483 Issues to Sites – Indicators of Sponsor Oversight Effectiveness

A U.S. Food and Drug Administration (FDA) Form 483 is issued to a company’s management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute a violation and/or objectionable conditions. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that correction action plan with speed and efficiency.

First, let’s look at trends. 483 observations identified during clinical study site regulatory inspections vary slightly by year, but are often related to the following:

• Failure to follow investigational plan (i.e., protocol deviations)
• Underreporting of safety events
• Inadequate case histories

With these common observations, the failure tends to be attributed to the site, and while the site is responsible, we must examine how these observations illuminate how well the sponsor and/or other vendors (i.e., Clinical Research Organizations) performed their oversight responsibilities.

Examining Common Findings

For discussion, let’s look at underreporting of safety events (i.e., adverse events). A recent article highlighted a study in which numerous adverse events, which had not been reported, were identified during a regulatory inspection. Besides asking the obvious question of why this occurred, another whole series of questions should be asked to help understand where, at the site level, were there process downfalls. Why had this not been previously identified through monitoring, whether that be on-site, remote, and/or centralized?

To start with on-site monitoring, one might ask, what was the experience level of the Clinical Research Associate, were they given access to all the source records, and what else could have been missed?

For centralized monitoring, was there an established signal that examined the adverse event rate across countries and/or sites? If there was an outlier, was this identified and not properly corrected or was it not on the ‘radar screen?’ There are many questions and routes of inquiry that can be taken.

Reflections on Study and Vendor Oversight

As we ask these questions, we unveil how the oversight of the study was initially set up and then continuously monitored. For example, were proper risks identified and the corresponding key risk indicators (KRI) available through a report? Unfortunately, there are often cases where a KRI that a vendor or sponsor is trying to measure is not exactly what a standardized report is measuring, thus resulting in the inability to effectively monitor the risk.

Therefore, the right technology and systems must be in place so that a vendor and sponsor can effectively provide oversight during a clinical trial. In addition, there must be processes around the analysis and review of the information provided by the technology or systems. Having information and doing nothing with it is as troublesome as not having it at all.

Halloran’s Expertise

Certainly, companies can correct their Form 483 findings, but it takes time and resources. Halloran has expertise with the essential components that should be in place to effectively run clinical studies according to regulatory requirements:

• Proper study start-up and execution through Halloran’s clinical trial leadership and operations
• Quality management system development and/or assessment, with a focus on vendor oversight
• Clinical and GxP technology identification and enablement to ensure you get the data insights you need
• Full-suite inspection readiness preparation

Preparing for an FDA inspection? We’re here to partner with you.