Monday, December 5, 2011

Notes To File (NTFs): Remedy or Enemy

People sat up straighter.  Some audience members leaned forward in their chairs.   The unmistakable sounds of pencil on paper could be heard as attendees hurried to scribble down a message they wanted to make sure they brought home.
These were the scenes at both the 2011 ExL Pharma and the ACRP conferences, when Leslie Ball of the FDA warned attendees that NTFs are a red flag to FDA inspectors.  Of course, NTFs can be appropriately used, whether to clarify seeming anomalies, for example, or to indicate the location of a document.  However, NTFs are increasingly becoming overused, even abused.  Too frequently, clinical research personnel view them as remedies for all manner of things gone wrong during the study, negating anyone’s responsibilities to actually fix the problems.  Ironically, rather than assuage FDA concerns about non-compliances, NTFs have begun to point to them.  Indeed, a recent Warning Letter stated that a sponsor’s method for securing compliance, by generating numerous NTFs to explain deviations, was not adequate.
Dr. Ball explained that the FDA encourages a proactive approach to reporting significant non-compliances, and that an NTF may be helpful in documenting the correction of a deficiency while a study is ongoing.  To that end, and to the extent that NTFs are used, it is important that they not only describe what happened, but why it happened, what was done to fix the situation, and what has changed to prevent future occurrences.
Example of a poorly written NTF:  “Urinalysis report for Patient #3 missing from Visit 6 records.”
This NTF does nothing more than record the deficiency.
Another example of a poorly written NFT:  “Jane Smith, our new study coordinator, began her assignment on 04/05/2010.  That same day, Patient #3 came in for his 6th visit.  Though all other records were filed by Ms. Smith, the urinalysis report is missing.  Ms. Smith has been diligent about her documentation duties, and this missing report does not represent a trend.”
While this NTF offers some assurance that the oversight was anomalous, since this was Ms. Smith’s first day, it implies that perhaps she was thrown into the deep end of the pool without sufficient training or supervision.  The NTF does not indicate that steps were taken to rectify the situation.
Example of well written NTF:  “Urinalysis report for Patient #3 missing from Visit 6 records.  Upon discovering the oversight, a duplicate copy of the report was obtained from the lab, reviewed by the PI, and included in the record.  All other patient records filed by Jane Smith, the CRC, were filed correctly; this oversight was anomalous and does not represent a trend.  Ms. Smith has been trained in her duties, as her Training Records reflect.  To further assist Ms. Smith and other staff members in verifying that all required records are included in subject records, our CRC developed a QC check list for our SOP governing the maintenance of essential study records.”
The FDA is pushing for earlier detection and correction of non-compliances, so it’s no coincidence that this example NTF reads like a mini CAPA plan.  As NTFs are increasingly used to document that problems were caught, fixed, and prevented, they may well begin to lose their red flag status.
Before an FDA inspection, companies would be well advised to conduct an in-house or third party records audit to determine whether their NTFs are indeed remedies, or are actually enemies.

Expert consultants at Polaris would be happy to help you with any auditing needs you may have.  Contact us at or visit our website at

by Laurie Meehan

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