Note-To-File
(or not)
Uses and Abuses
Connie Dagon, Lucy Miller, Christy Yoder, and Beth Zwickl
Solutions Newsletter – Carl Anderson
• What regulations require NTFs?
• Can an NTF be a positive practice?
• What are the specific elements of a useful
NTF?
• What requires documentation when a mistake
is made?
• What can be done to avoid NTFs?
It’s a handout!
NTFs Abused
• FDA and the Aventis Warning Letter
“Aventis’s method for securing compliance (i.e.,
the generation of more than 125 memos to file
for protocol and informed consent deviations
noted at the site) was not adequate.” pg. 4
www.fda.gov and use search engine warning letters
Notes-To-File
1. Should not be used exclusively as devices to
explain discrepancies
2. Should not be used exclusively to explain
missing or incomplete data
3. Do Not replace “adequate and accurate case
histories” (21 CFR 312.62)
4. Are Increasingly requested by sponsor
monitoring staff - not generally temporally
associated
5. Can be Red Flags
Essential Document?
“….those documents which individually and collectively
permit evaluation of the conduct of a trial and the
quality of the data produced.”
And
“….serve to demonstrate the compliance of the
investigator, sponsor and monitor with the standards of
Good Clinical Practice”
Generally a note or memo to file is for clarification, but
does it indicate compliance?
Standard Operating Procedures/Regulatory Guidance For
Notes-To-File?
• IRB – No
• VA – No
• FDA – No
• NIH – No
• GCP – No
What’s a Coordinator to do?
NTF – Location of Documents
NOTE TO FILE
Date:
July 3, 2008
To:
Evaluation of isogenic mutants in experimental human infection with
Haemophilus ducreyi (DMID# 06-0027)
From:
Sheila Ellinger, RN, MSN, CCRP, Indiana University
_________________________________________
Re:
Location of Annual Reports to the FDA and Appendix to the 2008 Report for
BB-IND No. 13064, “Experimental infection with Haemophilus ducreyi strain 35000HP
and/or its isogenic mutants in healthy adult volunteers”
Issue:
For submission to the DMID SMC, Dr. Spinola sent the FDA 2007 and 2008
Annual Reports plus an Appendix to the 2008 Annual Report to DMID Protocol
Champion, Hagit David PhD. Copies of these documents are located in the IND
binders under Serial 0007 and Serial 0013.
Deviations – Minor & Major
• Minor deviations - Keep a log – missed visits,
noncompliance with meds, incomplete data.
• Report major deviations
• Report all noncompliance
• Continuing Review – summarize – attach log
Deviation Log
• For reporting deviations that do not, in the
opinion of the PI, impact subject safety, affect the
integrity of study data and/or affect subject’s
willingness to participate in the study:
–
–
–
–
–
Subject ID
Event Date
Event Description
Action Taken (both corrective and preventive)
Documentation of PI review and assessment
IRB
• Are you compliant? Be knowledgeable about and refer often to the
IUPUI Standard Operating Procedures (SOPs) for Research
Involving Human Participants as one of your main resources for
human subjects research related requirements.
• They are located
here: http://researchadmin.iu.edu/Forms/human_subjects/hs_i
upui/Standard+Operating+Procedures+(05.01.09).pdf.
• The table of contents can be used to identify the SOPs applicable to
your work.
•
•
•
•
http://researchadmin.iu.edu/HumanSubjects/IUPUI/hs_forms.html
Prompt Reporting Form
Noncompliance Reporting Form
Continuing Review - Deviation Log
Note To File
•
•
•
•
•
Be generated on a case-by-case basis
Include the subject and protocol it refers to
Be signed and dated by the individual who is writing it
Be legible if handwritten
Explain clearly and specifically the reason for the
error/omission/discrepancy or process/policy it aims to
address.
• Should include any corrective and preventative action
or follow-up when applicable.
• Be filed with the document, subject file or behind the
study binder tab to which it applies
Focus on NTF Prevention
• The sponsor should be involved at such a level
that true NTFs are rarely necessary
• Educate research team initially and on an ongoing
basis so that situations that may require a NTF
are prevented in the first place
• Correct errors in data appropriately and in a
timely manner to prevent the need for numerous
NTFs (single line through with date and initial of
person correcting with a corresponding
explanation if not obvious)