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Section 02.01 of the TMF Reference Model includes Investigator's Brochures, protocols and amendments. One would think it would be difficult to mislay these foundational documents, but we typically find at least one gap in every Trial Master File audit.
To perform a good QC, first consider the timeline for the study, then identify the Investigator's Brochures that should be present in the Trial Master File. Typically, there is one edition a year, numbered sequentially. If there is no document version tracker for the study, confirm with both Regulatory Affairs and Clinical Operations to ensure that a minor update has not been missed. When the list of expected documents is complete, confirm each expected version is present in the file along with the review and approval documentation required by the governing SOP and, for updates, the Summary of Changes. Page through each document to verify that all pages are present, hyperlinks are rendered correctly, and appendices are included. Compare approval signature dates against each edition date to note any inconsistencies.
For protocols and synopses, follow the same process above to generate a list of expected documents, looking specifically for country-specific amendments. Follow the same steps to verify all versions, review and approval documentation, and summaries of changes are filed and that documents meet ALCOA+ standards.
Next, check the translation plan to verify whether any translations of protocols, synopses, or IBs should be present. The translation plan may need to be cross-checked against regulatory authority approval dates to determine which versions should have been translated. For expected translations, confirm that each translation includes the English master, translation, translation certificate, and back-translations, if required by the translation plan.
This QC activity will set you up nicely for the decidedly more difficult task of determining whether all required versions have been sent to and approved or accepted by regulatory authorities and IRBs/IECs, which we will discuss in a future post.
Denise DeRenzo Lacey, RQAP-GCP, has over twenty years’ experience in clinical Quality Assurance and clinical development operations. Her practice focuses on application of quality risk management techniques for clinical studies, including risk-based approaches to auditing, data quality and integrity, and SOP development. She has provided consulting services to a wide range of pharmaceutical, medical device, biotech and CRO clients in the US and Europe and has held senior positions at Vertex Pharmaceuticals and Radius Health.