Notes to File – Problematic or Preventive?
Posted by Lorrie Divers, June 21, 2010, 2:35 AM
I recently had the privilege of speaking at the Roswell Park Cancer Institute's Education Day for Clinical Research Staff on a topic chosen by the staff: How to prepare for sponsor audits. The topic selection alone was an indication of how engaged their clinical research staff is, and their questions demonstrated their proactive approach to improve overall study quality.
 
For example, there was a question regarding notes to file (NTF) that led to an interesting discussion. NTF are typically used to explain any discrepancies or missing/incomplete data during the course of a trial and are increasingly requested by sponsor monitoring staff to provide additional information or clarification. This practice has become prevalent, and yet simultaneously problematic.
 
When used properly, NTF can be valuable source documentation. However, when they simply note a problem and don’t resolve it, these NTF can raise more questions than they answer for auditors and regulatory authority inspectors. For example, issues can arise when NTF are written long after the initial occurrence or corrective action was taken. (Carl Anderson of Biologics Consulting Group wrote a great article on this topic in Applied Clinical Trials.) Further, improperly used, such NTF can lead to observations during an FDA inspection such as noted in this recent warning letter. 
 
Finding an NTF that only points out a problem is not uncommon to find during an audit. For example, what if during an audit at a clinical investigator site, an identical NTF noting a protocol procedure discrepancy is observed in several subjects’ records? The note only highlights the issue, which is apparent from reviewing the records anyway, so an auditor will be curious to learn how the issue was resolved and prevented. 
 
Upon interviewing the clinical investigator and study staff, information conflicting with that NTF is provided and the study staff admit the NTF was written as instructed by the monitor, but not entirely accurate nor applicable to all the subjects. FDA regulations clearly indicate that “adequate and accurate case histories” are the responsibility of clinical investigator [21 CFR 312.62(b)]. This obligation applies to any source documentation, including NTF. Now what? 
 
Good documentation practices are the answer and apply to all of us working on clinical trials – clinical investigators, sponsors, CROs, central laboratories and any other vendor conducting GCP activities. NTF can be effective when properly used, written in proximity to the issue occurring, clearly explaining the issue and how it was corrected/prevented, combined with demonstrating that the issue is not recurring by continued compliance and future accurate record-keeping.
 
The discussion at Roswell Park centered essentially on who “owned” NTF and what should be the policy to avoid any inappropriate or unnecessary NTF. If the clinical staff at the investigator site does not agree with the type of NTF they may be asked to create, do they have the opportunity to disagree or at least have a say in how the issue should be handled?
 
In my opinion, I think it would be beneficial for a clinical research site to develop a policy on NTF that indicates the circumstances in which they will record such notes, their content and approval requirements. A policy should clearly state that NTF need to include the root cause of a problem and state the corrective action to resolve that problem. 
 
Investigative sites can play a key role in ensuring that NTF can improve the quality of clinical trials. A similar policy at the sponsor level, for monitors to apply, would provide consistency and quality as well. We should all consider how we can improve our NTF practices and effectively support GCP compliance.
 
What are your thoughts on NTF? Have you encountered situations in managing NTF during a trial or audit? We would love to hear from investigative sites and sponsors on prospective solutions or ideas you may have.
 
Feel free to view my Roswell Park presentation on “Preparing for Sponsor Audits.”
Category: Quality Assurance
Comments
Lorrie Divers  4/19/2011 05:47:48 AM
For a key document that is shared between a sponsor and a service provider, such as a data transfer agreement, it is appropriate for the two parties to agree on the content of any addendums such as the one you describe. Typically, the changes to and rationale for such revised agreements would be incorporated into the revised document itself as part of the 'Description of Changes' or revisions table rather than in an additional note to file, however, this would depend on the procedure and template governing the agreement document. Regardless of the method of documentation, I would encourage seeking agreement on the content of the addendum and the associated note to file and discourage a chain of notes to file to notes to file.
Noemi Olivo  4/15/2011 06:57:24 AM
We recently received (from the study sponsor) a draft copy of an addendum to data transfer specifications document. In it was a link to a NTF to explain the reason for this addendum. We felt that the NTF did not fully explain why, and therefore offered a suggestion for rewording the NTF. Specifically the NTF did not clearly state that the reason for less data to analyze was a result of low enrollment and not a result of our lab's inability to process specimens. Were we correct in requesting a change to their NTF and if they do not agree to make a change to our satisfaction, can we write a NTF to their NTF? Thank you and PS, How can I view your response?
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