EFFECTIVE UTILIZATION OF A NOTE TO FILE

By: Louis Grue, Mila Erastuti, Tiya Saraswati, Virtania Meirina Agusta

Anyone who has been involved in conducting INA-RESPOND’s studies might be familiar with the term “Note to File (NTF)” and might have had experience in generating this document. The INA-RESPOND Good Documentation Practices SOP states that a NTF could be utilized and may be useful where additional information pertaining to a record is elsewhere required, while no such provision is available in prepared study documents or forms to accommodate it.

A NTF can be a helpful tool and can be typically generated when it is necessary o formally clarify a process, procedure, protocol-defined activities, or regulatory requirements, in order to satisfy Good Documentation Practice (GDP), fulfill inappropriate International Council on Harmonization (ICH) Good Clinical Practices (GCP) and local regulatory guidelines, therefore, it is an eligible document to be reviewed during regular site monitoring vis-its, regulatory inspections, or sponsor audits. We all may have heard a jargon (saying) during clinical trial conduct “if it isn’t documented, it didn’t happen”. The following are some instances in applying an NTF: defining regulatory document’s location, describing a test article storage temperature excursion, providing clarification of missing, unavailable or inadequate documentation during clinical trial process, documenting the reason for missing, delayed, or erroneous documents in Site Regulatory Binder (SRB), or discrepancy between site regular practice and study protocol.

INA-RESPOND has a specific NTF form which contains several sections of required information, such as, date of issue, protocol number, protocol title, site number, site Principal Investigator name, subject, description, the detail of person who prepare the NTF and the counter-sign review, if needed. A completed NTF should be filed in SRB at a clinical study site and uploaded into INA-RESPOND Electronic Data Management System (EDMS). Each part of NTF should be completed in a comprehensive manner to describe an issue or to elaborate on a specific situation. Root-cause analysis is strongly recommended to determine the underlying cause of an issue, to develop effective corrective and preventive actions.

It is important to understand the appropriate application of an NTF. Essentially a NTF does not replace the original source documents or forms. Any subject or topic should be primarily documented in appropriate study documents or forms. Recognizing all available original source documents or forms applied in the study is important, hence, easier to determine where a documentation or clarification related to the clinical trial process should be suitably written. Furthermore, if there is no specific suitable format clinical trial documents or forms are available, then clarification made in NTF could be considered and deemed applicable.

In practical settings, inappropriate utilization of NTFs were sometimes found, for instance, NTF is generated to clarify any missed study assessment, missed visits, or missed participant’s procedures while no documentation made in primary source documents, such as in the participant’s Medical Record or Source Document Work-sheet. An NTF is used to explain errors in a document such as SOP number, version, effective date. Nevertheless, direct correction according to GDP might be applied in a certain situation as deemed appropriate. Another example of an inappropriate NTF is found when it is generated to document protocol deviations, while Protocol Deviation (PD) form itself was not completed.

For example, Investigator did not obtain the Informed Consent prior to the screening process. Supposedly, this deviation should be documented in the Protocol Deviation (PD) form and to develop effective Corrective Action and Preventive Action (CAPA) to manage the deviation.

Moreover, inappropriate utilization of NTF causes scattered documentation which increases risk for incomprehensive documentation. Practically, an NTF should be filed alongside its referenced document within the same SRB section or aggregated in a separate SRB section. Difficulty in finding and connecting an NTF to its referenced document may arise when the entire NTF is stored in a separate SRB section away from its referenced document section, thus the NTF could not be directly accessed and the purpose of an NTF, for example to clarify an issue, itself could not be achieved. As a best practice, it is suggested to only file a ‘general NTF’ in a dedicated SRB section and leave a ‘referenced NTF’ pasted with its referenced document in respective SRB section. Developing an NTF listing would also be advantageous to identify all generated NTFs in the study.

A NTF quality control process is required to avoid any unnecessary NTF filed in SRB. On a regular basis, Research Assistants (RA) should conduct a file review process to assure the SRB is established according to EDMS structure and no redundancy of subject/topic results among the generated NTFs.

Effective NTF utilization will improve the quality of clinical research documents produced in the study and will support excellent data quality and integrity. Thus, it demonstrates clinical trial conduct has been implemented according to clinical research protocol, and GCP guidelines.

If you have any questions about the appropriate use of a NTF, you have resources within the INA-RESPOND Secretariat who are available to assist you with developing the most useful NTF for your specific issue.

References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088955/
https://www.lmkclinicalresearch.com/blogs/note-to-file-ntf-tips/
https://database.ich.org/sites/default/files/ICH_E6%28R3%29_DraftGuideline_2023_0519.pdf