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Chapter XX - Compliance Monitoring and Oversight Activities

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Initial review and continuing review through life cycle are the primary mechanisms by which the IRB monitors research. This chapter describes additional means by which the GA IRB fulfills its oversight and monitoring responsibilities.

DATA MONITORING COMMITTEES (DMC)
A DMC is a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from an ongoing research protocol. All clinical trials and many other types of human research protocols require safety monitoring, but not all trials require a DMC. The GA IRB may stipulate the requirement for a DMC when it finds that a DMC is needed to provide objective safety monitoring for a particular clinical trial or other protocol. This decision will be based on the size, scope, and risks of the study. In general, Phase III studies, large clinical trials, and studies presenting unusual risks to patients most often require review by a DMC. A DMC should also be established in trials where mortality and morbidity serve as the end points. The DMC is responsible for recommending trial termination when participant safety is jeopardized.

When a clinical trial or other protocol is determined by the GA IRB to require a DMC, the DMC will be charged with reviewing and monitoring the accumulating data from an ongoing clinical trial on a regular basis. The Principal Investigator must submit as part of the protocol submission to the GA IRB a copy of the DMC charter and a plan to assure regular submission of DMC reports to the IRB. After an appropriate analysis of the accumulated data, the DMC should advise the Sponsor and the GA IRB regarding the continuing safety of the participants in the trial as well as the continuing validity of research. The DMC should report any early evidence of benefit or harm to trial participants that may be attributable to one of the treatments under evaluation. DMCs conduct the following activities as appropriate:

  • Monitor and evaluate safety of the participants as pre-specified in the interim monitoring plan of a protocol and adhere to all appropriate human participant protectionrequirements;
  • Monitor and evaluate the efficacy of the treatments being tested as specified in the interim monitoring plan of a protocol;
  • Monitor for early-unanticipated therapeutic results;
  • Monitor the performance of the clinicaltrial;
  • Make recommendations to the Sponsor and the GA IRB to continue, amend, improve, terminate the study, plan additional and future clinical trials, recommend administrative adjustments, assess the appropriateness of the statistical assumptions, provide advice on an ad hoc basis to the Sponsor and the IRB for monitoring ongoing protocols, and ensure and preserve clinical trial integrity based on the interim analysis for safety andefficacy;
  • Review safety data on a regular basis during the study and provide a written opinion to the Sponsor and the GA IRB. The opinion willinclude:
    • Risk assessment: Are study patients being exposed to unreasonablerisk?
    • Study continuation assessment: Does the DMC support continuation of the study without changes to the protocol? Does the DMC support continuation of the study but with specific changes to the protocol? Overall safety assessment (upon completion of thestudy).

At any point during the conduct of the study should the DMC observe a clinically significant unexpected difference in the safety profile emerging between the treatment group and control/comparison group or a greater than expected incidence of major complications in the entire study population, the DMC may (i) request that enrollment be suspended while the safety of participants is further evaluated, (ii) recommend stopping the study, or (iii) recommend a change in the study for safety reasons. The final decision on the outcome of the DMC finding will be the responsibility of the Sponsor.

Based on information provided, the DMC has the mandate to recommend that the study be halted if there is strongly suggestive evidence of participant risk or treatmentharm. The DMC has the responsibility to request that enrollment be suspended at any time while a further evaluation of safety is undertaken.

VERIFICATION OF UNAPPROVED CHANGES IN APPROVED PROTOCOLS
32 CFR 219.103((4)(ii) requires written procedures which the IRB will follow for determining which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review; this is a part of the GA IRB’s monitoring and oversight activities. The GA IRB may consider the following in making determinations of which projects require this type ofverification:

  • Randomly selected studies;
  • Complex studies involving unusual levels or types of risk toparticipants;
  • Protocols conducted by investigators who previously may have failed to fullycomply with the requirements of the regulations or the requirements of the GA IRB;
  • Protocols where concern about possible material changes occurring without IRB approval has been raised, based upon information provided in continuing review reports, or from other sources;
  • Studies involving investigators with potential conflicts of interest, such as owning a significant amount of stock of the firm that is manufacturing the test agent;
  • Protocols where issues have been raised by the medical monitor or by a DMC regarding any discrepancies observed, the medical condition of the participants, or other matters that raise safety or other concerns.

Need for an independent verification may be raised during a scheduled continuing review, review of safety or other updates, and at or in advance of any scheduled meeting. The GA IRB Chair will determine if new reports and relevant IRB documents are immediately available or will have to be assembled for consideration at the next scheduled meeting.

GA IRB actions that may be considered include a finding of: (a) no verification needed; (b) examination of possible prior events through “For Cause” (FC) audit (see below); or (c) verification at specified intervals during the subsequent approval period.

If, because of verification efforts by the GA IRB, unapproved significant changes are found to have been deliberately instituted, the IRB will pursue the matter as a case of non-compliance with the federal requirements and may require immediate suspension of IRB approval as a first step.

“FOR CAUSE” STUDY AUDITS TO ASSESS COMPLIANCE
For Cause (FC) study audits to assess compliance are usually based on “red flags.” Examples of “red flags” include but are not limited to reporting of a high frequency of protocol deviations, investigators who repeatedly miss deadlines, or investigators who submit poor quality documents. Issues can be identified through review of the protocol or protocol life cycle actions, through information obtained on similar studies or studies conducted by the same Principal Investigator and through reporting of concerns to the IRB. A FC audit may stand alone or be initiated as part of an investigation into allegations of non-compliance.

A FC review by the GA IRB office may include: review of study master file documents; review of participant file documents, assessment of record management; focused review of consent form documentation; assessment of participant eligibility; assessment of source documentation; assessment of adherence to the approved protocol; review of test article accountability; observation of the informed consent process or study procedures; interviews with investigators and study staff.

At the end of the visit, the findings of the audit team, with any required corrective actions, will be provided to the Principal Investigator, the Institutional Official or his/her representative and/or other parties, as appropriate.

If the audit raises urgent safety or regulatory concerns, the GA IRB will be notified immediately to determine if a hold on new enrollment or study suspension is warranted pending further review of the audit report. Otherwise, the GA IRB will be informed of any findings and any required corrective actions at the subsequent IRB meeting.

Upon review of the audit report, the GA IRB may determine that additional actions are necessary. These actions could include but are not limited to termination or suspension of the research, training for the Principal Investigator and study personnel, or further investigation and consideration regarding serious and/or continuing non-compliance.

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