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EMA Reflection Paper on GCP compliance in relation to Trial Master Files 22/02/2013

Posted by Shirley Hallam in Essential Documents, GCP audit.
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filesThe EMA (GCP Inspectors Working Group) has issued a draft reflection paper on the maintenance of Trial Master Files. The paper has been produced partly in response to difficulties encountered during inspection in obtaining full access to the TMF. Although fairly short (18 pages) there is a great deal of detail about management and retention of the TMF which has not been spelt out previously.

The definition of the Trial Master File given is helpful, reflecting its purpose rather than simply describing it: “A TMF is the collection of documentation that allows the conduct of the clinical trial, the integrity of the trial data and the compliance of the trial with GCP to be evaluated.” It is therefore necessary to include not just all essential documents as defined in the ICH GCP guideline (these are described as a minimum requirement), but also evidence of key decisions made. Documents generated from following internal procedures should be retained, as should those created during the trial that might help reviewers to reconstruct and evaluate it. The reflection paper also recommends the TMF should be “a stand-alone set of documentation that does not require additional explanation from the associated sponsor or site staff.”

There is acknowledgement that some documents (e.g. the Investigator’s Brochure) may be applicable to more than one clinical trial, and that documents may be held across a number of company departments. In this case, cross references may be held within the TMF, but care should be taken, particularly at archive, to ensure that these will remain unchanged, and where there is doubt then a copy should be placed in the TMF.

Particularly welcome is the consideration given to maintenance of oversight by sponsors who delegate all or part of the management of the trial to a CRO. The paper suggests there should be an agreement between the sponsor and CRO which includes:
• which party holds the official TMF (or which parts of the TMF each party holds when this is divided);
• the process for filing documentation in the TMF
• the access arrangements for both parties
• the structure and indexing of the TMF
• where an eTMF is being used, the details of the system
• lists of applicable procedures to be followed and training requirements
• documents that both parties must retain
• arrangements for managing correspondence
• how the TMF would be made available if either party was inspected
• arrangements for when the trial is completed
• arrangements for oversight of the quality control/quality assurance of the TMF by the sponsor

With regard to correspondence, the paper stresses the important of maintaining that from both parties. For example, if only approval letters are retained without applications, the audit trail is not complete. Different modalities for the retention of email are discussed.

There is discussion about eTMF, and a comment that “remote access to eTMF without the inspector visiting the site may assist in planning inspections and could, in future, potentially form part of the inspection.” Retention periods are covered, with increased stratification according to the lifetime of the product, with clinical study reports being kept for five years after the end of the period of marketing authorization.

The paper concludes with common inspection findings relating to the TMF, which include
• Inability to provide a full TMF (paper and electronic) for inspection purposes on request of the GCP inspectors.
• The paper TMF structure (poor indexing etc.) did not facilitate timely review to evaluate the conduct of the trial.
• The sponsor provided an “artificial TMF”, thus failed to provide adequate direct access and led to issues with documentation not being consistent with that of the official TMF.

Specific eTMF findings include:
• Staff that were put forward as “system users” for eTMF were also unable to locate documents requested by the inspector.
• Failure to fully document and perform effective QC checks on documents uploaded into eTMF. Discrepancies were seen, e.g. missing pages, incorrect documents, poor quality scans, undermining confidence in the eTMF
• Incorrect documents located in the TMF and eTMF
• Poor labelling of files
• activities (e.g. training, Project Team Meetings) were not filed.
• Inadequate equipment for the inspector to review the eTMF, e.g Lap tops with tiny screens.

Comments on the draft to the EMA are invited by 30 April 2013.

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