains the following items:
7.2.1 Schema All treatment studies should include a brief schema depicting the treatment regimen(s). 7.2.2 Objective(s) The objectives should be stated clearly. They generally should be stated as hypotheses to be tested. The study design should be capable of answering the questions posed by the objectives. The statistical section should clearly state how the data will be analyzed in relation to each of the objectives. The hypotheses to be tested in ancillary studies also must be clearly stated, and the statistical section should address analyses of the data in relation to these hypotheses. 7.2.3 Background and Rationale Sufficient background information should be included so that the rationale for the study is clear. Any unpublished data relevant to the rationale should be included in either this section, or, if extensive, as an appendix to the protocol submission. In addition to the background and rationale included for therapeutic aspects of a study, information should be provided to support ancillary studies to be performed. The rationale should be clearly stated for studying particular correlations between tumor characteristics and outcome measurements (response to therapy, disease-free survival, overall survival, etc.). The choice of the particular techniques to be used should also be justified. 7.2.4 Patient Eligibility Criteria The issues here have been discussed previously (Sections 4.1.3 and 5.1.2.2). Studies with objective response as an endpoint should include clear statements specifying whether tumor sites to be followed for response must be measurable, what criteria must be fulfilled to consider disease measurable, whether evaluable disease is permitted, and if so, at what sites. For ancillary studies, this section should include information regarding the choice of tumor sampling technique. For example, will aspiration biopsies be sufficient, or will surgical samples be required? How much tissue will be needed? What measures will be imposed to assure that the histopathologic diagnosis is not compromised? How will issues of tumor heterogeneity be addressed? What biases may be introduced by the sampling techniques and the amount of tissue required for the studies proposed? 7.2.5 Pharmaceutical Information A separate pharmaceutical section is required for each agent. The content of the pharmaceutical section is dependent on whether the agent is investigational or commercial. 7.2.5.1 Investigational Agent Pharmaceutical Section
7.2.5.2 Commercial Agent Pharmaceutical Section
7.2.6 Treatment Plan Describe the protocol treatment clearly so it can be followed by all staff involved in the treatment of patients and in the conduct of the study. See Appendix XVI, Guidelines for Treatment Regimens: Expression and Nomenclature. 7.2.7 Procedures for Patient Entry on Study Procedures for patient entry, whether randomized or nonrandomized, should be specified. Required information includes a description of the randomization process and the patient characteristics and stratification factors (if any) to be provided at the time of entry. Patients should be registered on study prior to beginning treatment. 7.2.8 Dose Modification for Adverse Events The plan of dose change for adverse events should be stated for each study agent. Dose modification criteria should be described in terms of NCI Common Toxicity Criteria. Protocol Authors should carefully review the Investigator's Brochure for all investigational agents to be sure that they have included all reasonable measures to monitor expected adverse events. Instructions for reporting adverse events should be included in the protocol text.
7.2.9 Criteria for Response Assessment The criteria for scoring responses should be included. These should be specific for both measurable and evaluable disease. Disease-specific criteria are often required and should clearly indicate acceptable means of measurement, i.e., CAT scans, radio-nuclide scans, ultrasound, etc. 7.2.10 Monitoring of Patients Specify how patients will be followed for assessment of treatment adverse events and therapeutic effect. A table of follow-up parameters that incorporates the schedule is particularly useful. The DCTD Common Toxicity Criteria should be used for all DCTD-sponsored trials. 7.2.11 "Off-Study" Criteria Criteria for terminating protocol treatment and/or removing a patient from treatment or from study should be specified. 7.2.12 Statistical Considerations An adequate statistical section discusses the study design in relation to the objectives of the study and the plan for the evaluation of the data, specifically:
7.2.13 Records to be Kept Specify the document on which each of the following is to be recorded, where it is to be sent, and on what schedule.
7.2.14 Participation All protocol treatments and observations will be made by investigator-physicians affiliated with a research base (refer to Section 3), and registered with CTEP. Under certain defined circumstances, it may be appropriate for interim treatments to be administered by certain physicians not registered with CTEP (other than trainees, who are assumed to be under the supervision of a registered investigator). In such cases, the protocol should state:
7.2.15 Multicenter Trials If an institution wishes to collaborate with other participating institutions in performing a CTEP-sponsored research protocol, then the following guidelines must be followed: Responsibility of the Protocol Chair:
Responsibilities of the Coordinating Center
Inclusion of Multicenter Guidelines in the Protocol
Agent Ordering
7.2.16 Laboratory Approaches to be Used for Ancillary Studies This section should include a description of the technical approaches to be used for ancillary studies. The description does not need to be extremely detailed, but it should provide sufficient information for the reviewers to determine whether the approach is appropriate and the proper controls are included. For example, if flow cytometry is to be used for analysis of ploidy or S-phase fraction, the methods section should indicate whether frozen tissue or paraffin-embedded tissue will be used, the number of cells to be counted per sample, the control cells to be used, etc. Details are not required regarding reagents to be used for standard techniques; reference can be made to the technique. Some evidence should be presented regarding the investigator's experience with the techniques to be used. 7.3 Informed Consent Each informed consent document must be protocol-specific and contain the elements required by Federal regulation. These regulations do not specify the language of the document but provide a list of elements that must be addressed in the text of the consent form. A checklist of these elements can be found in Appendix VII. CTEP will not approve a protocol if its informed consent form fails to address each of these elements adequately. The use of a model informed consent by a research base can assure inclusion of the essential elements and permits tailoring of the protocol-specific elements to the needs of individual studies. Minor changes to the model informed consent form may be made by the individual institutions. However, any changes in risks or alternative procedures should be approved by the originator of the informed consent document. CTEP will not approve a protocol if its consent form fails to address each of these elements adequately. Protocol authors should be certain that the description of expected adverse events is complete and balanced and reflective of the treatment plan to be used. Consult the Investigator's Brochure for information about expected adverse events for investigational agents and the package insert for commercially available agents. Adverse events of other modalities used in the study (e.g., radiotherapy, surgery) must also be described. In response to concerns that many informed consent documents for cancer clinical trials have become complex, lengthy, and difficult to understand, NCI convened a working group of medical, ethical, communication, and consumer experts along with officials from OHRP and FDA. The result of this initiative is the development of guidelines for writing consent documents that are more understandable to prospective research participants. They are called the Recommendations for the Development of Informed Consent Documents for Cancer Clinical Trials, which include a fill-in-the-blank consent form template and four sample consent forms. The Recommendations have the potential to improve the quality of informed consent in cancer clinical trials. We strongly urge you to use them as you write informed consent documents for cooperative group protocols. Also, you are encouraged to share the Recommendations with your IRBs. The templates are available as a working document on the CTEP website.
7.4 Protocol Templates NCI staff have developed several model protocol templates. To facilitate rapid review, you are encouraged to utilize the NCI protocol templates. Many clinical trials organizations have also devised model protocols and consents because the essential elements of a protocol are standard for a given class of studies, the elements of which can be altered to suit the needs of a particular study. The use of model documents is an effective way of ensuring a complete protocol. Those who use such models, however, should make certain that inappropriate "boilerplate" text does not get carried over to protocols where it makes little or no sense. Our experience is that disease-oriented background information and statistical sections (sample size estimates and stopping rules) are at greatest risk for the "word processor syndrome."
7.5 Protocol Checklist A protocol checklist is available (Appendix VII, also consult NCI web site, http://www.cancer.gov/, under Conducting Clinical Trials, Guide to Understanding Informed Consent, Safeguards-Simplification of Informed Consent Documents: Templates) to assess if your protocol document is complete. The protocol checklist also includes NCI-approved boiler plate language for administrative and agent-specific issues.
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