by Laurie Meehan & Lauren Kelley

Q: If Notes to File can be regulatory red flags, should you quit using them?

A: No, and here’s why…

Regulatory inspections are often conducted long after the conclusion of the study. When an FDA investigator asks you a question about an anomaly five years after it’s happened, will anyone recall the circumstances well enough to satisfy the regulator’s concerns? You’ll be doing yourself a huge favor if you write NTFs that answer the questions regulators might one day be asking you.

NTFs can be used to effectively explain an irregularity, locate a document, or note a change in procedures. While there are no regulations or guidances that govern NTFs per se, ICH E6(R2) 2.10 states “All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.” A well-written NTF will not only describe an event, but will document who made the notation and when, why the problem occurred, what was done to fix it, and what changes were made to keep it from happening in the future. That’s a lot, so it’s a good idea to develop an NTF template to remind authors to include these elements.

Example of a poorly written NTF:

Informed Consent for study BH-90210 was revised by the IRB 01/7/2017. Subject 867-5309 was not re-consented at her next study visit, as per IRB instructions.

This NTF does nothing more than document the deficiency.

Improved NTF:

Informed Consent for study BH-90210 was revised by the IRB 01/07/2017 to include lab procedures on Visit 5. IRB instructions required a re-consent for all enrolled subjects at next study visit. Subject 867-5309 was not re-consented at her next (2nd) study visit, but was re-consented at her 3rd visit.

This version of the NTF gives us a little more context and lets us know that the subject was re-consented before the new lab procedures were performed. The oversight was corrected in time to preserve Jenny’s1 rights, but we still don’t know why it happened; there’s not enough information to satisfy a regulator that failure to re-consent was not a pervasive problem. What were the site’s re-consenting procedures at the time of this study? Were they being followed? Who do we ask?

Complete NTF Using Template:

Protocol BH-90210
From CeeCee Arcy, Study Coordinator
To Subject File: 867-5309
Date 01/26/2017
Issue IRB approved revised ICF 01/01/2017 to include lab procedures on study visit 5. IRB instructions required a re-consent for all enrolled subjects at their next study visit. Subject 867-5309’s next study visit, her 2nd, was 01/11/2017, but she was not given the revised consent on this visit.

 

Action The oversight was discovered on Subject 867-5309’s 3rd visit on 01/25/2017. She was re-consented on this visit.

When Sue Sarr (CRC) was distributing the revised ICF document among subject binders on 1/7/2017, Subject 867-5309’s binder was being reviewed by a CRA and was not with the rest of the subject binders.

 

At the next Study Review meeting, the Study Coordinator stressed the importance and timeliness of re-consenting and reminded all staff distributing revised ICFs to account for binders that may be temporarily missing from the CRC’s desk (whether with CRA, PI, etc.).

Signature

1 If you know why Subject 867-5309 goes by “Jenny”, one of your friends wore a pink tux with shoulder pads to prom.

Since the subject was consented before the additional lab procedures were performed, there was no violation of informed consent regulations. This was an oversight with no ill-effects, not a significant break with procedures. Discussing it at the departmental meeting is an appropriate, proportional response. (Note that if the subject had not been re-consented before the new lab procedures were performed, the site would have been in violation of consent regulations and an NTF would not have been sufficient. Both the IRB and the sponsor would need to be informed of the failure to consent.)

A poorly written NTF – one that doesn’t provide enough information, one that identifies a problem but no solution, one that is inadequately standing in for proper record keeping – won’t satisfy a regulator’s concerns. These are the sorts of NTFs that can actually do more harm than good. A well-written NTF, on the other hand, is something your future self will thank you for.

A version of this article originally appeared in InSite, the Journal of the Society for Clinical Research Sites.

Laurie Meehan is the Social Media Manager for Polaris Compliance Consultants, Inc. She writes the company blog and eNewsletter, manages the company website, social media accounts, and internal training platform. Prior to joining Polaris in 2008, Ms. Meehan worked at a major telecommunication R&D company and taught math and computer science at local university.

 

Lauren Kelley is the Associate Director of GCP Compliance for Polaris Compliance Consultants, Inc. She has worked for over 35 years in the pharmaceutical industry and specializes in GCP auditing. Ms. Kelley also serves as an instructor for the Western Institutional Review Board and the Drug Information Association, and is a frequent speaker at SoCRA and other professional meetings.