11/18/2025

In July, 2025, the US Food and Drug Administration (FDA) issued a warning letter to an investigator conducting a clinical trial for pediatric participants. The warning letter was the result of a routine inspection part of the FDA’s Bioresearch Monitoring Program (BIMO) as well as the investigator’s written response to the Form FDA 483 which was given at the end of the inspection. The warning letter states that the investigator did not adhere to the applicable statutory requirement in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312.

The objectionable conditions observed during the inspection fall under 21 CFR 312.60: failure to ensure the investigation was conducted according to the investigational plan. According to the trial’s protocol, participants between the ages of 5 and 9 years old were to be administered 0.5 mg of the investigational product (IP) daily starting on day 1 and increase to 0.75 mg a day starting on day 5. There was also an additional/optional second dosage increase to 1.5 mg of IP a day starting on day 8. However, in 2 separate participants it was observed that they had been administered 3 mg a day, that is twice the amount of IP the protocol allowed for. For the first participant, this overdoing occurred for at least 16 days and 22 days for the second participant. Fortunately, neither participant experienced any subsequent adverse event or reactions to the additional dosage, both had their dosages adjusted after the mistake was realised, and additional safety screenings were conducted.

One of the most concerning aspects of this case is that the trial deals with pediatric participants, a highly vulnerable population. As they are still growing and developing physically and mentally, any medical interference in these changes can have life altering consequences. This is why additional consideration is needed for planning and conducting pediatric studies and why deviations from the plans are especially worrisome for the safety and welfare of these participants. Regardless of the the participants demographic, all trial protocols must be strictly adhered to in order to obtain reliable and accurate results, and protect the rights, safety, and welfare of participants. Prior to trial commencement the protocol is required to obtain approval from an institutional review board or committee (IRB) that reviews it and other relevant documents to ensure that participants are not being introduced to unnecessary risk. These IRBs will often have additional members who are experienced in the field of pediatric healthcare for trials such as this in order to further ensure that this vulnerable population is not subject to any undue risk of harm.

Site staff are expected to be trained on this approved protocol before they begin any work on the trial and raise any questions or concerns at this time with the trainer or sponsor who authored the protocol. Should any part of the protocol be interested as vague or unclear, it should be brought to the sponsor for clarification before any further steps are taken, especially the administration of the IP to a vulnerable population.

In their response to the FDA’s 483, the investigator said the reason for the overdosing was due to a misinterpretation of the study protocol and provided the brief explanation that the protocol had “unspecified dosing amount provided within the protocol respective to each milligram dosage”. They also gave a summary of their Corrective and Preventative Action plan (CAPA) which included retraining staff, contacting the sponsor in any else in the protocol is vague or unspecified, and having pharmacy staff present to double check dosages. However, despite listing both corrective and preventative actions, the investigator’s CAPA was deemed inadequate which according to the warning letter was due to lack of detail about these actions. The letter concludes that together with the objectionable conditions of the study conduct and inadequacy of the investigator’s response, the FDA is still concerned for the safety of the study participants as well as the integrity of the trial data collected.

BIMO inspections are a considerable hurdle for any trial to pass, which is why proper preparation and training is essential as early as possible. If you or your company are conducting a trial that falls under the scope of BIMO, Clinical Pathways can assist you throughout the entire process with our inspection readiness consulting services. These services include training and education for all site staff on responsibilities and etiquette during an inspection, mock sessions and inspections to give staff a chance to practice how they would respond to FDA inspectors, and post-inspection support such as writing responses to any inspectional observations like the one in the warning letter above. While you are there take a look at our other programs and services and sign up for our free blog and newsletter to get clinical trial related news like this.

-The Clinical Pathways Team

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