Procedures for Scientific Review and Monitoring
The Protocol Review Committee (PRC), where direct protocol review is conducted as part of the Cancer Center’s Protocol Review and Monitoring System, was established in April of 1993 in response to NCI’s policy statement dated December 7, 1992.
The PRC is charged with the review of all clinical cancer protocols proposed at the University of Vermont prior to initiation and on an ongoing basis with the following goals:
- To evaluate the scientific rationale for the protocol.
- To determine that high quality and appropriate clinical trials and statistical design have been incorporated in the protocol.
- To determine that the Informed Consent Form accurately reflects the scientific content of the protocol.
- To determine that appropriate physician and facility resources for performance of the protocol are available.
- To prioritize the protocol based on scientific merit and consideration of other protocols available within the institution.
- To advise the Cancer Center Director on the merits of the protocol for allocation of shared resources.
- To monitor the protocol for serious adverse events.
Clinical research that must be reviewed by the PRC includes but is not limited to the following:
- Physical interventions for the treatment, staging or diagnosis of cancer or cancer-related problems.
- Interventions to obtain specimens from cancer patients for the sole purpose of performing basic laboratory studies related to cancer.
- Interventions to obtain specimens from normal subjects for the sole purpose of performing basic laboratory research studies related to cancer.
- Use of stored specimens from cancer patients or normal subjects for basic laboratory research related to cancer.
- Physical interventions for the prevention of cancer.
- Physical and non-physical interventions for the determination, management, and study of cancer risk in normal subjects.
- Physical interventions for the detection of cancer in normal subjects.
- Diagnostic tests that affect medical decision-making for the cancer patient.
- Behavioral and nutritional studies that are cancer-related, such as those studies that increase behaviors (e.g., cancer screening, food intake), eliminate or reduce behaviors (e.g., smoking, sun exposure), and/or improve coping and quality of life/reduce the negative effects of treatment.
IRB approval to activate requires compliance with this adopted definition of the scope of the PRC review process, and requires PRC approval.
Protocol Submission Criteria and Process
The protocol review process is initiated by the submission of required protocol information to the PRC by the Principal Investigator (P.I.). The protocol may be submitted simultaneously to the IRB for review, but cannot be activated until both the IRB and PRC approve it.
Externally peer-reviewed protocols (NCI or cooperative group) are assigned a single primary reviewer; protocols without external peer review (investigator-initiated protocols or industry protocols) are assigned two primary reviewers. A full copy of the protocol is distributed to each reviewer. Reviewers are usually members of the PRC; ad hoc reviewers may be recruited to provide special expertise at the discretion of the Chair. All externally peer-reviewed protocols receive directed reviews for resource utilization by the Nursing Service, Pharmacy Service and Data Management Office. All investigator-initiated and industry protocols also receive directed reviews for resource utilization by the Nursing Service, Pharmacy Service and Data Management Office as well as a separate review by the Biostatistics Office. Each primary reviewer completes a "Protocol Checklist" which includes items such as clarity of goals, appropriateness of study design, adequacy of patient population, and relevance to VCC goals and importance of study.
The PRC meets once a month (the second Tuesday of the month) with meetings timed to occur approximately one week before the meeting of the IRB (third Wednesday of the month) so that progress of a protocol through the review system is not unnecessarily delayed. P.I.’s may attend the PRC meeting but are not required to attend for the review to move forward. Each protocol is presented by the reviewer(s) and discussed by the full Committee, followed by a Committee vote. Based upon reviewer(s) comments and those of other members, one of the following recommendations is made: 1) approve, 2) approve with revisions, 3) table, or 4) disapprove. This information is transmitted to the investigator and to the IRB. If a protocol is Approved or Approved with Revisions and it competes with another protocol, a priority (high, moderate or low) is assigned by Committee consensus. The P.I. is informed in writing of the Committee’s action and, if appropriate, member comments. If a protocol is Approved or Disapproved, no response is required. If a protocol is Approved with Revisions or Tabled, a written response is expected. If no response is received within 90 days, the protocol is considered to have been withdrawn. The status of each protocol for which a response is pending is reviewed at each meeting as Old Business. If a protocol has been Approved with Revisions, the PRC Chair may grant "Interim Approval" immediately upon receipt of a satisfactory response, with Approval being certified at the next PRC meeting. If a protocol has been Tabled, the response must be reviewed and discussed at the next PRC meeting before the protocol status is changed.
Once a protocol is approved the investigator is required to update the PRC with patient registrations, serious adverse events, study closure, and future plans and publications. All of this information is communicated to the Cancer Center’s Clinical Research Oversight Committee (CROC). All PRC meetings are minuted and a master copy is kept in the PRC file. Minutes are reviewed and approved at the next meeting and are distributed to PRC members, the IRB, and to the Cancer Center Director.
Any substantive amendment to an ongoing investigator-initiated or industry protocol must be submitted to the PRC for review and approval. Cooperative group amendments are not reviewed by the PRC.
Protocol Review Criteria
The criteria for non-peer reviewed protocols are more rigorous than those for externally peer-reviewed protocols. In the case of the latter the focus is whether the protocol competes with an investigator-initiated study and the use of Cancer Center resources. In the case of non-peer reviewed protocols, reviewers are asked to evaluate the protocol goals, study design, background information, eligibility criteria (including inclusion of women and minorities), evaluation criteria, provisions for toxicity and side effects, feasibility of completion, use of nursing data management and pharmacy resources, and Informed Consent Form. Although the Protocol Checklist allows a simple check-off, reviewers are encouraged to provide comments describing any areas of concern. Other members of the PRC receive a copy of the Lay Summary of the protocol although they may request a full copy for review.
To assist investigators and reviewers alike, the IRB has developed a Human Research Protocol Form (PDF). Failure to follow the Model Protocol format will result in a delay in review (i.e., a study that does not include the required elements will not be reviewed until all elements have been addressed).
As noted above, externally reviewed protocols are assigned one primary reviewer, while investigator-initiated protocols (and industry studies) are assigned two primary reviewers. All investigator-initiated and industry protocols are reviewed by a biostatistician and every protocol must include a statistical considerations section.
All investigator-initiated and industry studies also receive directed reviews for resource utilization i.e. Nursing, Pharmacy and Data Management by representatives of those support services that are on the committee.
In early 1997 the VCC Clinical Research Oversight Committee (CROC) was charged with responsibility for Data and Safety Monitoring. The CROC is a senior leadership committee.
The Committee has adopted the principles of monitoring and data safety as outlined in the NIH Policy for Data and Safety Monitoring, specifically that:
- All clinical trials require monitoring.
- Monitoring should be commensurate with risks.
- Monitoring should be commensurate with the size and complexity of the study.
- Monitoring must be performed on a regular basis, and conclusions of the monitoring reported to the appropriate individuals/groups.
Current monitoring activities include the following:
Internal Audits of Investigator-Initiated Studies
The monitoring of the study is the primary responsibility of the investigator. The Vermont Cancer Center's CROC reviews internal audits of investigator-initiated trials. The intent of these internal audits is to improve clinical research at UVM/FAHC. Please read the attached documents which review the audit process and a sample of an Audit Report which will be given to the PI after the internal audit.
Phase I Studies
Because of the nature of a Phase I study, the monitoring of the study is the primary responsibility of the investigator. Any unexpected/serious adverse event is immediately reported to the IRB, study sponsor, FDA (if appropriate), and the PRC. A Quarterly Data Safety and Monitoring Report form was instituted in 1999 to assist investigators in monitoring Phase I studies.
Phase II Studies
Same as above. Multi-center studies must include a provision for audit.
Phase III Studies
N/A. Phase III studies are beyond the scope of the patient and infrastructure resources of our institution. Phase III studies will be conducted through the cooperative group or similar mechanism.
All studies are monitored for accrual through a mandatory registration system. Investigator-initiated study accrual data is reported quarterly to the PRC. The CROC reviews all data annually.
Criteria for Early Review
Early protocol review or circumstances that would prompt an early review are:
- Planned interim analysis at specified time points or after reaching specified accrual levels (e.g. interim analysis prior to dose escalation).
- Unexpected/serious adverse events.
- As a result of audit.
- Low (>30% below projected accrual) or Excessive Accrual (>10% above total projected accrual).
In the case of planned interim analysis, the investigator is responsible for notifying the PRC of the results of the analysis.
Unexpected/serious adverse events must be reported to the PRC. Upon receipt of notification, the PRC Chair, depending upon the seriousness of the event, may immediately take action or wait until the next meeting of the Committee.
Early review may also be required following an audit to document corrective action as outlined in the corrective action plan.
Criteria for Termination of Protocol
Criteria for termination of a protocol are the same as those for protocol closure. Protocols may be closed for the following indications:
- Serious unexpected or adverse event(s) may result in protocol suspension or protocol closure.
- Serious (or multiple) deficiencies in study conduct (e.g., lack of informed consent, violation of patient eligibility criteria, failure to report an adverse event(s) in a timely fashion, etc.)
- New data suggesting the active protocol is irrelevant in terms of study objectives and patient benefit.
- Inadequate accrual (> 30% below projected accrual) with little or no likelihood that study's target will be met.
- Excessive accrual (> 10% above the total projected accrual).
- Target accrual and/or study objectives met.
- Principal Investigator leaves institution.
Last modified February 13 2013 01:10 PM