07/29/2025
On May 29th, 2024, the US Food and Drug Administration (FDA) issued a Form FDA 483 and subsequent warning letter to a Principal Investigator (PI) as the result of objectionable conditions found during an inspection under the Bioresearch Monitoring Program (BIMO). The FDA investigators cite 3 sections of the Title 21, Code of Federal Regulations (CFR) Part 312 that were violated during the conduct of the trial:
1. Failure to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational product [21 CFR 312.62(b)]
The protocol for this study stated that if data was not entered during a study visit then it should be recorded on paper and that paper would then be considered the source documentation. However, during the inspection, it was observed that 144 primary efficacy assessment values had no source documentation, paper or otherwise. Furthermore, there were significant time gaps between when the assessments were completed to when the data was entered, some were found to be entered 25 days after the fact. It was also observed that the times and dates were edited so the times and dates of the data entry lined up with when the assessments were conducted. The PI’s response to this observation was that the site had poor internet connections due to the COVID-19 pandemic so the raters entered the data into tablets in “offline mode” at a later time based off written notes or memory which was then uploaded into the database once the internet connection was restored. The FDA investigator listed multiple reasons why this response was inadequate, starting with how the PI’s explanation contradicts what both sub-investigators had told the FDA investigators during the inspection and that the “offline mode” on the tablets was unable to be shown during the inspection. Additionally, the visits that the 144 values were from also occurred prior to the start of the COVID-19 pandemic and the values were deemed to be potentially inaccurate due to time gap between the assessment and the data entry. For all these reasons the reliability of the data and integrity of the study conduct was being called into question.
2. Failure to ensure that the investigation was conducted according to the signed investigator statement, the investigational plan, and applicable regulations; failure to protect the rights, safety, and welfare of subjects under your care [21 CFR 312.60]
This observation speaks to the aforementioned editing of the 144 assessment value’s times and dates to make it look like they were entered at the time of the assessment which the audit trail revealed they were not. The study protocol stated that only authorized personnel could record or make changes to the data, however, the times and dates were changed months after the assessments by non-study personnel. During the inspection the PI told the investigators that they did not know how or why they were changed, but this answer changed in their written response stating that the changes were done by an eResearch Technology team at the request of the sub-investigator. The FDA investigators again found this response to be inadequate because, like the previous observation, the response contradicts what the investigators were initially told during the inspection. The PI’s response also did not explain why the times and dates were changed in the first place.
3. Failure to retain records required to be maintained for a period of 2 years following the date a marketing application is approved. [21 CFR 312.62(c)]
One of the site staff admitted to discarding handwritten notes prior to the 2-year post-approval period which is considered a failure to retain records. The PI claimed that it was an isolated event and sent a photo of the discarded assessments (INCAT scales) stating that while the handwritten pages was destroyed, there was an electronic file retained of them. The response was once again deemed inadequate since the photo was not available during the inspection and there was no way to prove the validity of the photo.
The warning letter then emphasizes on the PI’s responsibility to ensure the study is conducted in accordance with the investigational plan to protect the rights, safety and welfare of the subjects and ensure the integrity of the data. The letter also reiterates that the PI’s written response conflicts with the information given during the inspection and lacks any sort of corrective and/or preventative actions to correct the mistakes made and ensure they do not happen again. The full warning letter can be found on the FDA’s website.
There are 3 important concepts were not applied by the PI, the first being the principles of ALCOA-C. All study data should be attributable, legible, contemporaneous, original, accurate and complete.
In the first 2 observations above, the data was found to be not contemporaneous or accurate, audit trails will always reveal when data was actually entered and if it was edited.
Since the data was later found to have been entered in part by memory after the assessment, the accuracy of the data is also compromised since someone memory cannot be considered a reliable source.
The originality of the source documentation is also compromised when no written notes were created for the 144 assessments or retained during 2 visits for which the source documentation was destroyed which further degrades the reliability of the data.
The second concept is inspection readiness, in each of the observations, the PI’s responses contradicted what was communicated during the inspection which leads investigators to further question the validity of what they are being told and the study data by extension. For reasons such as this, sites are encouraged to be proactive in regards to FDA inspections which are inevitable in most FDA regulated studies and look for areas where issues such as the ones above can be found. In doing so the site can prepare the relevant staff members such as the sub-investigators for how they should answer any questions from the FDA and be of one mind when it comes to the response.
The final concept is Corrective and Preventative Action plans (CAPA), a complete CAPA addresses how the immediate problems are being taken care of and what steps are being taken to make sure that the problems do not reoccur. If an incomplete or inadequate CAPA is presented in a response letter, the FDA will likely still be concerned about the study conduct and data integrity and if not properly addressed may lead to enforcement actions such as early termination of the trial.
Clinical Pathways offers training and consulting services that cover each of these concepts including Inspection Readiness. If you or your company could benefit from training in any of these areas, visit our website and take a look at our online store and course catalog to see if any of our services would be the right fit. While you are there, consider signing up for our free blog and newsletter to stay up to date on clinical trail related news and activity such as this.
-The Clinical Pathways Team
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