Essential Documents and the Trial Master File

In this step, Lisa Leighton and Razia Meer-Baloch, write about essential documentation within randomised clinical trials.

Essential Documents are defined as the documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced.

By reviewing these documents, the conduct of the trial can be assessed in terms of its compliance with Good Clinical Practice and all applicable regulatory requirements. For example, a completed participant consent form can be reviewed for the quality of its completion; and if reviewed against the Research Ethics Committee (REC) approval and the delegation of duties log, it can also inform a reviewer whether the approved version of consent form was used, by an authorised individual, on a date after which the document had received REC approval. These assessments provide confidence in data quality and the maintenance of participant safety. In addition, essential documents are critical for the successful management of the trial by the trial team. Good clinical practice requires that all essential documents relating to a clinical trial are collected, managed and stored in such a way as to allow monitors, auditors or inspectors to make these evaluations.

The planning and delivery of a clinical trial can generate extensive documentation and Essential documents can be grouped on the basis of when in a trial they would normally be generated:

1. Before the trial commences

For example: trial protocol; sample case report forms; sample labels for IMP; patient information sheets; statement of insurance; signed contracts; REC approval and regulatory approvals, curriculum vitae for investigators.

2. During the conduct of the trial

For example: trial protocol amendments; REC and regulatory approval of amendments; monitoring visit reports; relevant communications with sites; correspondence relating to serious adverse events; participant screening and enrolment logs; annual progress reports.

3. After completion or termination of the trial

For example: final report to ethics committee/regulatory bodies/funder; trial closure monitoring report; documentation of IMP destruction

Section 8 of ICH E6 (R2) Guideline for Good Clinical Practice contains a more substantive list of the minimum documents that are considered essential. However, these lists are not exhaustive – each trial is unique and will require all documents which are essential to reconstruct that specific trial.

The Trial Master File

Effective organisation of Essential Documents is required not only to facilitate inspection and audit by persons unfamiliar with the trial, but also for those involved in conducting the trial who will require regular access to the documentation to undertake their various tasks. The Essential Documents of any trial must tell the story of the trial and like any good story, must have a logic and flow, telling the complete story without parts of the plot (or documentation) missing. Essential documents are normally filed in a Trial Master File (TMF) and for clinical trials of an investigational medicinal product, this is a legal requirement.

The TMF is normally comprised of a sponsor file, held by the sponsor (or by the trial team appointed by the sponsor to manage the trial on a day to day basis) and an investigator site file, held by the Principal Investigator of each of the sites recruiting participants into the trial. These files together are regarded as comprising the entire TMF for the trial and will contain a number of the same documents. However, there are some documents which contain participant identifiers, for instance patient screening logs which will be held in the investigator site file, but should not be provided to the sponsor as this would compromise subject confidentiality. There can be some exception to this, for instance, trial teams will often collect completed participant consent forms in order to perform quality checks. In this instance, justification for collecting this patient identifiable documentation must be provided in the approved trial protocol and patient facing documentation and explicit consent for the arrangement must be obtained from the trial participants.

The TMF may be stored on paper or electronically. Whichever form is used, the TMF should be kept securely throughout the trial and access restricted, to avoid any unauthorised changes or deletions being made. If the TMF is being stored electronically, additional controls will need to be in place to ensure its security.

At the end of the trial the TMF must be archived for a specific period of time which will be determined by the nature of the trial and in compliance with any national regulations for archiving trial material in that country. The TMF must be stored in such a way that it can be easily accessed and the full set of documents for the trial reviewed as part of audit or inspection.

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