FDA Warning Letter Breakdown: Missing the Basic Requirements of Clinical Research
A clinical site collected samples from a subject who declined consent twice. The FDA's issue wasn't just the mistake, it was the response.
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A warning letter recently sent to a clinical researcher alleges that he collected samples from a patient as part of a clinical trial for an investigational product, despite the patient's repeated refusal and in violation of basic informed consent procedures.
The investigator attributed this event to an inadvertent mistake and outlined a series of corrective and preventive actions to prevent it from happening again. The collected samples were also destroyed.
But the FDA wasn’t satisfied, and the reasons why are worth understanding, because they apply far beyond this one case.
Let’s quickly break it down and pull out the lessons it offers.
What happened at a glance
The FDA conducted an inspection of a clinical site in Denver between October and November 2024 under its Bioresearch Monitoring Program. The inspection reviewed the investigator’s conduct across two clinical investigations involving investigational drugs.
The core finding: a subject enrolled in one of the protocols had declined consent twice, in September and October 2023, for the collection of optional aqueous humor samples used for pharmacokinetic and pharmacodynamic assessments.
Despite that documented refusal, the site collected an aqueous humor sample from the subject’s study eye at a visit in March 2024.
The protocol was clear here. Subjects were required to sign the appropriate informed consent form before optional aqueous humor samples could be collected. This subject had explicitly declined. Twice. And yet the procedure was performed anyway.
The investigator's response
In a written response to the 483 dated December 3, 2024, the investigator acknowledged the event and characterized it as inadvertent.
The response described several corrective actions:
The site reported the incident to the IRB after the sponsor's medical monitor flagged it.
The subject was notified at their next visit.
The collected sample was submitted for destruction (which the sponsor confirmed).
Going forward, the investigator stated the site would implement quick-reference labels on subjects' source binders and use an informed consent form tracking feature in the site's clinical trial management system (CTMS) to flag optional procedure consent status. The investigator also noted these measures would carry over to a new practice location.
Why the FDA found the response inadequate
The FDA acknowledged the corrective actions but found the response insufficient on a specific and telling basis: the investigator did not explain how the proposed corrective actions would actually be implemented.
The FDA wanted details on how they planned to operationalize the actions they outlined:
How the labeling system or CTMS notation would work in practice.
What training would be provided to the investigator and site staff.
How those procedures would be used to accurately determine a subject’s consent status for optional procedures during a clinical investigation.
Put another way, the FDA’s issue wasn’t with the corrective actions themselves. It was with the lack of specificity about execution. Saying you’ll use labels or a CTMS feature is a plan in name only if you can’t describe the workflow, the training, and the accountability behind it, which is exactly what the FDA wants to see in just about every response, no matter what it’s for.
The FDA also flagged a deeper concern: the subject’s refusal was clearly documented in the record. This wasn’t a case where consent status was ambiguous or difficult to locate. The subject declined twice, and those refusals were in the file. The procedure happened anyway. That sequence of events (clear documentation, ignored documentation) raises questions about whether the site’s processes ensure that consent status is actually reviewed before procedures are performed, not just recorded somewhere.
A few practical lessons here
This letter is a useful case study for any clinical site or sponsor, not because the underlying issue is complex (it isn’t), but because it illustrates how a relatively straightforward compliance failure escalates when the response doesn’t meet the FDA’s expectations.
Informed consent is not a one-time checkbox. Consent status, especially for optional procedures, needs to be verified at the point of care, every time. If your site relies on staff memory or a single consent form filing to ensure optional procedures are only performed on consenting subjects, that’s a process gap. Consent status for optional components should be visible and confirmable at the moment the procedure decision is made, not buried in a binder that someone has to go find and flip through.
