Clinical event committee or event adjudication committee (CEC)

Clinical event committee or event adjudication committee (CEC) File:Clinical Trial-6--.pdf

Overview

Clinical Events Committee (CEC) provides comprehensive clinical endpoints services for clinical trials and registries. The CEC services includes data management, document collection, document hosting, medical review and adjudication services. Current trials employ a paperless electronic clinical events adjudication system that allows for rapid communication, adjudication and archiving of events. Physician specialties include interventional and general Cardiology, Hematology, Neurology, Oncology, Endocrinology, and Hepatology to provide broad expertise across safety and efficacy events encountered in clinical trials.

Purposes

• The purpose of the CEC is to adjudicate and classify all events identified as potential organ system injury events based on investigator reported terms and identified Preferred Terms (PTs).

Roles

• The role of the CEC is to assist in identification of, and adjudicate the defined clinical events, in a blinded (treatment assignment, lipid results, and other core lab values that could unblind an adjudicator), consistent, and unbiased manner throughout the course of the study.
• The importance of the CEC is to ensure that defined events that have been reported are judged uniformly using the same definition by experts who are blinded to the treatment status.
• The aim of the CEC is to eliminate inherent variation by using standard criteria and definitions to adjudicate potential adverse events.

Responsibilities

• CEC responsibilities include making recommendations for site and adjudication CRF design, participating in testing of the adjudication system, assisting in event identification including review and approval of the Medical Dictionary for Regulatory Activity (MedDRA) trigger terms, determining required source documents for adjudication, assisting in site/CRA training, training of adjudicators and CEC support staff, event adjudication, and providing adjudication results to sponsor/Contract Research Organization within the agreed upon timelines as defined in the charter.

CEC Membership

• A CEC Chairperson oversees the CEC operations and has ultimate responsibility for the adjudication of all events.
• A CEC Project Manager coordinates all aspects of the clinical event adjudication process.
• The CEC Manager is responsible for the oversight of the organization and execution of the CEC process with the proper allocation of resources and adherence to the research protocol and CEC charter requirements. A complete list of the adjudicators for the trial is maintained on a separate signature and delegation log

Qualification and Selection of CEC Members

Individuals who will serve as CEC members are identified based on the following criteria:

(a) Credentials

The physicians participating in the adjudication process will meet the following requirements:

• Chairperson: Board-certified (or equivalent) cardiologist, with previous research experience as evidenced by publications and/or participation in clinical trials as a Principal Investigator or Co-Investigator. CEC Chairperson is responsible for oversight of the adjudication process and training of the adjudication team. He/She will also serve as the tie breaker for CV events when the initial adjudicators are not in agreement. He/She may act as a resource to the hepatic and neurologic adjudicators as needed.
• Potential Hepatic Injury Adjudicators: Phase I adjudication for potential hepatic injury events are performed by two specialists with advanced training in hepatology (liver disease), with previous research experience as evidenced by publications and/or participation in clinical trials and trained in the adjudication process. Phase II adjudication of potential hepatic injury events is performed by the same two individuals via teleconference.
• CV and Death Physician Adjudicators: Phase I Adjudication for death and cardiovascular events is performed by two cardiology fellows who are also board certified (or equivalent) in Internal Medicine, and have completed at least the first year of their cardiology fellowship and are trained in the adjudication process. Phase II adjudication will be performed by a board-certified or equivalent cardiologist or the CEC Chairperson also trained in the adjudication process.
• Neurology Adjudicator: Phase I Adjudication for neurologic events are performed by two board certified neurologists (or equivalent).
• Manager: A Research Program Manager, who is responsible for the operational oversight of the CEC
• Project Managers: Personnel with both clinical and research experience that are knowledgeable about the coordination, implementation, and the conduct of the CEC process. This person is the liaison between CEC and the sponsor.

(b) Affiliation

• Issues surrounding affiliations are resolved in accordance with the terms and conditions of the agreement.

(c) Previous research experience

• The adjudicators selected will have previous research experience as evidenced by publications and/or participation in clinical studies.

(e) Trial association

• The CEC Physician Adjudicators should not adjudicate for studies in which they are the Principal Investigator, a Co-Investigator, or in which they have any other direct or indirect involvement (e.g., Steering Committee Member, IDMC Member, Consultant, etc.).

Training

Training documents are maintained in the electronic trial master file (eTMF). Training may include the following:

(i) Overview presentation of the protocol.

(ii) Clinical events to adjudicate and their definitions.

(iii) Explanation of the clinical event package contents.

(iv) Utilization of the IBM Clinical Development Endpoint Adjudication System (EAS).

(v) Familiarization with adjudication conventions (e.g., electronic adjudication forms completion, generating queries, password reset, etc.).

(vi) Discussion of adjudication commitment, timelines and workload.

(vii) Demonstration of adequate performance on adjudicating test cases.

Addition or Replacement of Adjudicators

• Over the course of the study, it may be necessary to add or replace members of the CEC. The additional and replacement Physician Adjudicators will undergo the same selection (qualification) and training process as initial adjudicators. If necessary to replace an adjudicator attempts will be made to onboard the new adjudicator prior to the retirement of the leaving adjudicator(s).

Responsibilities of the CEC Members

Chairperson Responsibilities

The CEC chairperson responsibilities include:

• Oversight of the adjudication process.
• Co-development with the sponsor and the Executive Committee and approval of this CEC Charter, including endpoint definitions.
• Co-development and approval of study specific triggers.
• Selection, approval, and training of CEC Physician Adjudicators.
• Phase II adjudication of all events. May also do Phase I review if there is an urgent need.
• Communication with IDMC as needed.
• Attendance at meetings with sponsor as needed.
• Providing recommendations for improving quality of clinical event dossiers.
• Reviews the Quality Assurance (QA) results and makes recommendations for additional training and/or definition revisions as needed.

CEC Manager Responsibilities

The CEC manager responsibilities include:

• Oversight of the organization and execution of CEC process with the proper allocation of resources and adherence to charter requirements.

• Assessing timelines, implementing strategies to address deviations from proposed timelines and budget.

CEC Project Manager Responsibilities

The CEC project manager(s) responsibilities include:

• Facilitate the CEC Chair and study team in writing endpoint definitions

• Adjudication form content development and ensuring endpoint variables are collected on that form.

• User Acceptance Testing of the CEC project manager and adjudicators roles in the EAS.

• Developing data collection tools for the monitors and study coordinators.

• Tracking of all events and closely monitoring data flow.

• Coordinating all operational aspects of the CEC adjudication process.

• Reviewing all supporting documents to ensure complete data for CEC adjudication and requesting additional data via the EAS.

• Maintaining study documentation.

CEC Physician Adjudicator Responsibilities

The CEC Physician Adjudicator responsibilities include:

• Independently adjudicating all potential clinical events in a timely manner.

• Communicating whether additional documentation is required for adjudication in the chosen EAS.

• Completing adjudication forms for each potential event adjudicated in the EAS.

Specifics of CEC Operation

Specific Procedures at Sites

• Sites will be provided a detailed instruction manual for the reporting of events.
• When a protocol specified endpoint has been identified, the investigator (or designee) must complete the appropriate pages of the electronic CRF. In addition, source documents related to the event must be collected and blinded (as described in the site manual) for submission via the EAS.
• Site personnel are responsible for collecting the appropriate source documents related to potential events in a timely manner, retaining them in their study file, and uploading into the EAS.

Dossier Preparation

• Code of Federal Regulations Title 21 compliant electronic databases should be used for dossier preparations (e.g. IBM Clinical Electronic Adjudication System- EAS)
• EAS will manage tracking of all events, source document collection and requests, and status reporting of the flow of adjudication and re-adjudications. This includes identification of events and assuring that duplicate events are not sent.
• An escalation plan should be in place to address timeliness of document submission from the sites.
• EAS will have available tracking and activity reports to ensure that timeliness of adjudications is maintained.
• A report will be made available reconciling events adjudicated as resulting in death; against the adjudicated cause of death. This report will be available on a regular basis for the Sponsor and Executive Committee if requested.
• Cases will be assigned randomly to adjudicators
• Each Clinical Event Dossier will reside in EAS (no paper adjudication files will be maintained) and may consist of the following:
  • Patient Profile: This is a list of selected CRF fields (including SAE form information) that contain event related information, including a cumulative list of previous clinical events submitted.
  • Supporting Documentation: The CEC will use the source documentation received in the event adjudication process. Copies of both the original language and English translation should be included in the event dossier and blinding should be maintained.
  • Narrative Form: Brief narrative in English is required and entered by site personnel (as defined in the delegation of authority log) summarizing the potential event when source documents are not available. In the event that no additional source documents are available from the site/subject, this narrative will serve as the basis for the adjudication. The recommended content for the narrative will be provided in the Site Instruction Manual. The site will complete the paper narrative and upload it as a Portable Document Format (PDF) in the EAS.
  • Event Adjudication Form: This is the form completed in the EAS by the CEC adjudicators and will serve as the final record of the event’s adjudication.
  • Paper Type Documents: Charter, Trigger Documents, Curriculum Vitae, Training documents, etc.

Request for Additional Information

• EAS is used to request for additional information if necessary.
• A query is generated for additional information to the study site within 2 business days of receipt of the query and followed-up with the site until the requested information is obtained or until written documentation explaining that the information is permanently unavailable is received.
• In the situation where documents cannot be obtained, the narrative provided will serve as the basis for the adjudication.

Re-adjudications

• Re-adjudications may be required after an event if:
  • 1) Key fields (identified in a separate document) on the eCRF change
  • 2) New relevant source documents are available
  • 3) Critical changes occur in the protocol or CEC charter that are deemed significant
  • 4) An obvious error is detected and picked up incidentally
  • 5) During QA process a systematic error is discovered, it may be determined that a re-adjudication is deemed necessary if the changes or new information could conceivably change the adjudication result
• If yes, the EAS administrator will be directed to move the case to a status so the update can be presented again to the adjudicators for re-adjudication.
• It is the sole discretion of the CEC Project Manager to determine whether the additional source document has clinically relevant information that has impact on adjudication results, requiring event re-adjudication.
• These decisions will be documented within the EAS. All re-adjudications (including the reconciled death/events resulting in death re-reviews) will be finalized prior to database lock. If re-adjudication is required for any reason other than new source documents or information in a key field changing the reason for the re-adjudication(s) will be documented.

CEC Commitment and Workload

• Clinical event dossiers should be available as soon as information is collected and all available source documents are reviewed.
• CEC adjudicators generally have 10 working days to complete adjudication forms via the EAS.
• This timeline may be shortened before key study milestones such as IDMC meetings, interim analysis, or database lock.
• With the proper advance notice, the CEC will remain flexible to fluctuating timelines to meet the demands of the study. Clinical event adjudication will occur on a regular and consistent basis throughout the course of the study.
• The sites will receive the proper training to ensure they are aware of the importance of reporting events in a timely manner and are aware of what is required when reporting an event.
• From start-up to study close, there will be consistent communication between the CEC and the study team for day-to-day issues related to overall progress and other issues that may arise, such as protocol amendments, study timelines, IDMC requests and requirements for expedited clinical event adjudication, etc. To achieve this, teleconferences will occur between the appropriate parties whenever needed.

Quality Assurance

• It is the goal of the CEC to provide a high quality service and to remain consistent in adjudicating clinical events for the entire length of the study. The CEC will conduct all of its operations under Good Clinical Practices (GCP) and based on the CEC SOPs.
• To ensure accuracy and consistency of the adjudications, a quality assurance (QA) assessment will be performed on the adjudication process and results from this study.
• Results will be assessed by the CEC Project Manager and CEC Chair throughout the study per the CEC QA plan.