Sponsor

Trial close-out is one of the key aspects of quality control. Activities undertaken during close-out ensure that all essential and necessary documents are archived as per Standard Operating Procedures (SOP), Good Clinical Practice (GCP) and regulatory guidelines for inspection or retrieval in the future. Trial close-out is the responsibility of the sponsor,which may sometimes be delegated to a Contract Research Organization (CRO). The Clinical Trials Agreement (CTA) signed prior to initiating a trial, must include details of trial close-out, i.e., roles and responsibility (sponsor designee – CRO), arrangements for storage of bio specimens, trial files and data (if applicable), and/or archival information.

Plan for trial close-out or closure must be included in the protocol. Trial close-out is the act of ensuring that all activities related to the clinical trial are appropriately reconciled, recorded and reported at the end of the trial. End of trial declaration should be in accordance to the protocol, relevant SOPs, and applicable regulatory and GCP guidelines. In most instances, the trial is considered closed after the finalisation of clinical study report post database lock.

Site Close-Out

A site may be closed due to the following reasons:

1. Routine site close out post database lock.
2. Inability of a site to recruit participants: The sponsor and PI assess site recruitments, periodically. These assessments form the basis of determining whether the site can accomplish its recruitment targets within the timeline. If it is determined that the targets will not be reached, then, the sponsor must decide if the site should continue with enrolment. If it is decided to suspend enrolment, then, the site is closed.
3. Significant protocol violations and/or lack of compliance: Serious breach in GCP compliance and/orprotocol violations may lead to jeopardizing participant safety, and data validity and credibility. If during monitoring it is determined that the site has not been complying with applicable guidelines and protocol, or that the participants are subjected to unreasonable risk, then, the sponsor may decide to terminate the enrolment at such sites. The investigator must notify the site EC and the regulatory agency, and cease enrolment.
4. Misconduct and/or fraud at any of the participating sites may undermine the integrity of the trial, and data generated.
5. Premature termination or suspension: A trial may be prematurely stopped or temporarily suspended on the basis of recommendations of Data and Safety Monitoring Board (DSMB) or if constituted, the Trial Steering Committee (TSC).

Site Close-Out procedure/process

The Trial Management Group (TMG) / Study Management Group is entrusted with the responsibility of ensuring close-out visits and related activities. It is conducted in accordance to the monitoring strategy and/or plan, and other relevant SOPs. Some of the key activities undertaken during site close-out are outlined below:

• Site close-out visit:

During the close-out following should be ascertained:

• Recruitment status: The TMG must confirm that enrolment has been completed or stopped at the site, prior to close-out.
• Participant related documents: The Case Record Forms (CRF) that have been completed, are checked for completeness. For each participant recruited in the trial the following documents must be filed in the Investigator Site File (ISF) or participant file:

1. Signed informed consent documents
2. CRFs
3. Source documents –documentation for each visit, medical records, laboratory and/or imaging reports, participant specific IP accountability logs, diary cards (if applicable), etc.
4. Any other trial specific document used

• Query resolution: All outstanding data clarifications and/or queries must be resolved, and the data should be frozen.
• Follow-up: Follow-ups of all ongoing Adverse Events (AE) and Serious Adverse Events (SAE) must be complete, and appropriately documented. The Site Investigator must be aware of any future reporting requirements pertaining to AEs and SAEs, and follow-up of ongoing SAEs.
• Investigational Product (IP): All IP related documents (accountability logs and forms, shipment logs and forms), must be reviewed, and filed appropriately in the Investigator Site File (ISF). A final reconciliation of the IP must be done, and if there is a discrepancy then, it should be documented and filed in the ISF. IP and trial supplies must be returned to the sponsor or destroyed, as per the protocol. It should be ensured that these activities are carried out, and appropriately documented. For example, if the IP is destroyed at site, a ‘destruction certificate’ should be filed in the ISF (if required by the sponsor). If the IP is to be shipped back to the sponsor, then completed forms and logs for shipment should be filed in the ISF and TMF accordingly.
• Randomization code envelopes: If the randomization strategy of the trial used randomization code envelopes, then, during the close-out visit these must be collected from the site. It should be ensured that all envelopes are accounted for, and the seals have not been broken. Reasons for any unsealed envelope must be documented.
• Final inventory: A final inventory of remaining or unused trial supplies (including equipment loaned to the site like computers, tablets, CRF, ICD, etc.), must be completed. These should be returned or destroyed, in accordance to the sponsor’s requirement, and appropriately documented.
• Finances: It should be confirmed that there are no outstanding payments related to the trial, at the site.
• Documents: The ISF should be checked to ensure that all essential and required documents have been filed appropriately.

Generally, after a site close-out visit, a close-out report is sent to the site investigator and the sponsor. The Ethics Committee (EC) has to be notified of trial completion/termination at that site. This is the responsibility of the site investigator. A copy of the notification letter sent to the EC along with a copy of the close-out report must be filed in the ISF.

A final trial close-out can only be done, once all sites have been closed and the Project Manager and/or monitor has reviewed both, the ISF and TMF, and confirmed that all necessary documents are in their appropriate files. The database is locked, once all queries have been resolved, and the data is ready for analysis. A final close-out report is prepared by the TMG to document the activities required for close-out are complete, and the essential documents have been filed appropriately.

The final report and close out status report is also submitted to regulatory authority i.e. CDSCO.

References

• Good Clinical Practices for Clinical Research in India, Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, 2001, available online (last accessed on 26.02.2019).
• ICH Harmonised Guideline, Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), current step 4 version, dated 9^th November 2016, available online (last accessed on 26.02.2019).
• Clinical Development Services Agency SOP for Site Close-Out, version 1.0, dated 29^th June 2015.
• MRC Clinical Trials Unit at University College London SOP for Trial Closure and Reporting Requirements, version 2.0, 2018.