11/07/2023

On August 8, 2023, the U.S. Food and Drug Administration (FDA) issued an investigator Warning Letter to Angela M. Stupi, M.D.. There were multiple deficiencies noted at Dr. Stupi’s clinical site. The site enrolled participants who were ineligible per protocol and did not follow the requirements for administering the investigation product.

Here are the specifics highlighted:

1. Failure to Ensure Eligibility Criteria Were Met

Participants were enrolled who did not meet the enrollment criteria per protocol. This failure raised concerns about the integrity of the data and the safety of participants. The sponsor’s original protocol inclusion criteria included a minimum salivary flow rate. According to Dr. Stupi’s response letter, she notified the sponsor of the difficulty of obtaining this in the study population and the sponsor later amended it, but still at least one subject should have been withdrawn from the study but was not removed.

2. Lack of Radiologic Evidence

The protocol required prior documentation of radiologic evidence that fulfilled the enrollment criteria. Dr. Stupi enrolled subjects without this evidence, putting the accuracy of data and participant safety at risk.

3. Non-compliance with Administration Sites

The protocol also outlined specific body locations for administering the investigational product, which Dr. Stupi failed to adhere to. Instead, the investigational product was administered in one particular subject’s forearms (which is not a listed administration site according to the protocol) a total of 10 times.

In Dr. Stupi’s response letter, the shortcomings were attributed to lack of communication with the sponsor, difficulty in obtaining saliva in the study population to meet the sponsor’s inclusion criteria, and oversight from the monitoring reports. However, it is a regulatory requirement for the investigator to follow the protocol (21 CFR 312). The Warning Letter noted Dr. Stupi’s Corrective and Preventive Action Plan (CAPA) that was outlined in the response was inadequate and failed to provide solutions because it “did not provide details concerning any planned or completed trainings for you and your staff related to the responsible conduct of clinical trials or compliance with FDA regulations.” Since the investigator is responsible for the conduct of the trial at their site, the Agency is looking for a response where the investigator is including themselves in the corrective actions.

The FDA Warning Letter to Dr. Stupi serves as a reminder of the critical role and responsibility played by clinical investigators in maintaining the integrity of clinical trials and protecting the welfare of participants. The deficiencies identified in this case could have serious consequences, both for the integrity of the clinical trial and for the health and safety of the participants involved. Following the principles of a technique like DIGR-ACT(R) could have helped Dr. Stupi and the clinical team use critical thinking to conduct an adequate root cause and develop an appropriate CAPA in response to the inspection observations.

For more information about DIGR-ACT(R), visit the website HERE.

The full Warning Letter is available on the FDA’s website HERE.

-The Clinical Pathways Team

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