TMF. ISF. What’s the difference – Part 2

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 The EMA draft guidance on GCP compliance in relation to the trial master file that was circulated in 2017 states that the investigator TMF is “often referred to as the Investigator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.

Posted in e-records, Regulations, TMF | Leave a comment

TMF. ISF. What’s the difference?

Over the last few days I’ve been seeing a few posts on LinkedIn that have been getting me a little frustrated. The reason? Poor use of terminology! Let me explain.

The Trial Master File – or TMF – is defined by the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guideline as being “those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.” There is something really important to note here. The TMF includes not only the records generated by and managed by the trial sponsor. It includes the records generated by and managed by the investigator. They are held separately from the sponsor documents but they’re still part of the TMF.

We sometimes use different terms for the investigator-managed records…. typically the Investigator Site File or Regulatory Binder. But listen up: they are part of the Trial Master File!! So, when you hear people talking about the TMF or when read guidance about the TMF, it is not just referring to the sponsor essential documents, it includes the ISF too.

Why is this important at the moment?

An industry group has developed a reference model for trial essential documents over the last 9 years called the TMF Reference Model. It was created with the full scope of the TMF in mind…. in other words, it includes not just sponsor essential documents but also investigator essential documents. Yes, that’s right! The TMF Reference Model already includes the ISF. It doesn’t just contain 2 site documents (the subject log and source data)….. it includes them all! It is not called the “Sponsor TMF Reference Model” or “ISF Reference Model” because that’s not the terminology that ICH GCP uses. ICH GCP refers to both of these components as “the TMF” so that’s what the reference model is called! I’m going to make this absolutely clear here so there can be no ambiguity. If someone tells you the TMF Reference Model does not include ISF documents, they’re wrong. Just take a look for yourself. Download the Reference Model here: Open up the spreadsheet and take a look at column O. Where you see an “X” in the cell, these are ISF documents for trials on medicinal products. Look at column Q. Where you see an “X” in the cell, these are ISF documents for trials on devices.

So, here’s the next question. Is the TMF Reference Model perfect for the ISF essential documents? No it is not. This is recognised by the project team and one of the things we’ve committed to do is to get it more closely aligned with the requirements of the site. For example, for each artifact in the model we list individual document types that correlate with the definition and purpose of the artifact. These are currently mostly focused on the sponsor’s needs but it would not take a great amount of effort to also include specific site documents. A separate initiative (NOT part of the TMF Reference Model!) is current embarking on a project to create a completely separate ISF Reference Model. An initial draft has just been published and I can say with confidence that EVERY document is already included in the TMF Reference Model with full classification. So I ask myself, why is a completely separate reference model being created for Investigator Site Files when we already have a Reference Model that includes this…. it just needs improving. I also ask myself, which scenario would it be better to have: a single TMF Reference Model that meets the needs of both the sponsor and the site, or sponsor and site using two different models, with different terminology, different filing structure, and different metadata? Surely a single reference model would support efficient information exchange between sponsor and site and ensure we’re aligned with the way we name and file our documents?

Recent surveys indicate the TMF Reference Model is used on over 80% of clinical trials. The TMF Reference Model has been downloaded over >10,000 times from the TMF Reference Model website. Let’s work together to make this work as effectively for sites as it does for sponsors. How? Join the team and make it work!!

Need help developing your TMF processes and systems? I’ve worked on over 30 TMF projects. Give me a call! I’m here to help.

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.

Posted in Regulations, TMF | Leave a comment

Do You Have Records Management Problems?

If you look through my blog posts and LinkedIn updates over recent years, you’ll be forgiven for thinking that all I do is support pharmaceutical companies with their trial master files (TMFs). It is true that this has taken up a significant proportion of my consulting time in the last 5-7 years, largely because of the heightened focus on these records by regulatory authorities. And it is always enjoyable to work with my TMF colleagues…. we joke that “TMF” actually means “Too Much Fun”!

However, I’d like to take this opportunity to remind you that we do much more than this! Let’s run through the scope.

In terms of the industry sectors that I support, my main experience and expertise is in health sciences…. so that is the pharmaceutical and biotechnology industry and other organisations that work on health, medical devices and medicines development. However, I also have experience in other sectors, such as financial services, education and engineering services. Many of the records management principles that are applicable in health sciences are transferable to other sectors.

What aspects of records management do I support? I guess the right question to ask is what aspects of records management do I NOT support! I actually cover most, and this would include:

  • Policy development, for example: records management policy to comply with GDPR and other requirements; legal hold policy to prevent the inappropriate destruction of records during litigation or other disputes; IT acceptable use policy; employee exit policy to ensure the orderly management of records prior to employees leaving the company. Do you have all of these in place?
  • Process development, for example: processes to support the identification, classification and correct disposition of records; processes to support creation and management of an archive (on site, off site or digital); optimisation of record keeping processes in specific business functions; alignment of record keeping processes with applicable regulatory requirements to ensure compliance and efficiency.
  • Record classification, including the development of taxonomies that support effective management of records in the business, in records centres, in archives and that support defensible destruction. Associated with this is the review and/or development of records retention schedules…. having in place an approved document that describes how long specific types of records are to be retained for (for most companies, this is a requirement of GDPR).
  • Training, including development and (if needed) delivery of training to support your records management policies and procedures, record clean-up days, GDPR requirements.
  • Strategy development, providing advice and support in areas such as deployment of electronic signature technology, organisational models for records management support, outsourcing of record keeping activities, and risk management.

And the list goes on! In short, if your organisation has records management issues that you are struggling to manage because of a lack of experience, expertise or resource, please reach out to me. I’m here to help!

ps. feel free to use the “Like” and “Share” buttons!!

Posted in Compliance, Data protection, Records management practice | Leave a comment

Launch of our new Training Programme

We are very excited to announce the launch of a new series of training events.

Some of you will know that we have scheduled one-day workshops on various topics from time to time but these have often been poorly attended due to the timing not being convenient for attendees and the inability of some delegates to travel due to budget constraints or company policy.

We’ve therefore taken the decision to offer training as short webinars on specialist topics to be purchased and made available “on demand”.  These are listed on our website but are available for purchase and viewing from a third-party hosting partner. These are high quality, affordable and accessible. Our first webinar – The TMF Reference Model – is available now.

Over the coming months, new topics will be added to the curriculum (please let us know if you’d like to see a subject added or if you have any feedback for us).

Some of our workshops may still be available in traditional workshop format – for example, our TMF Masterclass – and we continue to offer bespoke training on site, upon request.

Hope to see you online soon!

Posted in TMF, Training | Leave a comment

Last call for TMF Masterclass

Last call! There’s only 3 weeks to go until our TMF Masterclass and still some delegate spaces to fill. Early-bird discounted booking closes in a few hours so please do not delay. This is not a standard presentation-style workshop. If you have challenges with your TMF process and/or system, this is THE event for you. We won’t be covering “the basics” because you already know those! We’ll be rolling up our sleeves and finding solutions to the problems that you bring to the workshop. So perhaps you are about to embark on an eTMF project or maybe struggling with improving compliance of your TMF processes. These are topics we’d love to cover with you. All this for £350. Don’t miss out – book now!!


Posted in TMF

Here’s How to Achieve TMF Excellence

Since becoming a freelance consultant in 2004, I have been involved with around 50 different projects to improve practices for managing clinical trial records (aka the trial master file or TMF). In many of these, the company concerned had chosen an electronic document management system for TMF management (eTMF) and required my assistance to implement the technology as efficiently and effectively as possible. This involves re-engineering the processes to be aligned with functionality of the technology and implementing various change management activities. The projects were much more complex than this but in a nutshell, that was usually the primary objective (simplified for the purposes of this blog!).

Several months ago, I took a step back and assessed the effectiveness of those projects. In many cases, the changes introduced were not always delivering the results that I expected and it was apparent that the primary reason was the company’s choice of process that was implemented; I never impose a process on a client….. it is always their choice and I do my best to optimise the choice that they have made.

In addition, last year I conducted research across the industry to try to determine how successful companies were at managing their trial master files and if they were struggling, what the root cause was. This research included three workshops that I conducted at industry conferences (DIA, IQPC and ExL-Events), involving almost 100 participants in total. My analysis shows:

  • despite efforts to improve processes and adopt best-in-class technology, companies are still not achieving great levels of compliance with regulatory requirements;
  • where some success has been achieved, it has usually required significant ongoing expenditure on quality control activities (i.e. high financial cost); and
  • improvements in TMF completeness and quality are often only achieved through dependence on constant monitoring of quality and implementing laborious checks.

Does this sound familiar? Is this your experience too? Have you implemented an eTMF but are finding that it is still a real struggle to achieve any significant improvement in TMF quality or completeness without constantly badgering people to conduct their quality reviews?

The good news is that the research I conducted also showed what the solution is….. and VERY clearly! I am very excited to start sharing this with colleagues and helping turn their situation around. I am confident that I have the solution to this puzzle…. and it is not dependent upon spending huge sums of money either!! If you want to be part of this, just give me a call and I’ll be only too pleased to let you in on the secret!

Posted in e-records, TMF, Uncategorized

Ready for a TMF Masterclass?

After a break of almost two years, we are planning to schedule another TMF Masterclass. Is this something that you or a colleague would benefit from? If so, please read on.

This will be an intensive 1-day, interactive workshop for colleagues who are already familiar with the fundamental principles and requirements for the Trial Master File (TMF). It will take your knowledge to the next level by examining the requirements applicable for an eTMF environment. Maybe you are about to start considering the implementation of an eTMF solution or you are struggling to make your eTMF work effectively within your company? This workshop will definitely be for you!

We will look at a range of different topics and, where possible, will adjust the content to meet the specific needs of those attending. We’ll likely be covering topics such as:

  • metadata and naming conventions;
  • quality control – when and how to manage quality;
  • record lifecycle management with an eTMF;
  • signature technologies;
  • how to increase levels of compliance;
  • how to differentiate between systems during the procurement process.

Space is limited for this event so please consult colleagues within your company quickly to reserve your place. The date is likely to be during the last week in March but we are currently flexible on the timing until we have the required minimum number of attendees. In the first instance, please register your interest in the Masterclass (no financial commitment) and we’ll get back to you.

Posted in Uncategorized