FDA's risk targeting apt to find more mistakes

Sponsors receiving warnings too

The U.S. Food and Drug Administration (FDA) in recent years has shifted its focus in ways that are resulting in more warning letters and audits conducted based on risk analysis targeting. Also, sponsors are being held responsible for what research sites do, and their own decisions about which sites to select for studies are being questioned by regulators.

"FDA warning letters are coming out more frequently now, and some in the research community feel they're coming out for things that people wouldn't have gotten a warning letter about eight years ago," 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. Vulcano also is past-chair of the board of trustees for the Association of Clinical Research Professionals (ACRP).

"Overall, sites are doing better on their FDA audits based on historical trends," Vulcano says. "For those not doing well, a greater percentage is receiving warning letters."

According to Vulcano's data, the FDA's Center for Drug Evaluation and Research (CDER) issued 22 warning letters to clinical investigators in 2009, nearly twice as many as in 2008, and significantly more than at any other time in the past 12 years. Warning letters from the Center for Device and Radiological Health (CDRH) peaked in 2004 with 24 warning letters and 2005 with 21 warning letters, but had fallen to just four in 2009. And the Center for Biologicals Evaluation and Research (CBER) also have fallen considerably – to just one letter in 2009. Eleven of these letters from CBER were issued in 2000.

"The largest percentage of letters are coming out of the drugs division of the FDA," Vulcano says. "They've had the largest increase in the amount of warning letters; biologics have faded out."

Another trend Vulcano notes is that the FDA now is sending more warning letters to drug trial sponsors. CDER had not sent out any of these warning letters to sponsors before 2006.

For device trials, the CDRH's trend has switched from all letters going out to sponsors and clinical research organizations (CROs) prior to 2002 to all letters going out to sponsor-investigators since 2004.

One of the clinical research changes highlighted by the FDA's shifting focus is that the agency recognizes that study oversight is interconnected between the various parties, including sponsors, IRBs, clinical investigators and CROs, Vulcano notes.

"They're holding sponsors responsible for ensuring the monitoring of the studies," Vulcano says. "In other words, if the site is so egregious that they need a warning letter, the question asked is, 'Where was the sponsor? Why didn't they monitor this?'"

Sponsors are even being held responsible for selecting poor performing sites. In one letter, the FDA commented that the sponsor had failed to select a qualified investigator to conduct the study. When the investigator was found to be not recommended for lack of regulatory compliance, the sponsor had used the investigator and site anyway, the FDA warning letter states.

In another shift, the FDA began to send warning letters to both investigators and sponsors, Vulcano says.

"The FDA wanted to make sure the trial was conducted according to the plan and wanted sponsors to ensure that investigators were conducting the study according to the plan," he explains. "They're holding both accountable."

The FDA's recent warning letters to sponsors show that the agency holds the sponsor, more than the CRO responsible for site selection. So if a clinical trial site is noncompliant and there were readily available warning signs that this site would have problems, the sponsor is responsible for this failure, Vulcano says.

One FDA sponsor letter Vulcano highlights states, in part, "Based on your response, it appears that you either failed to actively participate in selection of the site or failed to review and address the study monitoring report that recommended the site not be used."

This shows that regulators are serious about investigator selection and wants sponsors to ensure their sites are compliant, Vulcano says.

Clinical trial sites soon will see another new trend in regulatory audits: the FDA is shifting to an integrated model of selecting sites for inspection based on more precise risk analyses. While the agency is not publishing all the details of this new model, which uses a multi-attribute algorithm, it would appear that the goal is to inspect fewer well-organized and compliant sites and more sites that have multiple noncompliance issues, Vulcano notes.

The FDA's risk-based analyses uses material submitted to the FDA and assigns a risk-based score to the investigator site. This could include information about the site's enrollment, prior inspection history, safety data reporting, site location, complexity of study design, and efficacy results.

"It's a much more complex formula with other variables to determine where they'll prioritize their selection of where to go to inspect sites," Vulcano says. "This is used as an internal method to tell them where to inspect, but they won't tell investigators what their risk score is, nor tell sponsors what their investigator's risk score is."

CDER is piloting the new system, he adds.