For many organizations conducting clinical trials, regulatory inspections are frequently feared and unwanted by clinical teams. Typically, chaired by the Quality Assurance department, TMF inspections bring with them a wealth of administrative tasks and procedural checklists to the table. In many instances, an inspection becomes a tedious exercise. The recurring problem is that inspection readiness is typically performed as a preparatory activity, whereas the most value is generated when inspection readiness is engrained into your organization from the start and daily maintenance is simply a part of the culture.
Related webinar: Preparing for and Surviving TMF Inspections: Best Practices
In the following article, we examine how to create a culture of compliance and build in inspection readiness into daily operations.
What is the process for regulatory inspections?
Upon notification of an inspection, the CRO, sponsor or investigative site must ensure that all study documentation is accessible, accurate and complete in preparation for the visit. In some cases, the regulatory authority may provide a specific time & date, as well a comprehensive package of what is to be assessed.
The scope of the inspection may be limited to one study only, as opposed to a site. However, if an investigator site is selected for an inspection, the sponsor should be informed and available to support or to attend on-site. Montrium’s Oliver Peace takes a deeper look into what the regulatory inspectors really expect for trial master files here.
Support for the auditors/inspectors is most often limited to the provision of documentation, answering study related questions, and being interviewed on processes and job functions.
What is Inspection Readiness?
Before we get into changing the mindset to promote better inspections, we first need to take a deeper look at what inspection readiness really means.
A trial master file inspection refers to “the act by a regulatory authority, in conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority to be related to the clinical trial and that may be located at the site of the trial, sponsor’s and/or CRO’s facilities, and other establishments deemed appropriate by the regulatory authority” (ICH GCP Sec 1.29).
Meanwhile, an audit is “a systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the study protocol, sponsor/CRO’s SOPs, GCPs and applicable regulatory requirements” (ICH GCP Sec 1.6).
Essentially, the focus for conducting an audit of your trial master file is primarily to verify the activities you have undertaken with regards to supporting your processes and the relevant regulation. Whereas the focus of a regulatory inspection is predominantly concentrated on the documents and records related to the clinical trial in question.
Inspection readiness is a quality objective - the objective being to operate at a level that is always ready for inspection, without requiring much preparation in the days or hours leading up to the inspection. Some teams even perform mock inspections on a regular basis to address data gaps and process issues, leading to tangible reports and lessons learned that can help proactively plan for inspection day.
As the TMF represents the “backbone” of managing trial documentation, it is often the object of scrutiny during an inspection. For this reason, the ongoing review and querying of TMF content by the different stakeholders of the project team is paramount to inspection success. However, in many organizations, this task is pushed to the side when juggling competing priorities, forcing organizations to tackle TMF inspections in a reactionary state.
Building Readiness into Your TMF Process
Inspection readiness is more than a “one-time” event; it is the product of strict adherence to organizational procedures and policies. These procedures and policies are designed to consider the constantly evolving variables of clinical research including; staff turnover, new investigative sites, new vendors, protocol amendments and evolving regulation. Ensuring your team’s compliance with these organizational processes will promote positive outcomes in the event of a TMF inspection.
By building TMF inspection readiness into your processes, clinical teams can leverage a set of robust Standard Operating Procedures (SOPs) that cover a range of proactive TMF management measures, including how to plan for internal or mock audits and inspections. These types of self-compliance checks provide valuable opportunities for an organization to identify deficiencies in documentation or processes long before an inspector arrives.
The requirements for managing the TMF should be complemented by parallel processes such as a trial monitoring plan outlining the frequency and process for TMF review. The strategy for review, accessibility, and remediation, as necessary, should be built in as an initial component of any trial management plan, ensuring expectations are set from the beginning of the study. In the case of an eTMF, review is facilitated by allowing remote access to study documents from any place at any time, by integrating effective security features to avoid unwanted or unnecessary deletion or change of documents, and by establishing real-time metrics on filed documents.
An organization should also have a standard and comprehensive Table of Contents (TOC) structure for each TMF, ideally following the industry standard TMF Reference Model. Appropriate filing based on the structure – meaning continuous filing, throughout the life of the trial – in both a paper-based TMF or an eTMF. This approach reflects inspection-readiness much better than uploading or adding a bulk of the documents in “one-time” event where files are stored like a repository and then filed upon notice of inspection. With a proactive TMF management method, using standard nomenclature and associating metadata to content will allow for easy retrieval during an inspection.
The alternative is definitely risky. If that risk becomes an issue, it may come with some costly consequences such as invalid study data, time and effort for remediation of non-compliance, or most unfortunately even the halting of studies. These kinds of consequences mean that resources must be allotted towards a fix for work that has already been performed once, albeit poorly, instead of moving onwards to the next task. A shift in philosophy from reactionary to preparatory plays a crucial role in avoiding such re-work and will undoubtedly benefit study stakeholders as a whole.
An organization’s compliance culture sets the ground work for a successful audit or inspection. From day 1 of the clinical trial start date, to study completion– inspection readiness should be incorporated throughout the TMF planning strategy. Inspectors expect the full story being told by the study execution for a complete portrayal of the protocols followed, controls of access and decisions made.
Remember, TMF inspection readiness is the state of continual preparedness everywhere and at anytime in managing a TMF system for a GCP inspection. Continuous filing over the course of the trial in a timely manner - from creation to archive - is a smarter approach, rather than rushing to file the bulk of documents at the notification of inspection. This proactive mindset strongly supports the three parameters for TMF metrics: quality, timeliness, and completeness so that authorities can finish the study inspection with confidence in the processes and data they examine.
Over the past ten years working with CROs and sponsor sites, we have seen enormous potential for leadership teams to develop improvement upon existing processes and to invest in training and support. Providing the adequate resources and appropriate management of document workflows in studies enables proper prioritization of tasks and will enable success in the long-run. As a result, study teams can facilitate the perpetual readiness mindset for enabling a culture of inspection-readiness and improved compliance.