Ask the TMF Experts About That Note to File: Your Questions and Answers

April 12, 2022

Meet Sholeh Ehdaivand and Ben Rodgers. Ehdaivand and Rogers are a part of LMK Clinical Research Consulting’s family of TMF experts who share over 500 years of combined life science support experience.

If you missed the second event in the Ask the Expert series, “About That Note to File…”, on Thursday, October 21st, no worries! We’ve captured a few of the most thought-provoking questions and answers from the webinar.

Sholeh Ehdaivand is the Founder, President, and CEO of LMK. Ehdaivand has over 15 years of experience in the pharmaceutical industry. Ehdaivand’s expertise in all areas of study management and clinical trial operations has made her a trusted industry expert.
Ben Rodgers is the Manager of TMF Education and Employee Development at LMK. Rogers has extensive experience in the clinical research industry and has worked in nearly all aspects of TMF operations, including as a TMF Manager and Senior Manager of Site Management Services and TMF.

Why Do We Care So Much About the Note to File?

Rodgers: The Note to File is a controversial topic. To understand why, we need to focus on the fundamental purpose of the TMF: to tell the story of a clinical trial. Clinical trials are the product of the humans that run them. By nature, this means that every TMF is imperfect. The Note to File is a necessary tool to address this imperfection. We use the Note to File to fill in the missing pages of the story. When used correctly, the Note to File adds detail and clarity to explain incomplete, contradictory, or missing parts of the TMF’s narrative. I think people love to hate the Note to File because, of course, in a perfect world, there would be no need for the Note to File and the expected TMF documents would speak for themselves.

Ehdaivand: Ben is right. The Note to File is a compromise and an unhappy compromise at that. The Note to File is a tool, but it usually is a hinderance as well, especially when the Note to File is used as a crutch to avoid important corrective action. There are dozens of examples of serious inspection findings mentioning Notes to File, especially when there is an overabundance of them filling a TMF. There are so many better tools in our toolbox that can be used in place of the Note to File. No Note to File can take the place of your due diligence.

Should I File a Note to File in a Missing Document’s Place or in a Designated File Note Location?

Rodgers: Before I give my own opinion on this question, I would note that you need to follow your organization’s own processes regardless of what I think is best. It’s essential to be consistent when dealing with the Note to File, even if your organization’s policies might not be the best or most efficient. In my opinion, if your Note to File is addressing a single missing document, or even missing information in a filed document, it makes sense to put the Note to File in the place of the missing document or with the relevant flawed document. If it is filed in a general File Note section, inspectors might not notice it. The idea of using a Note to File for a missing document or incomplete document is to allow an inspector to quickly understand what is going on without having to search for or reorganize your File Notes. Sending the inspector hunting in a different folder isn’t achieving this goal.

Ehdaivand: In addition to what Ben said, I would recommend using the document linking functionality for single document related Notes to File if your eTMF has that functionality. We see this question a lot, and I think the confusion stems from the TMF reference model that is commonly used in the industry. There is a general File Note section in the model—it was put there to accommodate the many ways organizations choose to organize their Notes to File. You don’t have to use this section just because it’s there. In fact, nobody should be using the reference model without customizing it to fit their specific organization’s needs and policies. The reference model is meant to be a starting place, not a rule for how every TMF should look.

Does a Note to File Need To Be Signed?

Ehdaivand: Again, I would advise you to follow your organizations specific policies here. Nowhere in ICH GCP or FDA 21 CFR is there any specific guidance on what needs to go in a Note to File. We have some basic expectations based on the good documentation practices that we apply to all documents in the TMF. In fact, when it comes to signatures, ICH GCP asks for only five document types to be signed: protocols and amendments, agreements and contracts, complete informed consent forms, complete CRFs and corrections, and signature sheets/logs. If you are developing a Note to File process or are in a leadership role where you can shape the process, I urge you to think about the implications of adding that signature line. Adding a signature line introduces multiple workstreams and a lot of complexity and regulatory risk. What do you hope to gain by adding it?

If you must include the signature line, make sure your process is clear about the details. Who can sign a Note to File? How long do they have to sign? What is the purpose of the signature? A signature line without clear expectations will likely work against you during an inspection.

We invite you to share your most difficult TMF questions with LMK’s experts!  Simply email us with your question… the answer might end up in our next interactive webinar.