Electronic Trial Master File
This course is an overview of the Emissary Trial Master File (eTMF) capability used to maintain regulatory document and patient medical records in context with the case report form in the VISION Electronic Data Capture (EDC) system. It is a required course for study coordinators, site regulatory document specialists and project team members prior to receiving a password for the online clinical trial system. It should be taken after the Basic EDC training course.
The course consists of a written discussion, a short video and an online quiz. Registered and logged-in students obtaining a passing score on the quiz will receive a certificate of course completion. For members of an Emissary study project team, this certificate should be saved and uploaded to the eTMF to serve as part of the regulatory documentation for the trial.
Time required: 20-30 minutes.
The Trial Master File (TMF) is the huge collection of regulatory documents (a/k/a study documents, essential documents) that are produced during a clinical trial. At the investigational site level, these documents are usually stored in 3-ring binders called the Investigator Document Files (IDF). The Sponsor maintains a duplicate copy of the documents from every site. Oftentimes, the site monitor will have yet another working copy (informally called a shadow file) which helps the Clinical Research Associate (CRA) ensure the investigator's file matches the sponsor's file.
These documents must be collected, processed, cross-matched, verified, periodically-updated, and retained for a very long time in a readily-accessible manner for potential regulatory review. Clearly, this requires tremendous effort, an effort that can be significantly reduced using modern Internet-based technology. That is exactly what Emissary International has done. We collaborated with Prelude Dynamics to create a one of the clinical research industry’s first Electronic Trial Master Files (eTMF) using our VISION EDC (electronic data capture) online case report form and eClinical software platform. By building the eTMF system within VISION, it meets all the strict regulatory requirements for electronic trials such as 21-CRF-11 and, in context with other safeguards and SOPs, all patient privacy requirements internationally.
Some of the unique advantages provided by the Emissary eTMF are:
- Secure, rapid, 24x7 access to the essential documents from anywhere in the world while eliminating duplication, reducing workload and paper-handling costs and allowing paperless clinical trials.
- Integration with the case report form, allowing functionality such as presenting a list of site staff having required training documentation when asking who conducted a patient procedure.
- Improved regulatory compliance arising from revision tracking, automated Delegation of Responsibility Log, access restrictions, and the ability to easily see the status of required documents.
- Document and calendar-based notifications, such as an automated reminder sent 30 days before the next IRB renewal or a notice sent whenever a certain document is revised.
- Offsite backup and disaster recovery, simplified archiving and long-term storage of the study documents at the end of the trial.
The eTFM supports all required essential documents for a clinical trial required under Good Clinical Practice regulations such as ICH E6. It has two designs, supports two types of documents. The first design is for those documents matching a predefined list, often called the startup documents, such as:
- Study-level documents – protocol, investigator brochure, etc.
- Site-level documents – FDA Form 1572, IRB approval letter, protocol signature page, etc.
- Study staff documents – curriculum vitae, financial disclosure form, training records, etc.
- Patient-level documents – source docs, DICOM imaging files, etc.
For the documents needed for each staff member at the investigational site, the eTMF will present a pre-defined list of “upload slots” based on what functions and responsibilities have been delegated. For example, the sub-investigator having responsibility for conducting a particular patient procedure will be presented with a slot for uploading documentation of training on that procedure whereas the site pharmacist will see a different set of requirements.
The second type is for those documents where the quantity or explicit need cannot be predefined such as correspondence or monitoring reports. In this case, the eTMF allows for the creation of new tabs, analogous to a separate binder or file folder, and a repeating table design (see the EDC training course) to allow the list to expand indefinitely.
Where Are Documents Located?
The Emissary eTMF is deeply integrated into the Prelude VISION EDC system. You may want to first review the Basic EDC training course for a discussion of the VISION structural areas.
Study-level documents such as the study protocol are uploaded by the sponsor at the project level (Show: Info) where they are then made assessable to all sites, eliminating the need for every site to maintain a separate duplicate copy. Documents in this area will be read-online-only and/or download-only for the investigator and coordinator.
Site-level and study staff documents are uploaded by the investigator-designee (usually the coordinator or site regulatory document specialist) and/or the sponsor in the Site structural area of VISION (Show: Sites). Here, the coordinator will have upload slots for predefined startup documents plus the ability to create binders/folders for things like correspondence.
Patient-level documents are uploaded within the case report form (Show: Patients). Again, there will typically be predefined lists (specific imaging files, certain required source documents such as a discharge summary or local lab reports at specific patient visits) and the ability to create additional folders/tabs for things like patient correspondence.
How Do I Upload a Document?
Uploading a document is simple. First, just navigate to the proper location and, if applicable, identify the correct predefined slot. Then, click the BROWSE or CHOOSE FILE button (depending on how the study was configured) for that row in the table, and select the file on your local computer using the dialog box similar to how you would attach a file to an email. You should then enter any requested metadata. For an IRB approval letter, the requested metadata might be the date of approval, the version of the protocol that was approved, and the date when the approval expires. You must then click SAVE in the floating footer before the EDC will execute the upload. This allows you to set-up a long list of documents for uploading all at one time. As with other EDC forms, moving to another tab will trigger an automatic save, but closing the browser or linking-off to another page will not, and you could lose the metadata you entered.
You can upload a new version of a document in the same way and in the same slot. The eTMF will automatically archive the original version and create the new revision upon save, copying all the prior metadata to reduce re-typing; you can edit this as necessary. Prior revisions are viewable by clicking the +/- icon in the first column.
You can delete a current file by clicking the DELETE box and saving the form. But, once a new version has been uploaded, the prior version along with its associated metadata becomes non-editable and cannot be deleted. Depending on the configuration, you can usually mark a row as PRIVATE (by clicking a labeled box and saving the form) so that it is readable only by you.
Site Staff Tabs and Delegation of Responsibility
A difficult task in starting up a new site is compiling all the documents required for the many members of the site team such as CVs, medical licensure documents, financial disclosures, etc. The list is long and varies based on what responsibilities have been delegated to each person. In the eTMF, this is handled much more efficiently. First, using the standard VISION capability to ADD FORM, the coordinator can easily create a new tab for each person. A checklist at the top of the form asks what responsibilities have been delegated to this individual; the list of required forms is modified based on these responsibilities. For example, if that person has responsibility for drug preparation, the eTMF, depending on the study configuration, might ask for a pharmacist license or a specific training document.
With this assignment of responsibility, the eTMF then has all the information necessary to automate the Delegation of Responsibility Form. This burdensome paper document is replaced by a summary report that, depending on the study configuration, can be signed by the investigator using electronic signature tools.
The eTMF can generate two types of notifications: calendar-based reminders and immediate notifications upon upload. Calendar reminders are limited to predefined lists of documents and are setup in the initial study configuration settings, whereas immediate notifications are user-activated and can be used with any document type.
When setting up the trial, the project manager has the ability to create metadata questions that can be asked on the predefined (startup) documents. A common metadata is the document expiration date. The project manager has the option on such date-based metadata fields to establish a Days to Notify setting. The eTMF will use this to generate an email or internal notice when that date +/- the Days to Notify has been reached. For example, for an IRB approval document, the Date Next Review Required might be a requested metadata field, and the project manager may set the Days to Notify to be 30 days before. In this case, the eTFM would send a notice 30 days prior to the next IRB approval due date.
Immediate notifications are set-up by simply check the user role(s) to notify. Then, anytime the document is saved and this slot has changed, a notice will be sent to the selected user roles.
Notices can be sent to external email addresses (setup in the user settings) or to the internal Notification area within VISION (Show: Info > Notifications). Calendar-based notices are queued in this area as well, under the pending tab, until the send data. They can thus be modified or deleted from here if necessary.
Notes and Queries
As with other forms in the VISION EDC system, the eTMF allows coordinators to click SHOW NOTES in the footer, select from the musical note symbols that appear next to the document and its metadata fields, and add a comment. Similarly, Clinical Research Associates or Emissary/Sponsor regulatory managers can generate queries (red question marks) for the coordinator to address.
Form States and Workflow
Also, the eTMF incorporates the standard VISION form states and workflow functionality. Thus, forms can be signed-off to show completion and locked to prevent further changes. Also, as with other forms, the change history for the page is retained in the audit trail.
Summaries, Reports and Export
And, like other data in VISION, the eTMF data can be used in predefined summaries, user-defined reports and included in exports. This allows for extensive project management capabilities such as easily tracking the status of regulatory document compilation, site staff listings, status of IRB approvals, etc.