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FDA discourages use of memos, looks for more CAPA responses
Watch for documentation sloppiness
The U.S. Food and Drug Administration (FDA) wants clinical trial sites to prove their compliance with regulations through better documentation of corrective actions, an expert says.
"Right now the FDA is not fond of memos to file," says Kathy Valasek, JD, a quality assurance and regulatory compliance consultant with cQA Solutions in San Diego, CA. Valasek speaks about FDA audits and quality assurance at national clinical trial conferences, including the MAGI Conferences.
"The FDA is looking at CAPA-type responses," she adds. "This means they want somebody at the site to have identified a problem, do a root-cause analysis, and then fix the specific problem."
This corrective and preventive action (CAPA) strategy is familiar to most clinical trial professionals, but it may not be systematically applied at every research site.
"Some clinical trials (CT) people are starting to do it, and some are doing pieces of it," Valasek says. "The FDA is expecting to see the CT site following this because it's a good program, and it works."
When attempting to solve a problem at a CT site, one could do a quick, shallow fix or get to the bottom of what's wrong and find a solution that will prevent the problem from recurring. This is the strategy the FDA wants to see sites take, she adds.
"Sometimes the right answer is not the one that's popular with management, Valasek says. "Because sometimes it really is that staffing levels are low and people have too much work to do when you get down to it."
The FDA's increased vigilance comes at a time when the agency has been under a great deal of public scrutiny. As a result, the FDA has hired more staff to conduct inspections, and the agency has changed the way sites are selected for audits, she explains.
"The FDA used to select high enrollers," she says. "Now they've developed more of a risk-based management approach."
This change can have a big impact on research sites. For example, if the FDA audits a low-enrolling study that has four sites and two of those sites have significant issues, then the FDA will say that 50% of the sites have problems, Valasek says.
"The burden is put on the sponsor to go back and demonstrate to the FDA that these problems were not replicated at all of the clinical trial sites," she adds. "This is very expensive for sponsors, who have to assemble teams of independent auditors to ensure all sites and problems did not exist at other sites and that they can stand behind their data."
The FDA made another change by doing inspections in real time as studies are ongoing, which means that phase I and phase II studies might as easily be investigated as phase III studies.
Here are some suggestions for how clinical trial sites can prepare and handle FDA audits:
Learn and use CAPA: Find resources online or in an institutional library about CAPA, which is part of Good Manufacturing Practice.
The Internet has resources, and there are courses available, as well.
Also, CT sites might check the FDA's guidance on the various responsibilities of clinical research investigators and personnel and explore how to conduct a root cause analysis and apply corrective actions, Valasek suggests.
Analyze problems: When something occurs at a clinical trial site, the first step is for the compliance director or other leader to meet with the team and ask for opinions on what caused the problem, Valasek says.
They can ask these sorts of questions:
What do we think is the cause of the problem?
What contributed to it?
What could we do to fix it to prevent them from occurring again?
"Initially, they say it's training, but that probably is not what it is," Valasek says. "Sometimes, it's just that we're too busy."
Present a good attitude: "You can't fake your way through an inspection, but if you act properly and have things organized, and they appear to be in good control, then you often can get through some things that have sticky areas in it," Valasek says.
Sometimes this means an investigator will need to explain calmly why a particular new FDA regulation should not be applied to an old study, which had been initiated before the regulation went into effect, she adds.
"It might be the FDA expects you to have done something more to keep with the current standards," she says.
Keep documentation accurate, up-to-date, and logically organized: "Make sure all documents are there and put them in an easy order," Valasek says. "This helps make the inspection much easier."
A recent trend with FDA audits involves auditors finding very sloppy documentation at sites, Valasek says.
Sometimes the results are so bad the site receives a warning letter, she adds.
For example, there have been incidences where a site documented that one staff member was working with two different subjects at the same time, which was obviously inaccurate, she says.
A solution to this is to purchase a radio-controlled clock that will make certain accurate times are recorded for procedures, she adds.
Also, sites might assign someone to be a coach to play-act the role of an auditor finding a problem.
"How would you respond to it?" Valasek says. "Work on your response a little bit and get them to explain what happened in clear and concise words, not giving too much detail."
The key is to give a brief explanation of what happened in a calm tone.
Improve source documents: "Source documents often are inadequate from an auditor's perspective," Valasek says. "You need music and lyrics on the same page, meaning that when sites use sponsor-provided documents they need to have these incorporated into their own source documentation because that's what people follow."
The problem is that sites frequently don't include enough information in the source documentation, such as vital signs, diagnostic tests administered, etc.
Keep trial activity details in source documents, along with the correct order of doing these activities.
"If you do three EKGs in 10 minutes, include this, and document how many doses are given and whether or not you are collecting diaries," Valasek says.
Keep an up-to-date delegation log: FDA auditors will want to see that all necessary signatures are on documentation. So this means research sites should keep up with obtaining signatures and making certain an auditor can find out who made that signature.
"Sometimes there is a problem of different handwriting, and you don't know who wrote that signature because you don't recognize the handwriting," Valasek says. "So you need to go back and check the delegation log to see that the person with XYZ initials is a nurse who was delegated that responsibility."
If the signature came from someone not listed in the delegation log, then there is a problem, she adds.
"The FDA could disqualify data," Valasek says. "You don't want an auditor saying this person was not qualified doing the medical history or obtaining informed consent, so you need to close those loops."