This post continues the discussion regarding the differences between the TMF and ISF (or Investigator Site File). Several years ago, I created a pictorial representation of the TMF to illustrate that the TMF was more than just the minimum list of essential documents that are identified in ICH GCP Chapter 8. It seems that another picture might help here too.
So this shows what the TMF is comprised of. It includes TWO sets of documents: the sponsor TMF and the investigator TMF.
It is interesting that industry has developed a separate term for the investigator TMF, namely the ISF or Regulatory Binder, though not for the sponsor TMF. However, it is worth noting that neither ‘Investigator Site File’ or ‘Regulatory Binder’ are recognized terms in ICH GCP, FDA Code of Federal Regulations or European Directives or Regulations. The EMA draft guidance on GCP compliance in relation to the trial master file that was circulated in 2017 states that the investigator TMF is “often referred to as the Investigator Site File (ISF) or Site Master File (SMF)” but also reinforces the point that the TMF is actually both sets of documents. The MHRA GCP Guide refers to the TMF as being composed of a “sponsor file” and an “investigator site file”…. in other words, the TMF is NOT the sponsor file….. it is BOTH sets of files.
Unfortunately, we’re often seeing articles published, comments made online or people presenting about the TMF and they use the term “TMF” as if it just refers to the sponsor essential documents. For example, they refer to “the ISF and the TMF”. “Is this such a big deal?” you might ask. Well, the continued misuse of the term TMF to mean just the sponsor file has led to significant misunderstanding. For example, many colleagues mistakenly believe the “TMF Reference Model” does not include the contents of the ISF because they equate the term “TMF” with just the sponsor records! Or site staff do not get involved with conferences and other meetings that are promoted as “TMF” events because they don’t perceive the relevance. See how easily these misunderstandings can arise? So, if you read material or listen to colleagues talking about “the ISF and the TMF”, you really want to ask questions about what is meant. It is a little like saying “I travel to work either by car or by a motorized vehicle”. A car is a subset of motorized vehicle so the statement doesn’t make any sense! Similarly, the ISF is a sub-set of the TMF so it doesn’t make sense to say “the ISF and the TMF”; you mean “the ISF and the sponsor TMF”!!
So, now that we’ve cleared up the terminology, what about the content? Well, take a look again at the graphic.
There’s a lot in common between the investigator TMF (ISF) and the sponsor TMF. As much as 90% of the documents found in the investigator TMF are also found in the sponsor TMF (these can be identified in the TMF Reference Model by filtering on columns N – Q). Despite this overlap, the two parts of the TMF must still be treated as two separate sets of documents, one managed by the sponsor and one managed by the investigator. This point was specifically reinforced in the recent revision to ICH GCP. However, the sponsor TMF also includes a very large number of documents that are not held by the site. In addition, the investigator TMF (ISF) also holds content that the sponsor does not hold. It is important to note that there is not an expectation that the sponsor’s TMF hold everything that is in the investigator’s TMF. ICH GCP identifies specific documents that must be in both (see Chapter 8), but otherwise, there must be justification and a good rationale for transferring site documents to the sponsor, especially in the light of data protection legislation such as GDPR. Finally, the site also holds the subject’s medical file or medical notes. Some of these will be source data and filed in the investigator TMF (ISF) but others are not needed in the TMF and must remain in the medical notes in accordance with relevant regulations.
Just for information, a project is currently ongoing under the auspices of MAGI to create a comprehensive list (or reference model) of documents that comprise the investigator TMF. As agreed between MAGI and the TMF Reference Model Project, once final, the TMF Reference Model will be updated to include all of this new content.
Feel free to get in touch if you have any questions or need assistance in implementing or interpreting TMF regulations.
nb. For the avoidance of doubt, whilst I am a member of the TMF Reference Model Steering Committee, this is posted as a personal opinion and not as an official representative of the TMF Reference Model project team or Steering Committee.