Overview

G&L Healthcare Advisors was engaged by a client developing a novel therapeutic agent for the treatment of solid tumors.

The client required clinical quality assurance expertise to conduct a comprehensive Trial Master File (TMF) audit to evaluate the completeness, organization, and overall inspection readiness of the TMF.

This involved ensuring the TMF complied with Good Clinical Practice (GCP), the study protocol, and regulatory requirements. The audit aimed to assess the health of the TMF, identifying areas of improvement to mitigate risks that could impact the reliability of clinical trial results.

Challenges

Several key challenges were faced in conducting the TMF audit:
Comprehensive review of extensive documents: The TMF contained thousands of documents, and a thorough review was needed to ensure that both core and recommended essential documents met ICH E6(R2) standards, were appropriately filed, and were retrievable.
Ensuring sponsor-CRO alignment: The client relied on a Contract Research Organization (CRO) for TMF management, requiring a review of the CRO’s Standard Operating Procedures (SOPs), TMF governance, and oversight to ensure compliance. Aligning both Sponsor and CRO expectations was crucial to maintaining TMF quality and inspection readiness.
Inspection readiness risk: The absence of essential TMF documents or poor document management could have negatively impacted the trial’s credibility and compliance with regulatory requirements, particularly regarding inspection readiness.

G&L’s Approach and Solution

To address these challenges, G&L conducted a meticulous review of the client's TMF over five days, focusing on ensuring completeness, compliance, and retrievability of essential documents. Key activities included:
TMF document review: G&L reviewed 3,045 documents, ensuring adherence to ICH E6(R2) sections 8.1, 8.2, and 8.3, confirming that both core and recommended documents were retrievable, unique, translated (if required), legible, and original.
Governance and procedure review: G&L evaluated the TMF governance procedures, including the CRO’s SOPs, Work Instructions (WIs), TMF Index, and TMF Plan, to ensure compliance with industry standards and the specific trial’s requirements.
Maintenance and oversight: The TMF maintenance and quality control processes executed by the CRO were reviewed, assessing their oversight and consistency with the established TMF Plan and the CRO’s SOPs.

Impact and Outcomes

The audit and subsequent actions led to multiple benefits for the client:
Remediation of TMF findings: The client collaborated with the CRO to address the identified findings, improving the completeness and quality of the TMF.
Increased awareness of documentation importance: Both the Sponsor and CRO gained a deeper understanding of how the absence of essential documents could impact the trial’s credibility and reliability, emphasizing the need for thorough TMF oversight.
Ongoing oversight and compliance: G&L advised the client on the importance of continued oversight and maintaining open communication with the CRO. This included ensuring expectations, actions, and deadlines were conveyed to ensure compliance and inspection readiness for the study.