The Memo to File or Note to File (NTF) is Overused

These memos are often sloppy, contradictory, confusing, or alarming (I once monitored at a site where the PI had written the following memo “Although employees and family members of Dr. XXXX and this facility were enrolled in the trial XXXX, they were in no way unduly influenced or coerced to participate.” Ummm, wow, this was part of the study record and you can’t retract it under any circumstances).  Memos to File have to be reviewed and reconciled between the Site Master File and the TMF.  Frankly, there are better ways to capture the information i.e. training logs, protocol deviation forms, monitoring reports, etc. so why do many monitors insist that the site generate a million NTF?  I actually ask my coordinators to take it easy on the memos and to avoid writing them unless absolutely necessary or at least after serious consideration.

Some Memos to File are global correspondence from the sponsor or CRO and are necessary to address operational issue or questions (expanded specimen shipping instructions, imaging vendor holiday operation hours, clarification on processes, tracking, substitution of lab kits, etc.) these are beyond the scope of my discussion here.

A Note to File may be well-intended but can also provide an
interested party or inspector with a roadmap to a finding – yikes!

On-site, a series of NTFs all with the same date, in preparation for an inspection, or as a corrective action from an audit are a huge red-flag for me as a monitor.  Just document along the way, during trial operations, and avoid lengthy notes to file.  Personally, when I see file notes, I get a bit suspicious and inspired to dig deeper to make sure I am being given the whole story.  I propose that many NTF raise additional concern rather than actually addressing deficiencies.

Don’t misunderstand, I would propose that a NTF can be a good tool to supplement the clinical conduct record but please try to minimize how often these are used and ensure that they are accurate and contemporaneous.  For example, a NTF can be helpful when you are explaining gaps in documentation or inconsistencies, “B. Hill received rater training on 11-Jan-2011 but the certificate is unavailable, please refer to the training log. “  I would tend to use a Memo to discuss trial-related gaps rather than subject-related documentation issues.  A simple post-dated progress note in the subject’s source can address any ICH/GCP concerns instead.

I’ve used Memos to File to organize Site Master File binders “The pharmacy temperature log for this study is located in Suite 1027 and updated twice daily.  Please refer to the original logs.” and also in the sponsor level TMF to address gaps or clarify, “CRF approvals are filed in section 7.1.2.” “Translation certifications are filed at TMF level 3.6.”

A Memo to File can also be very helpful to reconstruct a record of conduct or to explain corrections that are made to documents that might raise questions.  For example, if an Informed Consent Form had a mistake (the wrong date was written, a signature was not obtained, an incorrect version was used, etc) it may be helpful for the study staff to generate a NTF to explain when the error was realized and what corrective actions were taken to come back into compliance.  If the subject forgot to date then the subject could be asked to date at the next visit and the SC could write a note explaining why a later date was used.  The corrective action could be additional site training and a procedure to review the consent form by a second person at the time of consent; this revision to the procedure would be helpful to capture in a NTF.

I am assuming this will be a controversial topic because monitors tend to be very passionate about whether these notes are a hindrance or a help; please leave a comment with your thoughts.  There is no regulatory requirement to produce Memos to File but I think in some cases sponsors and sites can benefit from them at times…they are, however, more powerful when used in moderation.   Oh, and if you produce a NTF please sign and date it, accurately.



You may also like...from The Lead CRA archives:

• Site Master File: Correspondence March 2011
• Routine Monitoring Visits March 2008
• Close-Out Visits July 2008

Site Master File: Correspondence

The Site Master File (SMF) or Regulatory Binder contains all of the essential documents to provide a record of study conduct. The SMF when reviewed with the clinical charts and archived study materials allows sponsors, auditors, regulators, and all other interested parties to reflect back on a clinical trial and understand how things were conducted, when, and by whom. The Regulatory Binder is created at the beginning of a study, updated as needed throughout, reconciled with the sponsor's Trial Master File (TMF) along the way during routine monitoring visits, and then archived at the end of the study.

The SMF is usually a big chunky (broken) three ring binder (or series of many binders) stuffed to the gills, bulging at the seams, and typically just a little bit intimidating.

Most sponsors maintain documents electronically but our industry is very much still a world of paper and at a site level, most study documentation is physical original or copied papers. For a list of the required items in a regulatory binder for a US trial please refer to ICH E6 Guidance Document on Good Clinical Practice (E6), Section 8 “Essential Documents for the Conduct of a Clinical Trial.” (protocol, Investigator's Brochure, trial logs, lab documentation, IP documents, correspondence, etc.).

Today I am going to review the Correspondence section of the SMF and in a separate post provide some tips for monitoring this item. As a general rule, monitors do not enjoy reviewing the SMF; I would propose that the Correspondence section is one of the most detested sections and often skipped. I have seen correspondence that spans multiple volumes for longer trials and have personally lived the nightmare of organizing these on more occasions than I can count. Some people insist on filing every little stitch of paper but I encourage you to review the regulations, your company SOPs, and to file sparingly. Only file items that truly support the record of conduct and that tell the story of what happened, when, and by whom.

What needs to be filed in Correspondence?

Important emails/threads (As I discuss in a different post – not every email!), Note to File (sponsor/vendor generated), Official study memos, newsletters, Investigator Recruitment Plans, etc.

If found in Correspondence, File Elsewhere:

• Monitoring Visit Confirmation and Follow-Up letters (file these with the monitoring log or in their own tab for ease in reconciliation)
• Budget/Contract, generally anything with $$$ listed
• Duplicates (just shred the copy)
• Audit reports
• Training Files, agendas, and slide decks
• IND Safety Reports
• Investigational Product Documentation (packing lists, confirmation of receipt, destruction or return documents)
• Packing slips (study supplies, lab supplies, etc.)
• Subject identifying information (check-stubs for study participants, copies of IDs, medical records that have not been de-identified, etc.)
• Notes to File (site generated) If subject-specific file with the chart, If more global in nature, just give them their own tab (ensure copies are retrieved and submitted to the TMF)

How should correspondence be organized?

Please file correspondence in reverse chronological order; old stuff at the back, new stuff on top, sorted by date.

You may also like...from The Lead CRA archives:

• Efficiency Tips for Tackling the Correspondence Tab March 2011
• Routine Monitoring Visits March 2008
• Email Management April 2011

Close-Out Visits

I've done about 10 close-out visits in the last few months so it feels like a good time to write a short article explaining what the objectives of these visits are and how a typical close-out visit (COV) is conducted.

A COV will occur once subjects are no longer being dosed, all the data have been collected (there are no more outstanding AEs/SAEs & all outstanding Queries/data clarification forms have been resolved appropriately), the database is locked and ready for statistical analysis, and the study conduct has ended. At this point, the site's contributions are over so the monitor returns for one final visit to shut down the site. The whole concept behind a close-out visit is to ensure that everything is neat and tidy at the study site and that the documentation is well organized and will remain intact and be accessible in the future as needed for regulatory reasons. A sponsor or the FDA should be able to return to the place of study conduct years later and re-create exactly what occurred at all points during the trial by reviewing the regulatory documentation, subject and source documentation, full medical charts, and any other applicable study records. Documentation is everything in our industry and we are always saying, "if it isn't documented it didn't happen." If thorough and accurate records are not maintained, the PI cannot prove that the study was conducted in accordance with the protocol and all applicable regulations and that subject safety was adequately monitored throughout the conduct of the trial.

Site Supplies and Drug Return

We are using tamper evident tape to
box up investigational product for return.
If the tape is lifted it leaves behind an
artifact to show it has been tampered with.

One of your major objectives at the COV will be to assist the site in dealing with any unneeded study materials or supplies. With permission from the sponsor, some of these activities can even take place before the close-out visit as you remotely supervise. The close-out duties will likely include disposing of or retrieving all unused lab or study supplies such as patient handouts, electronic diaries, etc. In most cases, you will have the site generate a file note or similar documentation so there is a record indicating that study supplies were disposed of or moved off-site. 9 times out of 10, the Investigational Product (unused and the used packaging) will need to be inventoried, accounted for in drug logs, and then shipped to a depot or destruction facility. Sometimes the drug will be destroyed on site by a pharmacist or according to the site's SOP but this is really the decision of the sponsor. If you are lucky, you were able to pack up and ship back drug routinely throughout conduct otherwise you will have to deal with it all at the end.


Essential Documents
You will have the PI sign off on any tracking logs that were used during the study. The original will be placed in the site's Regulatory binder but you will retrieve a copy for the Trial Master File. You will ensure that a Subject Identity List was completed and will be kept that lists the contact information for all treated subjects (you will not take a copy of this document as it has private information and stays at the site only). Documents you will take copies of include: Site Visit Log, Subject Screening AND Enrollment Log, Delegation of Authority Log, Proof of Drug Receipt, Subject Specific Investigational Product (IP) Accountability Logs, Copies of temperature/freezer logs, Site Initiation Statement, Training Documentation, Overall Site IP Log, Protocol/Amendment Signature Pages, Any updated 1572s, medical licenses, or CVs, Site communications to the IRB/IEC (ethic committee), and the IRB Final Status Document. Obviously in a study with many safety reports, a long line of routine monitoring visits, multiple site hand-offs/transitions between several different monitors, or a slew of important correspondence, checking that the essential documents binder(s) is in perfect order can be a time-consuming task.

Subject Records
Although you will have already verified this throughout conduct, the close-out visit is your last opportunity to be absolutely sure that the appropriate version of signed and dated Informed Consent Forms are on file for every subject. You will also check that all source is complete (all lab reports and ECGs have been signed and dated with Clinical Significance assessed by the PI/Sub-I) and that all AEs/SAEs have been signed off by the PI/Sub-I and that they were followed to resolution as specified by the protocol. Finally, check that all significant Protocol Deviations (study procedures not conducted according to protocol, enrollment of inappropriate subjects, dosing errors, consenting errors, unblinding, subjects developing withdrawal criteria yet continuing in study, etc.) have been properly recorded and the sponsor/IRB has been notified as appropriate.

PI Responsibilities
Discuss with the PI his/her responsibilities including: query/data collection following the close-out visit, essential document retention, publication rights, and the necessity to update the Financial Disclosure statement if there are changes in their financial interest for up to one year following completion of the study. Finally, explain to the PI the potential for regulatory agency inspection and the requirement that the site notify the CRO/sponsor immediately if contacted for an audit/inspection.

Assuming you have done a thorough job in monitoring throughout conduct, the COV should be a relatively short-visit. Meeting with the PI to discuss their regulatory responsibilities post trial conduct and obtaining required signatures usually takes less than 20 minutes assuming they are an experienced investigator and are already familiar with the GCP schpeel. Drug return often takes several hours but you can prepare most drug return documents in advance of the visit by using sponsor or IVRS reports and usually save a considerable amount of time on-site. You should have been reviewing the regulatory binder at every visit throughout conduct so it should really be in order at this point and stuffed to the brim - I usually budget no more than an hour to ensuring that the binder is complete.

After you complete the close-out visit, you will write a report to the sponsor to let them know that all of the objectives were completed and a follow-up letter to the site thanking them for their participation and informing them that there are no further pending action items. Any new regulatory documentation you copied while on site will need to be forwarded to the Trial Master File so that the sponsor's documentation is a true mirror of what is on site.

You may also like...from The Lead CRA archives:

• Introduction to Monitoring December 2007
• Meeting with the PI August 2011
• Routine Monitoring Visits March 2008