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Conducting a TMF Audit for Inspection Preparedness

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Conducting a Trial Master File (TMF) audit is an important aspect of maintaining the quality and integrity of clinical trial data, as well as preparing for inspections. In this article, we will explore five key areas that should be considered during a TMF audit to ensure inspection readiness. 


5 Key Areas to Consider During your TMF Audit

1. Review SOPs and Evaluate TMF Content Quality 

Start by reviewing the Standard Operating Procedures (SOPs) associated with the creation and management of TMF content. This will help outline what activities should have been taken and highlight those that may not have. In addition, this step helps ensure that the documented processes align with industry best practices and regulatory requirements. Don’t forget to evaluate the quality of data and documentation in the various systems that support the trial. Look for completeness, accuracy, and consistency across all systems holding study data. Incomplete or inaccurate documentation can hinder the assessment of the trial's true state and study conduct. 

A Cautionary Tale: 
Prior to inspection, a study director did not conduct an audit of the TMF. In the resulting audit, the FDA found that the study director failed to assure that the protocol, including any changes, was approved as provided by 21 CFR § 58.120 and was followed; that all experimental data, including observations of unanticipated responses of the test system were accurately recorded and verified; and that unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study were noted when they occur, and corrective action was taken and documented.
Because they failed to ensure that all experimental data were accurately recorded and verified, and that all entries and changes in entries were properly documented, FDA had concerns about the integrity of the data generated from the nonclinical toxicity studies conducted. The entire study was called into question, and significantly delayed.
Had this study director conducted a TMF audit prior to their inspection, the audit would likely have surfaced these issues!


2. Assess Oversight Documentation 

In addition to reviewing spreadsheets, it's important to assess oversight documentation such as communications and meeting minutes. These records provide insights into the activities conducted throughout the trial. By thoroughly evaluating oversight documentation, auditors can determine the level of compliance with study conduct using these essential documents. 

3. Evaluate Training Compliance 

Conduct a comprehensive review of training for all study team members, including the CRO team. Verify that the training records are complete, up-to-date, and demonstrate adherence to the required training curriculum. Adequate training ensures that all team members have the necessary knowledge and skills to perform their roles effectively and in compliance with regulatory guidelines. 

4. Ensure Compliance with Plans and Proper Documentation 

One important aspect of a TMF audit is assessing evidence of adherence to various plans. It is essential to verify whether the trial activities followed the predetermined plans and if any deviations were clearly documented. Auditors should look for evidence that demonstrates compliance with protocols, consent forms, and other relevant study plans.  

5. Interview Study Team Members and Assess TMF Contents 

Interview study team members to gain insights into study events, deviations, and safety reports. These interviews help auditors assess whether the TMF contains evidence of the steps taken to address issues and ensure patient safety. The TMF should provide a comprehensive record of study-related activities, capturing all relevant information and actions taken. 

For additional insight into how to conduct a TMF Audit, download the whitepaper.

Avoiding Common Pitfalls 

With the complexity of trials and use of electronic systems, it is important to be aware of common pitfalls that organizations may encounter during inspection.  By conducting a thorough audit as part of the inspection preparation, these gaps can be identified and addressed beforehand. Here are some common areas to appraise: 

Incomplete or Inaccurate Documentation 

Incomplete or inaccurate TMF documentation is one of the most common findings during TMF audits and inspections.  If the TMF is missing key documents, or if the documents are incomplete or inaccurate, it can be difficult to determine the true state of the trial and study conduct. To avoid this, auditors should thoroughly review the TMF to ensure that all documents are complete, accurate, and consistent across all systems holding study data.  Taking a risk-based approach can help prioritize documentation review based on its significance to the trial. 

Poorly Defined Oversight Activities 

Another common pitfall of TMFs is poorly defined requirements for conducting oversight of study activities. If the activities are not clearly defined and documented, it can be difficult to determine the compliance with this important activity. If you are conducting an audit for inspection, focus the audit on the most important aspects of managing the trial. As part of the audit, one should clearly define the audit scope and ensure that all aspects of the TMF are covered in the audit. 

Suitability of Systems 

Systems used to collect and store records in support of a clinical trial should be fit for purpose. For example, eTMF software used for managing the Trial Master File must have the necessary elements outlined in regulations to ensure data integrity. This includes the capability to provide an audit trail that shows actions taken, who performed them, when they were performed, and what changes were made. This allows inspectors to trace activities and monitor changes effectively.  

Lack of Communication 

Effective communication is vital when conducting a clinical trial.  Lack of communication between teams, sponsors, CROs, and site personnel can lead to gaps in information collection and hinder effective inspections. Study Teams should establish clear lines of communication with all stakeholders, ensuring that all relevant information about the study is shared and discussed. Communication records including emails should be filed in the TMF to demonstrate transparency in activities and discussions. Relevant communications supporting study activities often occur through email Business rules should be established between teams (sponsor/CRO) to clearly identify the responsible party for filing emails, and when they should be filed. It is good practice to restrict your email thread to a single topic to make records easier to navigate. If additional discussion points are needed, initiate a new email. 



Closing the Gap: Addressing Audit Findings 

Once the TMF Audit is concluded, it is crucial to address any issues identified during the review. Even if the study teams disagree with certain findings.  providing documentation that supports an alternative view or engaging in discussions with the auditor can help resolve differences. We often see that audit findings are not appropriately addressed, and important findings remain unresolved before inspection occurs. Closing the gap of understanding and addressing the issues found during an audit can support meaningful conversations with the inspectorate.  

 In conclusion, conducting a TMF audit is a critical step in maintaining the quality and integrity of clinical trial data and preparing for inspections. By carefully reviewing SOPs, evaluating TMF content quality, assessing oversight activities, ensuring training compliance, and interviewing study team members, organizations can enhance their inspection readiness. Avoiding common pitfalls such as incomplete or inaccurate documentation, poorly defined oversight activities, unsuitable systems, and lack of communication is essential. Finally, remembering to address the audit findings and resolving issues promptly can improve your chances of successful inspection. 

If you have follow up questions regarding TMF Audits, we at Kivo are happy to help! Contact us at any time. 


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