02/19/2025

On October 10, 2024, the US Food and Drug Administration (FDA) issued a Warning Letter to a clinical investigator due to objectionable conditions observed during a Bioresearch Monitoring (BIMO) Program inspection in 2023. The warning letter addresses multiple violations to Title 21 of the Code of Federal Regulations (CFR).

§ 312.60 – General responsibilities of Investigator

In multiple instances, subjects were consented and enrolled into the study despite not meeting the eligibility criteria.
Calibrations of laboratory equipment were not preformed resulting in multiple endpoint data readings being unreliable and invalid.
Investigational product (IP) was administered before being released for infusion by the Quality Assurance Manager.
IP verification was performed by a staff member who was not delegated the task on the site study log for investigator delegation.
Missing informed consent process documentation.

The trial participant’s rights and safety are the primary concern in this section.

The sponsor selects the eligibility criteria based upon their knowledge of the investigational product, the target population, and to answer the questions they are exploring in the protocol. Participants who are enrolled despite not meeting eligibility criteria not only make it difficult to analyze the trial data, but most importantly, violate the rights of the subject under 21 CFR part 50 and can put the participant’s safety at risk.
Improper informed consent procedures impact participant’s rights to fully understand the implications of the trial before agreeing to participate.
Appropriate handling, distribution, and verification of IP is crucial for maintaining the integrity of the IP and ensuring the recipient patient’s safety and therefore should be accurately delegated, documented, and monitored throughout the course of the study.
The trial data integrity is also compromised when the equipment used to generate the data is not properly maintained and functioning.

§ 312.62 – Investigator Record Keeping and Record Retention

Multiple adverse events (AE) were not recorded.
Medical records were neither requested nor reviewed for a subject experiencing a serious adverse event (SAE).
Records of clinical procedures were not kept within subject files and time discrepancies were found between sponsor forms, progress notes, and electronic data capture.
A concomitant medication taken prior to transplantation was not recorded as required in the protocol.
A duplicate clinical assessment was conducted without explanation.

Investigator documentation, that follows the ALCOA-C principles, of trial participant’s study experience is critical for reconstructing and evaluating the sites compliance to the regulations.

Investigators are required to follow up with SAEs both to notify the sponsor of the history of events and for medical oversight of the participant.
Source documents need to be maintained contemporaneous to the procedures, or edits need to be made and appropriately dated and initialed at the time when there are changes. Otherwise, records have the appearance of being fraudulent.
Recording concomitant medications is necessary not only to ensure the participant continues to be eligible to continue on study but also for safety and data integrity for the trial results.
Duplicate clinical assessments that are not necessary are burdensome and potentially harmful to the participant. If they are necessary, the reason should be well documented. If they are linked to adverse events, those need to be recorded as well.

§ 312.66 – Assurance of IRB Review

Conflicts of interest were found for two IRB members.
The subject recruitment questionnaire was missing IRB approval.

The role of the IRB is critical for trial participant protections.

Both data integrity, and the trial participant’s rights and safety are jeopardized when IRBs membership requirements are not met. If members have any vested interest in the outcome of the trial, then their judgement is considered partial and potentially bias.
In addition, the lack of IRB review of the trial participant questionnaire also risks the protection of the trial participants.

§ 50.20 – General Requirements for Informed Consent

For this study, trial participants were to provide written consent for themselves, however, in multiple instances someone else signed for the study subject.
A signature was missing on a consent form for genetic testing, and the testing was still conducted.

Ensuring that the consenting of the trial participant is in compliance to the protocol and IRB requirements is a responsibility of the investigator.

Despite many trials allowing for legally authorized representatives of a trial participant to sign on their behalf, if the protocol or ethics committee requirements specifies that it must be the participant’s signature, anyone else’s would be considered noncompliance and a risk to the trial participant’s rights.
Furthermore, conducting any optional study procedures on a participant if they have not consented is a direct violation of their rights. In the case of optional genetic testing, it is potentially an invasion of their privacy. There are medical conditions where a participant may not want to know the outcome of genetic testing, for example Huntington’s disease.

While the list of observations was quite extensive, at the time of the FDA’s letter issuance, most of the investigator’s responses to the observations including the corrective and preventative actions taken were deemed acceptable if properly implemented.

The results of an investigator FDA BIMO inspection, and how any observations and warning letters are responded to, may have significant negative impact on adequate data for the sponsor to complete the study, but also may lead to a linked sponsor and/or CRO inspection. The adequacy of the sponsor oversight and the monitoring of the study are also evaluated during a site inspection. The FDA is not required to do linked inspections, but knowing that this can occur supports voluntary compliance and sponsor inspection readiness activities.

Clinical Pathways offers inspection readiness consulting, and virtual and in-person training for BIMO inspection readiness that educates stakeholders on how to prepare and host an inspection, as well as what to expect before, during, and after the inspection. For a full list of training and consulting service and to sign up for our blog and newsletters please visit our website: https://www.clinicalpathwaysresearch.com/.

-The Clinical Pathways Team

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