Applied Clinical Trials
Carl Anderson, senior consultant for Biologics Consulting Group, addresses the frequent overuse of Notes to File and concludes that documenting a mistake means absolutely nothing during an FDA inspection.
A common document at many clinical sites is the memo or note to file (NTF). When used properly, an NTF can be a positive practice. A useful NTF has the following parts: A problem is identified, a procedural change is identified for preventing recurrence, and this procedure is then instituted. In the event of an FDA or other regulatory inspection, the inspector may still leave a citation for the initial problem, but the change in procedure mitigates the citation and provides the site with a strong response to the finding.
Some in the clinical trials community, however, seem to think an NTF is a panacea for all things that have gone wrong. Make a mistake? Then write an NTF and stick it in the regulatory binder or subject case history. The practice has become so ubiquitous that new CRAs and study coordinators sometimes think that they are a regulatory requirement. But this is a misconception. There is nothing in FDA's regulations or guidance documents that requires sponsors and clinical sites to use NTFs. Nothing.
And many think that an NTF indicates a corrective action-with a quick one written without regard to correcting the problem. Sometimes, NTFs are even generated well after the deviation has occurred and all is considered right with the world-this isn't the case. In fact, FDA recently reprimanded a sponsor for after-the-fact memos.
In a Warning Letter dated October 23, 2007 (www.fda.gov/foi/warning_letters/s6551c.htm), FDA wrote: "Our investigation found (the sponsor) failed to take any action except to generate numerous memos to file after all the subjects completed the study." The Warning Letter then noted at least 89 memos were generated after a monitoring visit. Instead of writing NTFs, the sponsor's time is better spent qualifying the site and training study staff.
Documenting a mistake means absolutely nothing during an FDA inspection. What requires documentation is the corrective action taken and whether the action worked. If an effective quality system is in place prior to subject enrollment, then the sponsor, monitors, investigator, and study staff will each understand how the study will be monitored and how discrepancies will be communicated and corrected. Sponsors cannot depend on postmonitoring visit letters to secure compliance in serious situations.
During my own auditing experience, I have noticed that NTFs are frequently a contentious issue between monitors and study staff. I have seen trivial NTFs placed in regulatory binders at the request of inexperienced monitors. In addition, some study coordinators have developed a habit of writing NTFs instead of developing good recordkeeping practices. All an NTF accomplishes is documenting poor performance. And ineffective work seldom impresses FDA.
Clinical trials are hard work and require professional cooperation to quickly address queries and genuine findings that need correcting. Once an NTF is written and becomes a study record, it cannot be retracted. The result is a lose–lose situation for everyone. These NTFs are a road map for any inspector and air all of the site's faults.
A better solution is to develop a quality system from the clinical study's beginning that includes training on monitoring and data correction that everyone understands. Sites should document the actual corrective action and keep NTFs few and far between.
Carl Anderson Senior Consultant Biologics Consulting Group, Inc. email: firstname.lastname@example.org