A quality electronic Trial Master File (eTMF) is essential to the product development and approval process, as it is the foundation for clinical trial inspections by competent authorities. eTMFs for drug, biologic, and medical device trials should be actively managed as studies progress and should be inspection-ready at all times.

Components of the eTMF

The TMF is a collection of study documents used to document the conduct of a clinical trial. The combination of the many different documents collected through the course of a study that comprise the eTMF can be compared to the ingredients needed for a very specific recipe. Managing an eTMF is a delicate balance of compiling and maintaining the expected documents, working proactively with a team, and implementing both document and quality reviews as necessary.

eTMF files include essential and nonessential documents. Essential documents are those collected throughout the different phases of a clinical trial that are used to evaluate the ethical conduct of the clinical trial and the quality of data produced. Essential documents tell the “story” of the clinical trial. Always remember the Golden Rule of clinical research: If events are not well documented, then they did not occur. This is always a key consideration when obtaining, processing, and quality checking an essential document.

These files fall into the following categories:

• Trial Management Files: Documents used to manage the clinical trial (i.e., documentation of trial oversight, trial team, operations, monitoring plan, etc.)
• Central Trial Files: Clinical trial documents that are common to all investigational sites participating in the study (i.e., Investigator’s Brochure, protocols, sample informed consents, case report forms, study manuals, country regulatory documentation, etc.)
• Sponsor’s Investigator Site Files: Essential documents that are required for study participation and collected from participating sites (i.e., FDA Form 1572 or equivalent, CVs, financial disclosures, IRB/IEC approvals and acknowledgements, IRB/IEC-approved sample informed consents, completed case report forms, etc.)

eTMF activation

It is crucial that all study functional leads be heavily involved in the document selection and eTMF activation process. Their collective knowledge is needed to identify precisely which documents are required in the eTMF for any given study.

Given the complexity of the activation process, it is tempting to postpone dealing with it, with the assumption that the eTMF structure can be updated later. While this is true, activating the most accurate eTMF possible from the onset leads to more accurate metrics, minimizes discrepancies, and promotes inspection readiness.

eTMF pitfalls

Several common pitfalls that could compromise an eTMF and lead to shortcomings can be recognized and actively managed with sufficient preparation.

Missing documents

Throughout the course of a study, many documents (often from many different regions of the world) are distributed, completed, and collected. It is important to set anticipated milestones within an eTMF platform that will track these files to avoid missing documents. The eTMF lead should develop a clear line of communication with all parties involved on the sponsor, CRO, and vendor sides and establish due dates and expectations to receive documents in a timely manner.

Ineffective document processing

The eTMF frequently houses large numbers of documents, but the quality of these documents is essential to a study’s inspection readiness. Effective processing of documents should always reflect several key tools for maintaining their quality:

• Good documentation practice (GDP)
• ALCOA+ principles: Attributable, legible, contemporaneously recorded, original or a true copy, accurate, complete, consistent, enduring, and available
• International Council for Harmonisation guidance E6 (R2)

It is important that all relevant parties –sponsors, CROs, and/or other vendors, especially those on the eTMF team – be trained on GDP and ALCOA+ prior to the start of a clinical study and set a standard of quality.

Periodic quality reviews at all levels of the eTMF (including study, country, and site) and discrepancy reports can identify patterns of missing documents and/or document deficiency and provide real-time feedback to document owners as needed.

Document duplication

Duplicates, another common pitfall in the eTMF, often occur due to inconsistent metadata, misfiled documents, the migration of a study from one eTMF system to another, or a lack of communication among multiple submitters. Standard naming conventions for all documents that utilize key information can help avoid duplications and create consistency, as can limiting the number of team members responsible for uploading and processing documents.

Access mismanagement

Due to the diverse and dynamic composition of most study teams, including pivotal team members assigned across sponsors, CROs, and associated vendors, many people may need appropriate levels of eTMF access throughout the life of a study. Therefore, it is essential that user access be managed correctly from the onset of the study. This includes ensuring that each person receives required training and that the corresponding training documentation is compiled prior to being given access.

Study conduct often takes years, during which it is possible for assigned team members to cycle both on and off a study, CROs to transition work, and auditors or inspectors to request temporary access. For these reasons, a well-planned process for granting and revoking access as needed, as well as a living user list, are essential.

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Premier Consulting has deep experience facilitating data and document management for clinical trials, including eTMF setup, processing, maintenance, and quality control. If you’d like to learn more about how we can support your clinical program, contact us.

Authors:

Siegrid Delgadillo
Associate Director, eTMF Services

Sheridan Asuncion
Senior Associate, eTMF Services