In Part 1, we discussed the TMF and why it is so critical. While all TMF documents are important, some are more crucial to a trial than others. At the core of these are the essential documents, as defined by ICH Guideline for Good Clinical Practice, E6, Section 8, “those documents which individually and collectively permit evaluation of the conduct of the clinical trial and the quality of the data produced.”

ICH GCP groups’ essential documents into three sections based on the expected timeframe of their generation: before the clinical phase of the trial, during the clinical conduct, and after the completion or termination of the trial. These documents are essential because they serve “to demonstrate the compliance of investigator, sponsor, and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.” Another reason they are considered essential is that collecting them on time supports successful trial management. Also, essential documents are probably the first ones audited by QA or inspected by regulatory authorities as they help tell the story of a trial. However, ICH E6 addresses only some of the TMF documents generated in a clinical trial. So, are these essential documents adequate to reconstruct trial activities and any decisions made? EMA guidance states that the documentation listed in section 8 of ICH GCP is not a definitive checklist for TMF content. The EMA guideline goes on to provide examples of documents that are essential when generated for a specific trial, but not listed in section 8 of the ICH GCP guideline:

• Completed forms, checklists, and reports, etc. related to the trial, generated from following quality system procedures of the sponsor, investigator, or any third-party performing trial activities on their behalf
• Qualified person certification of the IMP
• Assay method validation report for analysis of IMP or metabolite(s) in clinical samples
• Advanced therapy investigational medicinal product (ATIMP) traceability documents
• Documentation to demonstrate validation of trial-specific builds of computer systems (e.g., electronic)
• Case report form (eCRF),interactive response technologies (IRT), and electronic patient-reported outcomes)
• Data management documentation (e.g., data management plan, data validation plan, and data-review meeting minutes)
• Statistics documentation (e.g., SAS program validation, statistical analysis plan, and sample size estimations)
• Delegation log as part of the investigator/institution TMF

The use of eClinical l systems such as CTMS, EDC, IRT, and eTMF has introduced a significant amount of new documentation that is now considered as essential by regulatory authorities. This is one of the reasons the TMF Reference Model is so appreciated. The TMF Reference Model “provides standardized taxonomy and metadata and outlines a reference definition of TMF content using standard nomenclature.” It has gone a step further than ICH GCP by defining “core “documents “meaning that if such a record exists, it must be in the TMF as dictated by either the ICH Guidelines, regulations, or the TMF Reference Model group (ONLY if applicable for the trial).”

So, what does the TMF Reference Model define as the core document list that is not mentioned by ICH guidelines? Apart from the documents generated by the use of eClinical technology, documents like database lock documents or regulatory IMP release documents are essential to the reconstruction of the trial. Some documents demonstrate oversight such as a TMF Plan or list of SOPs current during a trial. Also included in the Reference Model are documents recommended for inclusion. These are documents that do not have to be produced, but if they are created or collected, it is recommended they should be in the TMF.

To conclude, the essential documents (as defined in ICH GCP section 8) are a good start when thinking about TMF set up, but the TMF Reference Model is a more comprehensive list of documents to consider. Ultimately, the goal should be a TMF that has all the documents required to be inspection ready.