A Trial Master File (TMF) is a collection of all essential trial documentation that enables effective monitoring, data integrity, and compliance throughout the lifecycle of a clinical trial. Because the TMF confirms regulatory compliance, it is integral to clinical trial success. The success of your TMF starts with effective planning.
We partnered with Montrium, creators of Montrium Connect—a platform for clinical trial document and quality management, to outline 10 Essential Steps for Trial Master File (TMF) Success.
With the following steps, you’ll be able effectively plan for your TMF by learning:
- How to set roles and expectations
- How to clearly outline processes, maintenance, and tasks
- What to do when problems arise
1. Have a comprehensive TMF plan in place.
Challenge: Let’s say you are working with a CRO who has contracted with a pharmaceutical company where they want you to manage the Trial Master File. During study start-up, a Trial Master File (TMF) plan was never created. The sponsor was under the impression that the CRO was maintaining a hybrid TMF (paper and electronic). The CRO had been maintaining a paper TMF only. When the sponsor requested access to see the electronic documents of the TMF the CRO informed the sponsor that they have been maintaining a paper TMF only. If the CRO had worked with the sponsor on a TMF plan this would have been outlined and the expectation would be clear.
Solution: It’s imperative to have a comprehensive Trial Master File (TMF) Plan in place to document how the TMF will be managed. If you are looking for a template, the TMF Reference model has a FREE template that you can use as a guide to help you define the roles, tasks, and maintenance of the TMF: https://tmfrefmodel.com/resources. If you scroll down the page you’ll find TMF tools here: https://tmfrefmodel.com/wp-content/uploads/2018/02/tmf-plan-template-v1-2018-02-23.docx
Result: A comprehensive and detailed TMF plan will help the sponsor and the CRO know how the TMF will be managed and it shouldn’t leave anyone guessing on who is responsible and what processes should be followed throughout the life cycle of the study. By creating and following the TMF plan the CRO and the sponsor will be informed of the purpose, the setup, retention of original documents, maintenance, storage, how email correspondences will be filed, QC’ing of documents, transfer of documents to sponsor etc.
2. Embrace the Reference Model.
Challenge: Your place of employment follows their own custom TMF filing structure. You are working on a sponsor study (non-device) and you just received a Note to File from the site regarding a study enrollment log. You aren’t sure where to file the document with your custom TMF file structure. You do see a miscellaneous folder and so you file it there because you don’t know where else to file it.
Solution: Following the TMF Reference Model isn’t mandatory, however, it was designed by highly qualified leading experts in the TMF industry to standardize the way documents are filed in the TMF. This standardization helps with defining, consistency, and improving efficiency.
Result: By following the TMF Reference Model it will save you time, money (the file structure is FREE to download!) and energy when it comes to finding the right place to file and retrieve a document. Instead of spending countless attempts to find a document in a miscellaneous folder which could be equivalent to a junk drawer, the reference model has designed the file structure to make it very easy to find the right spot to file a document and to be able to locate it quickly and efficiently.
3. Follow all regulatory requirements and comply with the investigator, sponsor and ICH-GCP standards.
Challenge: A site has been activated and the first patient is enrolled in the study. You are performing a periodic review of the TMF and are QC’ing the Essential Documents. You notice that a sub-investigator’s CV is missing from the TMF and found out that it was never collected prior to the site being activated. This is a violation of ICH GCP 8.2.10. Upon further review you see a note to file stating that this sub-investigator’s CV was not obtained prior to site being activated.
Solution: ICH GCP section 8.2 provides a list of the minimum essential documents that you should collect from a site.
Result: By utilizing this checklist it will help you to ensure that you have collected the necessary essential documents and avoid writing a note to file.
4. File only complete and final documents in a timely manner.
Challenge: You are busy at work and have received several documents from a site. You don’t have time to file them when you receive them, so you place them in a to be filed folder on your desktop.
Solution: Never save any documents on your desktop. They are not safe or backed up. Saving any outstanding documents to review and QC later in a folder is not efficient. It’s important to review your TMF plan and your company’s SOPs to see how long you have to review and complete the QC process. Then prioritize you work.
Result: By reviewing your TMF plan and your company’s SOP policy this will help you prioritize your workload and ensure that you are following the process to file only complete and final documents.
5. QC documents using ALCOA-C (Attributable, Legible, Contemporaneous, Original, Accurate- Complete).
Challenge: You are performing a TMF QC and you notice on a 1572, section 2 wasn’t filled out. This indicates that the document isn’t complete.
Solution: Look at the audit trail to see who previously reviewed/QC’d the 1572 prior to uploading to the TMF and reach out to them. Review the TMF to see if the PI’s CV was uploaded. From there you can start your Corrective Action and Prevention Plan.
Result: By creating a CAPA this will boost compliance and prevent this error from occurring again
6. Monitor to ensure documents tied to milestones are received.
Challenge: You are performing your TMF quarterly metric review and notice serval artifacts are missing that are tied to particular milestone.
Solution: Using an eTMF and the reference model significantly helps you ensure that the documents tied to milestones are received. If you look at the excel sheet version 3.2.0 of the reference model, specifically columns U (Trial Level Milestone), W (Country Level Milestone) and Y (Site Level Milestone) in addition, to the tab at the bottom called, Milestones/Events & Descriptions, it clearly defines which artifacts are expected at each milestone.
Result: When the metric results are below expectations, for example, multiple artifacts are missing, further investigation will occur, a “root cause(s) will be determined and a CAPA will be put in place to stop the issue from reoccurring”.
7. Avoid writing Notes to Files when possible.
Challenge: You are reviewing the TMF and are creating a list of missing documents for the monitor prior to their visit. You notice that you need a financial disclosure form for a sub-investigator. The monitor reviews the site’s investigator site file and does not see one. The monitor brings this to the study coordinator’s attention. The study coordinator informs the monitor that a financial disclosure form was never obtained for that sub-investigator and they will write a note to file.
Solution: A note to file tells us that there is a problem, and this is how it was resolved. You want to avoid having a problem and catch it before it’s “too late.” One solution would be to review your metrics more frequently to see which documents are missing/expected.
Result: By reviewing your missing/expected documents more frequently you and the coordinator could work together to obtain the missing financial disclosure form and avoid writing a note to file.
8. Have only the appropriate permissions to access the files in a controlled environment.
Challenge: 5 people from the sponsor side have requested to have access to your TMF. You follow your company’s SOPs for activating individuals who wish to have access to the TMF and give them the appropriate permissions. You find out that one person who has access to the system, has left the company, however, they left 3 months ago. Now you have someone who has access to the TMF who no longer is employed. The person in charge of the permissions to the TMF failed to follow through with the company’s SOP and follow ICH GCP.
Solution: A component to 21 CRF Part 11 compliance is “limiting system access to authorized individuals.” By following ICH GCP and having a strong SOP by stating how often a review of the permissions group of the TMF should occur.
Result: By following your company’s SOP and the ICH GCP guidelines the person who is in charge of granting and deactivating access to the TMF by controlling who has access to the system in a controlled environment.
9. Tell the story of the clinical trial.
Challenge: A regulatory coordinator emails you documents that were missing in the TMF. You are overwhelmed with your workload and you delete the email and pretend you never got it. You also delete that email from your deleted to cover yourself.
Solution: The TMF should tell a story throughout the clinical trial. You never want to have a cliff hanger. This employee may need additional training on company SOPs, ICH GCP and on learning how to prioritize their work.
Result: By re-training and educating this staff member you are empowering them to be a better employee and to have them adhere to all standards.
10. Be inspection ready at all times.
Challenge: You are working on a study where you are responsible for filing all relevant email correspondences in the TMF. You are keeping these relevant correspondences in a folder in your email and are waiting until the end of the study to file them. On the contrary, the TMF plan states that relevant email correspondences will be filed contemporaneously throughout the clinical trial. An internal audit is done on the TMF and found that there are missing email correspondences. In addition to the TMF plan, your SOPs indicate how frequent the TMF will be reviewed/QC’d. The person assigned to the periodic review of the TMF should have caught that the missing email correspondences were not filed in a “timely manner.”
Solution: Having the designated person who is responsible for filing email correspondences in the TMF and the person responsible for performing periodic reviews of the TMF should be re-trained on the TMF plan, all applicable SOPs and regulatory guidelines.
Result: By performing periodic reviews of the TMF per your TMF plan, SOPs and regulatory regulations this will ensure that your TMF will be inspection ready at all times.
With some forethought and planning, the TMF can become an effective tool that helps ensure your clinical trial meets regulatory compliance and runs smoothly.
At every stage of the process, Criterium’s mission is to provide all our stakeholders (clients, staff, consultants, sites) with an extraordinary experience. Criterium’s proven formula for clinical trial success is based on the dedication of its executive management and project management teams: We deliver exceptional personal attention and services for all clinical trials elements — people, processes, and technologies.