Maintaining an electronic trial master file (eTMF) involves far more than storing study documents from different trial contributors either in paper or electronic form. These documents are generated by global and local project teams, located in different geographical locations.

Therefore, it isn‘t surprising at all to hear auditors and inspectors complaining about incomplete TMFs, missing audit trails, a lack of data integrity, and poor sponsor oversight. In order to obtain marketing authorization, a detailed and up to date documents is required.

According to the EMA, an eTMF requires sponsors and investigators to adhere to ICH GCP E6 regulations and to conduct the trial in accordance with GCP principles, two of which are:

  • All clinical trial information should be recorded, handled, and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of the trial subjects remains protected (Directive 2005/28/EC Article 5)
  • Systems with procedures that assure the quality of every aspect of the trial should be implemented (Directive 2005/28/EC Article 2)

It becomes clear how important the set-up and maintenance of a TMF is. Nevertheless, many sponsors don‘t pay enough attention to this topic from the start of a clinical trial.

Emerging Trends

Ten-twenty years ago, we saw sponsors introducing an electronic case report form (eCRF) offering important advantages over paper CRFs, such as:

  • Quick review by medical monitors and pharmacovigilance managers
  • Improved data quality
  • Shorter timelines (e.g. database lock)

Recently, we’ve seen a similar trend with paper TMFs and eTMFs, with a slow but steady growing demand from various sponsors (from small to big biotech/pharma/start-ups).

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The goal is to have a complete, up to date TMF that can be stored and reviewed remotely from any location. Some sponsors also use a mixture of both – paper and eTMF, but it must be clearly identified and documented where each document can be found (on the hard drive or in paper). This becomes more evident for auditors and inspections for marketing authorization.

Delegation of Responsibilities

Many sponsors may choose to contract certain duties and tasks to a CRO (e.g. regulatory activities, monitoring tasks, data management activities, etc.), which can increase the complexity of the TMF. The sponsor is still responsible for the trial and will need to maintain oversight, so access to the TMF (including remote access to eTMF) may be necessary. Failing that, the sponsor may decide the CRO needs to provide them with specific documents.

The role of the CRO in the trial should to be formally documented, usually in a written agreement with the sponsor, outlining in detail their duties and functions, such as the handling of the eTMF. When contracting with vendors/CROs, the following items should be agreed upon in writing:

  • The process for filing documentation in the eTMF (structure and indexing)
  • The access arrangements for both parties
  • Where an eTMF is being used, the details of the system
  • Training requirements and a list of applicable procedures to be followed
  • Documents that both parties must retain
  • Arrangements for managing correspondence
  • How the eTMF would be made available if either party was inspected
  • Arrangements for when the trial is completed
  • Sponsor arrangements for quality control of the (e)TMF and its documentation (e.g. audit reports, QC reports)

Please also refer to: Directive 2005/28/EC Article 7, Note for Guidance on Good Clinical Practice CPMP/ICH/135/955.2.1 and Recommendations on the content of the trial master file and archiving Section 6.

Archiving an eTMF

eTMF contents need to be retained for up to 30 years due to current underlying regulations. For paper TMFs, such retention periods usually involve high storage costs over the years and are mostly outsourced to companies. Therefore, quick access to these documents is not always easy. For electronic TMFs this raises two important challenges:

  • Compatibility issues: Contents can only be accessed if software tools are available to read the corresponding file format
  • Storage media lifespan: Common digital storage media (e.g. CDs, DVDs) may not work in 20-30 years or the technology itself becomes obsolete

Dealing with these challenges is a common problem in all areas where electronic records require long-term storage. The EMA’s reflection paper also addresses these challenges, but lacks specific recommendations with regard to file formats, software tools etc.

The Benefits of an eTMF

If you start your next clinical trial (depending on the size of the study and site locations) you should really consider using an eTMF for filing purposes as there are numerous benefits:

  • Real-time tracking of documents
  • Easy access to search and find documents
  • Increase of TMF compliance
  • Cost-effectiveness
  • Inspection readiness
  • Lower storage costs
  • Lower storage space

To increase the chances of conducting a successful trial, adopting an eTMF can simplify processes throughout the course of the study.


Dr. Volker Scherhammer

VS LifeScience Consulting

Munich, Germany