There is no "one size fits all" for the management of clinical trials. However, there is a clear requirement according to GCP (Good Clinical Practices) that the sponsor retains all responsibility for the conduct and reporting of clinical trials.
There are multiple ways for the setup of clinical trials. Trial management activities can be conducted in-house, parts of the activities can be outsourced or activities can be completely outsourced to third party organisations (e.g. Contract Research Organizations (CROs) and Clinical Trial Units (CTUs)). Therefore, it is important that the sponsor has systems and procedures in place to ensure adequate sponsor oversight. Failure to comply in this area can result in critical findings and also prevent the organization from sponsoring any further trials until the issues are resolved.
How can compliance in this area be improved? The current thinking of GCP Inspectors from the British Medicines and Healthcare Products Regulatory Agency (MHRA) regarding the sponsor oversight of clinical trials outsourced to vendors has been recently published in the MHRA Inspectorate Blog Sponsor Oversight - Part 1. According to the MHRA Blog "sponsor oversight is not just the initial vendor assessment process, it should be demonstrated throughout the trial". In detail Part 1 of the Blog deals with the following topics:
Contracts and Agreements:
It should be laid down that compliance with GCP is required which would supersede any internal processes and procedures.
Subcontracting should be mentioned in the contract and also how the sponsor maintains oversight of any further subcontracting performed.
"It is often seen on inspection that key legislative requirements are missing from contracts such as reporting of urgent safety measures and serious breaches, which can lead to non-compliance as the roles and responsibilities have not been clearly defined".
Mechanisms of Oversight
Vendor Assessment should be performed prior to using the vendor. It can also be used as a mechanism for ongoing assessment. The process could include a review of the vendor’s Quality Management System (QMS). The assessment may be in form of a questionnaire, review of Standard Operating Procedures(SOPs), a site visit or audit, or a mixture of these.
Where a number of different vendors are involved a communication plan should be in place along with any other plans which clearly identify the processes and procedures to be followed by each party (for example, if any potential serious breaches are identified).
Performance Reviews: If the inspector notices that a number of non-compliances were identified by the sponsor and not adequately rectified, then it would be asked why the sponsor continued to use them, and if any mitigations were put in place to prevent reoccurrence of issues.
Project meetings and status/ metric reports can be a useful method of keeping track of trial progress. It was seen in a serious breach reported to MHRA where a packaging issue was not rectified, resulting in a subject taking an overdose of IMP (Investigational medicinal Product) which resulted in a fatality. "Where status reports are received, it is important to know what to do with them, what the review entails and how issues are followed up and resolved".
Oversight by the sponsor can be demonstrated by review and approval of documentation (e.g. Monitoring Visit Reports(MVRs), Data Management Plans, Statistical Analysis Plans, review of deviation logs, audit trails etc.). "It should be clear within the sponsor’s QMS which documents are required to be reviewed by the sponsor and what the review entails".
There should be clear documentation of the co-monitoring visit by the person performing the visit. "It should be clear what activities were performed and any issues identified, with an appropriate Corrective and Preventative Action Plan (CAPA)".
Processes and procedures should be in place to ensure that the sponsor is promptly notified of issues. This includes the identification and escalation of any potential serious breaches to the sponsor so that they can be reported to MHRA within 7 days of identification (the clock starts as soon as anyone working on behalf of the sponsor (this includes vendors) identifies the issue).
Trial Master File(TMF) management is often outsourced and held by the vendor. "However, the sponsor should be able to demonstrate their oversight of trial activities which have been delegated, and to demonstrate this oversight during an inspection. This can be in the form of an oversight file which forms part of the overall TMF but remains with the sponsor".
In inspections it has been observed "that at the end of the trial the TMF retrieved from the vendor was amalgamated with the sponsor’s oversight file (and sponsor oversight documentation removed). It was therefore not possible to reconstruct what oversight the sponsor had of the trial whilst it was ongoing".
Part 2 of the Blog will cover inspection metrics and discuss case studies from both commercial and non-commercial organizations.