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| Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents
Part C: The Planning and Execution of a Clinical Trial8. Protocol Review and Approval at CTEP
8. Protocol Review and Approval at CTEP 8.1 The Protocol and Information Office (PIO) Within CTEP, the PIO manages the review process and maintains the official record of all CTEP-sponsored protocols, amendments, results, publications, and protocol-related communications as well as all protocol submissions for PDQ, http://www.cancer.gov/search/clinical_trials/, and FDA. More than 10,000 protocols are maintained in the PIO. All protocols and related correspondence should be addressed directly to the Head, PIO, Executive Plaza North, Room 7000, 6130 Executive Boulevard, Bethesda, Maryland, 20892. The PIO will distribute all mail to the appropriate CTEP physician staff. Please do not direct protocol-related materials to any other CTEP staff member. Doing otherwise will lengthen the time required for resolution or review. The fax number for the PIO is 301-496-9384. In the submission of each new protocol, please also include a Protocol Submission Worksheet, http://ctep.cancer.gov/forms/index.html. All telephone calls regarding status of protocol and amendment reviews should be directed to the PIO at 301-496-1367. 8.2 How to Submit a Protocol Each new protocol should be sent directly to the PIO. You must include in the submission:
If these items are missing or incomplete, the submission will be returned to the protocol source without review. Upon receipt by the PIO, each protocol is assigned an NCI protocol number. You will receive an acknowledgment of your protocol submission with the NCI-assigned protocol number. This NCI protocol number must be referenced in all subsequent communications with CTEP regarding this study. The assignment of this number does not imply approval; only the final approval letter signifies approval and the authorization to order investigational agents.
8.3 IRB Approval Each investigator must meet the requirements of the Federal regulations for human subjects assurances and informed consent and for IRB review and approval (45 CFR 46: http://www.access.gpo.gov/nara/cfr/waisidx_01/45cfr46_01.html and 21 CFR 50 and 56: http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr50_01.html. Also see Section 12.1.1 and Section 12.1.2). Except for Cooperative Group protocols, each protocol must have documentation of IRB approval prior to CTEP approval. Evidence of IRB approval may be submitted to CTEP at any time in the review process. If multiple institutional IRBs are involved, only the approval from the coordinating research base need be submitted for CTEP records; of course, each investigator must meet Federal regulations for informed consent and IRB review (45 CFR 46 and 21 CFR 50 and 56). Failure of investigators to submit evidence of IRB approval is a major cause of delay in protocol approval. The documentation requirements are satisfied by completion of Form 310, or by a letter specifying:
8.4 Protocol Review CTEP must review and approve every protocol involving DCTD investigational agents or studies that have any NCI support (funding). Each protocol is reviewed for completeness, scientific merit, duplication of existing studies, patient safety, and adequacy of regulatory and human subjects protective aspects. Click to review descriptors of CTEP's Review Types and Decision Tree (MS Word)
8.4.1 Receipt of the Protocol by CTEP Upon receipt, the protocol is checked for completeness (including legibility, complete pages, presence of required sections, and the informed consent). All protocols submitted to the NCI must also include the Protocol Submission Worksheet (Section 8.2). Each protocol is also examined to verify that the investigator/institution is eligible to conduct a DCTD-sponsored study; i.e., has an approved mechanism of sponsorship by NCI (Cooperative Group, Cancer Center, contract, R01/P01, etc.). Investigator eligibility is explained more fully in Sections 4.2, 4.3, 4.4, 5.2, 5.3, and 6.2. If the protocol is incomplete, or the investigator/institution is not eligible under the proposed category of sponsorship, then the protocol source is so informed and the study is not reviewed for scientific content. CTEP sends the protocol source an acknowledgment of studies that are complete and eligible at submission.
8.4.2 Scheduling the Protocol for Review The PIO schedules the protocol for review by the Protocol Review Committee (PRC) within approximately 2 weeks of receipt. The cutoff date for protocol receipt is Thursday at noon. Protocols that are complete and eligible are registered and scheduled for review the second Thursday after receipt. Therefore, a protocol arriving Thursday morning will be scheduled for review in 14 days; if that same protocol arrives Friday, it will wait another week for registration and distribution, and require 20 days to reach the review committee.
8.4.3 Review by the CTEP Protocol Review Committee All protocols are reviewed by the CTEP PRC. This committee, composed of the professional staff of CTEP, additional consultants from other NCI divisions, and chaired by the Associate Director, CTEP, meets weekly and usually reviews 10 to 20 protocols, LOIs and concepts at each session. Each protocol is assigned a minimum of five reviewers; as many as six to seven may be required for complex multimodality protocols. The protocol and informed consent form are reviewed by an oncologist(s), biostatistician, pharmacist and regulatory affairs professional(s) with expertise in informed consent issues.
8.4.3.1 The Review of the Protocol The PRC discusses the protocol after hearing the reviews of each assigned reviewer and makes a decision that the science and safety of the study are:
The PRC disapproves relatively few submitted studies and only does so when it feels that a proposal is unnecessarily duplicative or irretrievably flawed in concept, design, safety, or feasibility.
8.4.3.2 The Review of the Informed Consent The PRC also reviews the informed consent document to be certain that:
It is not the intent of the CTEP informed consent review to supplant the review of the IRB. Provided the consent document meets the requirements of regulation and law and contains sufficient information to enable an individual to make an informed choice, the local IRB approval of the contents of an informed consent document is generally to be regarded as definitive. Minor changes to the CTEP-reviewed 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.
8.4.3.3 The Review of Regulatory and Administrative Concerns The PRC also reviews each protocol to assure proper instructions for reporting adverse events are included, an accurate and up-to-date pharmaceutical section is provided, and necessary instructions for multicenter trials are given, if appropriate. Please refer to the protocol checklist for a complete list of all regulatory and administrative issues (Section 7.5).
8.4.3.4 The Consensus Review After the PRC meeting, the primary reviewer generates a consensus review, which states the collective concerns of the PRC. This consensus review, together with a cover letter stating the summary PRC decision, is sent to the protocol source within approximately 30 days of receipt of a complete protocol.
8.4.3.5 Responding to CTEP Consensus Review If revisions are required in the protocol or the informed consent, the investigator should send a revised protocol and/or informed consent document to the PIO. The revised documents should be accompanied by a cover letter that details the responses to the points raised in the consensus review. If the reviewers find the response satisfactory, then the protocol goes forward for final approval. The consensus reviewer may choose to send the revised protocol back to the full PRC for further consideration. In any case, if the protocol is still not accepted, then a letter is sent to the investigator detailing any remaining CTEP concerns. The investigator should respond to this re-review in the same way as described for the initial consensus review. This process continues until the science, regulatory, and administrative aspects, and informed consent are each accepted or the study is withdrawn or disapproved. Each evaluation of a revised study requires 10 - 30 days on average.
8.5 Protocol Approval Upon final acceptance of the protocol and the informed consent, as indicated by the concurrence of the consensus reviewer and appropriate CTEP staff, a letter of protocol approval is sent to the protocol source. Please note that protocol approval will not be given by telephone. Although CTEP staff may discuss the study with the protocol chair, he or she should consider nothing official until written notice is received. Approval letters are sent via fax if the protocol source has provided a fax number. After written approval is sent, orders for investigational agents will be honored. All approved protocols using DCTD-sponsored agents are submitted to the FDA as part of the IND file.
8.6 Amendments Any change to the approved protocol document must be documented point by point in a cover letter, and a replacement page(s) or a revised protocol document submitted to the PIO (See Protocol Submission Worksheet, http://ctep.cancer.gov/forms/index.html, Appendix VIII). Please reference the NCI protocol number, date each amendment, and number sequentially for each study. Upon receipt, each amendment is reviewed by CTEP staff.
8.6.1 Editorial Amendments To reduce unnecessary workload for all parties involved, amendments that only include editorial and administrative (except as outlined below) changes do NOT require prior CTEP approval. CTEP will send the Principal Investigator an approval letter for their records. CTEP would recommend that all editorial and administrative amendments for a given protocol be batched and submitted at one time. CTEP would recommend that the editorial comments be submitted on an annual basis or incorporated into an amendment that relates to scientific, safety, or other issues.
Examples of editorial changes would include:
8.6.2 Activation Amendment Any change in the protocol that occurs between CTEP approval and activation by the research base should be submitted to CTEP as an "Activation Amendment." Such amendments are often used when the CTEP approval letter conveys recommendations that the investigator wishes to implement.
8.6.3 Scientific and Participant Amendments
Each amendment is recorded in the official PIO protocol file, the agent distribution file, the IND file, PDQ, and by the CTEP Clinical Trials Monitoring Service (CTMS), where applicable.
8.7 Study Status Changes in study status should be communicated immediately to the CTEP PIO. Changes can be easily reported via amendment (See Appendix VIII). The following list shows the categories of study status recognized by CTEP and PDQ (also see Appendix IX):
8.8 Reactivation of Studies Protocols that are temporarily closed require written CTEP approval prior to reactivating if they are:
Protocols that are temporarily closed to accrual by the research base based on early stopping rules do not require CTEP approval to be reactivated.
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