04/22/2025
Photo by Nathan McDine on Unsplash
In November 2024, the US Food and Drug Administration (FDA) issued a warning letter to the sponsor as a result of a BioResearch Monitoring Program (BIMO) inspection which observed objectionable conditions. The warning letter cited two violations of the Title 21 CFR:
§ 312.58: (Investigational New Drug Application) Failure to permit an authorized officer or employee of the Food and Drug Administration to have access to and copy and verify records and reports relating to the conduct of a clinical investigation.
Critical electronic clinical outcome assessments (eCOA) used to measure primary and secondary endpoints of the trial were deleted along with their audit trials for all of the 47 subjects enrolled at the site.
The deleted endpoints were measurements of efficacy for the investigational product (IP), this missing data may put the marketing application at risk of not receiving approval. On the other hand, if the IP is later marketed the missing data may lead to inaccurate information informing the package insert which could put patients at risk. The sponsor claims that the deletion of the eCOAs was done by a third-party vendor, however the responsibility for the data integrity still rests with the sponsor who is required to have adequate oversight of the trial conduct including the tasks delegated to vendors.
§ 314.50(d)(5)(iv): (Applications for FDA Approval to Market a New Drug) Failure to provide a description and analysis of any other data or information relevant to an evaluation of the safety and effectiveness of the drug product.
Multiple sites within the study administered a lower dose (80% of dose require by protocol) to at least 19 trial participants due to mislabeled investigational product (IP).
The sponsor did not report the actual doses administered, instead they reported the dose levels stated in the protocol.
It is essential that sites have quality assurance measures in place to catch these errors before they are administered to the trial participants as it jeopardizes their safety and wellbeing. It is again the sponsor’s responsibility not only to investigate and provide an explanation for how it happened but also to provide a sufficient description of the corrective actions taken in response to the error and the preventative actions that will be implemented in order to ensure they do not happen again. The full warning letter is available on the FDA website.
Both of these findings are quite concerning from a regulatory perspective. In the case of the deleted and missing primary and secondary endpoints, these are FDA regulatory requirements and will likely result in some form of disciplinary action if not properly addressed and reconciled., Although the issue originated from the vendor, the inaccurate representation of the IP dosing was not caught by the study team, and the information that went into the clinical study report and submitted to the FDA is also inaccurate. Both findings will have direct impact on the New Drug Application (NDA) for the IP unless already marketed.
Findings from regulatory inspections may happen even with preventative measures in place. It is how these findings are responded to and the actions taken that matter the most. Knowing what is required in an acceptable corrective and preventative action plan (CAPA) per FDA standards is important for not only sponsors, but also principal investigators, CROs, ethics committees and other stakeholder that the FDA may inspect. A well written CAPA shows acknowledgement of the problem, demonstrates the attention and care put into rectifying the situation, and reassures the reader that steps are being taken in order to prevent the issue from reoccurring. If you or your company have an upcoming inspection or could benefit from further training on CAPA development, please visit out website and check out our “Corrective and Preventive Action (CAPA) Planning for Clinical Research Professionals” online course. While your there have a look at our course catalog and services to see if any would be the right fit for you.
-The Clinical Pathways Team
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