Examples of how to avoid regulatory snafus

Preventive actions are important

Clinical trial sites sometimes make regulatory audit situations worse by failing to respond with comprehensive corrective action plans, an expert says.

The U.S. Food and Drug Administration (FDA) typically has several first responses to a clinical trial site inspection, including no action indicated, official action indicated, and voluntary action indicated. The ideal finding would be the first one, says David Vulcano, LCSW, MBA, CIP, RAC, assistant vice president and responsible executive for clinical research at Hospital Corporation of America (HCA) in Nashville, TN.

"The official action indicated response typically is your warning letter, and that's the least desired response," he adds. "With the voluntary action response, the FDA will make suggestions but usually won't take any further actions against the site."

The FDA's Bioresearch Monitoring program's enforcement begins with on-site inspections, followed by a Form 483 if there are findings. Researchers have an opportunity to respond to the Form 483, but if their response is inadequate or if the findings are particularly extensive, then the FDA will send out a warning letter. If the investigator's response is lacking, the FDA's next step would be a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain Letter. Again, the research site has an opportunity to respond. A failed response could result in a Notice of Opportunity for Hearing letter, and this is followed by a judicial hearing.

The hearing could result in regulatory sanctions and restrictions, according to Vulcano's recently published paper on the subject, titled, "The 'New Normal' of Regulatory Oversight of Clinical Investigators."

"When the FDA cracks down, it's harder than it used to be," Vulcano says. "When they changed a couple of years ago to the six-step enforcement process, the cycle time to get warning letters out was decreased."

Although Vulcano has not measured the turn-around time recently, his historical data show that the medial time from the departures of the field inspectors to the date the site got the warning letter was about 120 days, he says.

Research sites often can steer clear of problems by sending the FDA a well thought-out corrective and preventive action plan, he adds.

"Writing those plans is something that is not to be taken lightly," he says. "The FDA clearly is noting when a site has a plan that is corrective, but not preventive."

For example, if a site's problem was that a study coordinator was noncompliant with regulations, then the corrective action plan would fail to satisfy the FDA it merely states that the coordinator was fired, Vulcano explains.

"That doesn't tell them how the site will prevent the next study coordinator from having the same problem," he adds. "A lot of FDA warning letters point out how sites do not focus on the preventive piece."

So when sites take action to correct their mistakes, they should document these actions plus all measures they take to prevent future problems, Vulcano says.

In the example of the fired study coordinator, preventive actions might include a retraining program for all staff with a focus on compliance and the use of checklists/tools to ensure proper procedures are followed, he adds.

Good corrective action plan responses will include specific documentation about how the site corrected inaccuracies and an acceptance of responsibility rather than shifting the blame to the monitor or staff.