The TransPerfect Life Sciences Trial Interactive team was excited to attend the 2017 TMF Summit in London this October, where discussions on the movement from paper to eTMF continued to be a focus.   At recent industry conferences, including both the Trial Master Files and Inspection Readiness (September 2017 in Amsterdam) and the TMF Summit, challenges were echoed by sponsors, CROs, eTMF providers, and regulatory agencies. While progress has been made in areas such as eTMF Reference Model adoption for index structures and metadata artifacts, it is clear that challenges still persist amongst the industry and TMF stakeholders. Regulatory authorities shared key insight and updates related to some of the reflection papers and regulations. As an example, EMA talked about eTMFs in final review, and the most recent July 2017 Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials that will come into effect in 2018 or shortly thereafter.

Common themes that have persisted, whether sponsor or CRO, are challenges in 1) getting documents into a TMF on a timely basis; 2) developing metrics and KPIs, and consistently measuring and assessing these on an ongoing basis to drive real-time inspection readiness; 3) better sponsor oversight and governance of CROs and other functional service providers for TMF management; 4) making cross-functional departments understand their obligation to submit relevant documents to the TMF on a timely basis; 5) a debate about “draft” documents being made available as part of the eTMF; and 6) access to video files (training) in the system and document images/scanning. Let’s take a look at each item:

1. Timeliness of TMF document submission
   Many presentations at the two conferences highlighted not only eTMF system benefits, but also concerns as reporting capabilities may expose weaknesses. Document submission timing was one specific example discussed, as some regulatory inspectors have asked to see when documents had been submitted. This may expose a dramatic increase in document submissions after the regulatory notification of an upcoming TMF inspection is sent to the sponsor. What the companies are highlighting is a weakness in their internal processes with their teams and how they view the TMF; many view it only as a final document repository. Until better change management occurs, with improved processes and constant training to reinforce positive habits, improvement will not be possible. This may be easier for emerging companies who embed the thinking  into the process from the outset.

2. Metrics and KPIs:
   Almost all sponsor and CRO presentations discussed the need for metrics and KPIs. Many companies seem to have them in place, as well as thresholds for their KPIs, but many also admitted the need to evolve KPIs and work with the business to yield improvement in TMF completeness and inspection readiness oversight.

3. Governance:
   This was a common topic of discussion, particularly at the TMF Summit in London. One of the panels asked the audience if they have a governance process around TMFs when they are outsourced to CROs or TMF providers. It was clear from the response that many do not, and that this is an opportunity for an improved process. Some commented that if there is sufficient knowledge and planning, this could be in the contract. Most agreed it was more likely something that would be highlighted in a Work Instruction or Governance Plan outside of the contract and kept on file for use throughout the study (or program) conduct.

4. Cross-functional department TMF timeliness:
   A few of the presentations talked about the challenge of engaging study teams throughout the essential document collection process, related to the study eTMF.  These companies shared that many of their study teams do not know what essential documents are required, and are unaware that they have a responsibility to file them as they become final. They agreed that developing a cross-functional team with departmental stakeholders yields better compliance and thus a more inspection-ready eTMF through accountability effectively distributed across the individual departments.

5. Draft documents:
   One of the panels discussed putting draft documents in the eTMF. From a show of hands, it was fairly clear that most companies do not put draft documents in the TMF, though one person commented that they keep a “working folder” for such drafts. Another mentioned that a regulatory inspector asked to see the draft documents. If the company SOPs are explicit in what documents constitute the eTMF, those documents don’t necessarily need to be made available to the regulatory inspector. While the regulatory authorities may want to understand the process of how items were developed and the process for sign off, draft documents are not necessarily something that need to be provided to the authorities by default.

6. Video files and document image scanning for your eTMF:
   As technology evolves to streamline the clinical development landscape, and without specific requirements by the regulatory agencies on every item (they are here to give guidance and recommendations), there will always be healthy debate about the right or wrong approaches. The last session at the TMF Summit in London included back and forth about the inclusion of video files in the eTMF, as well as the scanning of documents at investigative sites (which sadly are still mostly in paper) and their use in an eTMF.

   • Video Files - The updated EMA guideline EMA/15975/2016 references Clinical Trials Regulation (EU) No 536/2014 Article 57 that states, “the clinical trial master file shall at all times contain the essential documents relating to that clinical trial which allow verification of the conduct of the clinical trial and the quality of the data generated.”
     • The EMA and other agencies want to be able to easily recreate and trace the study via the eTMF, and view how the study was conducted to assure the safety of the study subjects and the validity of the data submitted in seeking product approval.
     • Depending on how the study is conducted, videos may be used. These may come in the form of training videos for study teams, investigative site personnel and/or study subjects, or, for medical device, an overview of the product(s) and how they are to be implanted, etc. These videos would likely need to be available to a regulatory inspector, and thus would need to be kept as part of the eTMF in the event of an inspection. While some at the TMF Summit suggested not storing videos in the eTMF, these special situations would necessitate eTMF inclusion.
   • Document scanning and submission – almost all of the presentations discussed metrics and KPIs and the need to have these as part of governance.
     • While companies all work on deciding what they should measure, one data point that many consider is the cycle time of getting documentation submitted to the TMF. One challenge around paper documents kept at investigative sites is that CRAs are required to either photocopy or scan documents that do not exist in the TMF in a timely manner. Most CRAs admit that they photocopy documents on site (which can often take considerable time in a hospital setting). At a later point in time (sometimes weeks) they then scan documents either from their office or home office.
     • The clock to get the documents into the eTMF (or paper TMF) has been ticking since they left the site, and many time can take up to a month or longer! Taking this into considering, how “real time” and “complete” is the TMF in the eyes of the regulatory inspector?

 
What is the significance of all of this you might ask? Well, all of the information is crucial for running effective clinical trials. However, these lessons learned also hint at the future of clinical. For example, there is already a better, 21 CFR Part 11 compliant alternative for navigating today’s environment—mobile applications as an extension of your eTMF. With the complexity of the above considerations, the convenience and quickness of a mobile experience can make things much easier. With issues of timeliness, effective distribution of accountability, governance, access to important metrics and KPIs, the logistics of scanning and document images, and the use cases for video, clinical trials are due for the familiar agility of streamlined mobile application experiences that simplify actions and insights. It‘s impossible not to see the advantages of a clinical-focused mobile applications as discussions grew about the topic.

Consider your favorite airline app (for CRAs who travel frequently) or Concur (for expense reporting). What are the reasons these are all valuable to users?

• Handheld access to information quickly while people are on the move
• In the case of Concur, scanning receipts remotely and efficiently getting your expense reports processed.

The eTMF is not all that different; you want to get documents in quickly, add metadata, and process rapidly to make them available to study teams. Some eTMF solutions exist to streamline tasks for the CRA on site, such as a mobile application that enables document scanning and applying metadata, follow up on eTMF queries and expired docs, and viewing the eTMF index, all within a mobile experience. Many eTMF providers allow CRAs to configure the app based on their particular needs, so when they arrive at the site they can easily access the eTMF and connect with relevant study personnel. All of this makes the work easier for CRAs (and study teams), while also meeting regulatory requirements. If you are not considering any of these options, you are missing an opportunity to make things easier for your teams.

In summary, the TMF Summit in London presented a lot of new and useful information for all attendees, particularly surrounding some of the current challenges with TMF/eTMF. The sessions offered a healthy exchange of ideas and a view into the not–too-distant future from a regulatory perspective. As the seasons change, hopefully we’ll continue to see change to the eTMF mindset moving forward.