Essential trial documentation is to be kept in two distinct files:
i) the Trial Master File (TMF) kept by the sponsor and
ii) the Investigator Site/Study File (ISF) kept by the investigator.
Although they overlap, the ISF contains information that ought not to be kept in the TMF, whereas the TMF may contain information that is of little – if any – use to the investigator. This well-established approach in accordance with ICH E6 GCP (Art. 82-84) and the EU Clinical Trial Directive is strengthened by the EU Clinical Trials Regulation 536/2014 (Recital 52 and Art. 57-58) and EMA/15975/2016 (“Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials” – 2017) Art. 3.1 « … In organising the TMFs, it is essential to segregate some documents that are generated or held by the sponsor only, from those that are generated or held by the investigator only, and vice versa »
Segregation of TMF and ISF is particularly relevant to Data Privacy & Protection. This is exemplified in EMA/INS/GCP/636736/2012 (“Reflection paper on GCP compliance in relation to trial master files (paper and/or electronic) for management, audit and inspection of clinical trials” – Jun.2015) Section 4.1: « In organising the TMFs, it is essential to segregate some documents that are generated or held by the sponsor from those of the investigator and vice versa (ICH E6 GCP Sections 8.2-8.4 | Recommendations on the content of the trial master file and archiving Sections 3.1, 3.2 and 3.3), as some documentation held by the investigator should not be provided to the sponsor, for example those documents that would result in breach of subject confidentiality (Directive 2005/28/EC Article 5, Directive 2001/20/EC Article 3 [2] c and ICH E6 GCP Art. 2.11) ».
Segregation serves securing confidentiality of the information that links the trial data controlled and processed by the sponsor with the patient’s identity that it is to be kept confidentially by the investigator (e.g. in the Subject Identification Code Log, the signed Informed Consent forms, and the medical files). In this way, data are “pseudonymised” at the level of the investigator, but become “anonymous” at the level of the sponsor unless access to the subject identification information would be taken.
The subject identification information is to be kept securely and confidentially in the ISF; access to this information by the sponsor ought to be restricted and controlled.
On-trial, access to the Subject Identification Information in the ISF is a mandatory aspect of the QC-verification of data and compliance.
Off-trial, conditional access to this information should be possible for QA/QC inspection of GCP-compliant conduct, analysis, and reporting of the trial.
Other access is not permissible (particularly if it could affect data processing) since it would violate the rulings on data protection, but cannot be entirely excluded. Although not intended, such undue access to subject identification information is ‘possible’; therefore, trial subject data remain “pseudonymised” also at the level of the sponsor.
More restrictive rulings on access to the Subject Identification Information might help keeping trial data “anonymous”; this could be achieved by imposing prohibitive rulings on access to the identification information once the database is closed; in such case, the information could only be accessed after database closure by sponsor-independent inspectors and not by sponsor-based or sponsor-assigned auditors.
Although ‘soft’, segregation of the TMF and ISF is an important quality mark in Good Documentation Practices. Considering the very long time such information needs to be orderly archived by sponsor and investigator (see previous), this results in complex logistic challenges to the investigator for which the sponsor can provide little remedy (see next).
{19.May.2018 | ACPS-CdM}.