The EMA guidelines which came into effect in June 2019 provide practical guidance, particularly when it comes to managing your archived TMF data, acknowledging your TMF data may be paper based, electronic or a hybrid of the two.
This guideline is intended to assist the sponsors and investigators/institutions in complying with the requirements of the current legislation (Directive 2001/20/EC and Directive 2005/28/EC), as well as ICH E6 Good Clinical Practice (GCP) Guideline (‘ICH GCP guideline’), regarding the structure, content, management and archiving of the clinical trial master file (TMF).
The guidance, although a European directive can offer practical guidelines for eTMF archiving regardless of where your organisation is located.
What do the guidelines say and what does this mean?
In basic terms the guidelines state that regardless of format, the TMF should provide for document identification, version history, search and retrieval as well as audit trails for any alterations of the contents. The guidelines go into detail about the following aspects of the Trial Master File:
- Structure and contents of the TMF
- Certification and Validation
- Transfer of the TMF
- Archive Guidelines and Retention Polices
The guidance talks about the difference in responsibility of the investigator and the sponsor, an important aspect of the guidance to note is that the Investigator’s responsibility in regard to the TMF extends to archiving and long-term management of the data. The investigator should maintain control and the data should remain completely independent from the sponsor. This is a big commitment for the investigator, particularly when you are often talking about maintaining this data for 25 years plus and the quality, and trustworthiness, of the investigator’s data archiving processes and costs involved should be considered up front.
The guidelines acknowledge that the requirements for handling live clinical trial data as opposed to archived data are very different, and a suitable eTMF archive solution needs to be in place as a requirement for anyone operating clinical trials. Whilst keeping your eTMF in your vendor’s system could certainly make access to your eTMF easy as well as having the required security controls, the guidelines require orgnisations to consider additional needs for archiving:
- Do you have full control over your data?
- Is your data immutable once archived?
- Are you able to preserve your data to tackle technology and file format obsolescence?
- Are you able to collaborate and re-use your data with other clinical data that you are generating?
- Do you know what data is where if you are using multiple CROs and potentially eTMF vendors?
- Is it auditable?
It’s important to ensure that the TMF data is suitably packaged and easily retrievable on demand. Regulations outline that eTMF systems include digital content archiving, access and change control audit trails, system validation, and of course, security. For your eTMF package to be inspection ready, it’s important that the data, metadata and audit trail are all packaged together in an easily retrievable format, mitigating technical obsolescence. This can be complicated, even more so when you add the requirement to manage this for the lifetime of the data too.
Another requirement for your archived data is to conduct regular quality assurance to ensure the data truly is inspection ready and the investigator is maintaining your archived data to the quality expected. You don’t want to find yourself in a “disaster” situation where you need to recover your data and check its integrity, audit trails and metadata have all been recovered too to test whether your recovery process is good enough.
GCP Inspections – Is your data inspection ready?
In the recent MHRA GCP Inspections report, some interesting critical findings were raised including under-reporting of SUSARs to the competent authority and inaccurate information being submitted in DSURs; incomplete TMFs being presented for inspection and supporting documents maintained in different, non-compliant, systems. An inability to find and access documents in the eTMF, incomplete documents and missing critical information, all contributed to a commercial sponsor receiving a critical finding for not keeping their data in an inspection ready state. No appropriate system checks to ensure their systems processes are working as expected, including checks on their automated report submissions resulted in the same sponsor receiving a second critical finding for pharmacovigilance.
During one CRO’s inspection, the TMFs selected for inspection were found to be significantly incomplete, to such an extent that the trial conduct could not be reconstructed, and the inspection had to be extended. This was found to be a systematic issue, with the eTMF being considered and used as a final document repository rather than a contemporaneous system used to manage the trial.
In order to ensure compliance with these guidelines, you need to ensure that your eTMF processes have provision for archived as well as live data. An archive needs to comply to the EMA and ALCOA guidelines.
We are holding a webinar on December 11th to present potential solutions to this challenge with digital data preservation.
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