Case Report Forms: Would You Manage Them in an eTMF?

August 15, 2013

  • eTMF Best Practices

During my years of working with regulatory document management systems, there was often debate over whether Case Report Forms should be included in the regulatory document management system. Of course, for US NDAs and BLAs, CRFs for deaths, dropouts and SAEs (and sometimes more) are required for submissions. But often they were already being managed in another repository, and sometimes publishing tools could access them directly in that repository or from a file system. As a result, bringing them into the regulatory EDMS might be a significant amount of unnecessary work and might even cause problems if they became “out of synch” with the original repository.

I am now starting to hear similar types of discussions related to eTMF. Clearly, CRFs are part of the Trial Master File. ICH 6 (8.3.14) calls for “Signed, dated, and completed case report forms (CRFs)” to be held as original documents at the investigator’s files and as copies in the sponsor’s files.

In the past, however, these documents were rarely brought into the electronic Trial Master File, usually for the same reason that they were not brought into the regulatory EDMS. However, I am seeing a trend towards at least considering the inclusion of CRFs in the eTMF for two reasons.

The first reason involves regulatory audit of the eTMF. All records that comprise the TMF are of course auditable, even if not stored in the eTMF. In the EMA’s recent “Reflection paper on GCP compliance in relation to trial master files (paper and/or electronic) for management, audit and inspection of clinical trials”, they state:

“GCP Inspectors will require direct access to the eTMF system as used by the organization. … There may be additional electronic systems that have TMF documents (identified in the TMF as part of the TMF structure), access to such systems is also required by the inspector.”

In other words, if the records are not in the eTMF, they will require access to the systems that hold them. Of course, this isn’t limited to CRFs, but also extends to other records typically held in other systems such as safety documents, CSRs, etc. Some sponsors are reluctant to increase the scope of the audit by including these systems, especially considering the EMA’s further remark, “Any training should be an option for the inspector to choose and is anticipated to be very brief (taking no more than an hour).” It would be challenging to train an inspector on multiple eClinical systems in under an hour.

The second reason involves archive. In the UK, for example, the archive must contain the entire TMF. If some records are stored in other systems, this may prevent the use of the eTMF as an official archive.

That being said, bringing CRFs into the eTMF will present its own set of problems. Presumably many of them will not be available in final form until the end of the study, resulting in a deluge of documents towards the end. If not already available electronically or as scanned documents, scanning and QC requirements will increase. An automated interface should probably be considered to import CRFs, especially if your organization runs large trials. The amount of storage needed for your eTMF will increase, and depending on country-specific retention requirements, retention and archive requirements may change as well.

I would be interested to hear more about opinions across the industry – what do you think the future holds in this area, and why?