Good documentation helps when FDA knocks on door
Consequences of noncompliance are serious
While the FDA’s enforcement efforts in the clinical trial industry has not changed much over the years, one reality remains: Many clinical trial site staff and administrators do not fully appreciate the consequences of noncompliance, an FDA enforcement expert says.
"You need to understand the worst-case scenario and what could happen if things went downhill dramatically," says Michael A. Swit, JD, vice president, life sciences, at The Weinberg Group Inc., a scientific consulting firm in Washington, DC. Swit often speaks about FDA regulatory and enforcement issues at national conferences, and he is scheduled to give a talk on this topic at the Drug Information Association’s 41st Annual Meeting, June 26-30, 2005, in Washington, DC.
Clinical trial staff should understand the criminal penalties and how any serious violations that can be linked to a serious health consequence or a subject’s death increase the potential for strong FDA enforcement consequences, he says.
"The FDA has the power to enjoin violations of the law and seize products in violation of the law," Swit reports. "If there’s a very serious problem the FDA is aware of then the agency will step in and put a lot of pressure on you to stop the trial."
Another repercussion would be for the FDA to decide a trial has been done so poorly that its data are unreliable and cannot be included in a published report, Swit says.
This level of enforcement is not common, but it is a potential risk of noncompliance, Swit says.
"The FDA has a number of more informal administrative ways to achieve the agency’s objectives," he notes.
Swit provides these examples of enforcement activities and best practice responses:
• FDA inspection/audit: The most common is a clinical auditor inspection in which FDA inspectors are specifically trained to look at a clinical trial site’s patient records, compliance procedures, inclusion/exclusion criteria, and training of clinical trial staff, he says.
FDA auditors will examine whether the clinical trial site has gone through appropriate IRB procedures with sign-offs before initiating the clinical study, Swit adds.
During the exit interview, the FDA provides the site with a 483 inspection form that lists allegedly violation conditions identified during the audit, Swit says.
"No inspector worth his or her salt comes out without a 483 unless the company is perfect," he says. "And depending on how extensive the 483 is, you might have a situation where you’re in substantial compliance with no major worries or maybe have a list with violations they’ve observed that may or may not require immediate action."
• Responding to 483: "The first thing you have to do is to respond to the sectional report," Swit says. "You need to promptly respond in a way that shows you appreciate what the FDA said and are addressing concerns. When you respond to the 483, start off with each observation made," he says.
Then it’s appropriate to say how the site has addressed or plans to address the concern or whether the problem noted is not valid.
For instance, clinical trial sites cannot administer study drugs to patients until after the informed consent document has been signed, and to do so before the consent has been signed is a violation, he says.
So if the 483 form notes that drugs were administered before the consent was signed, the clinical site should respond that "Yes, that did occur," Swit says.
"You can’t lie in these cases, but try not to admit that you were in violation," he suggests. "Explain that you investigated the incident and found out how it happened, such as maybe you didn’t get the consent signed, but did go through the consent process."
While technically it wasn’t done correctly, at least there is an explanation for what happened, Swit adds.
"So put in your response what you have found and how you will address it, including measures you will take to give the FDA assurance that your have taken actions to prevent the violation from occurring again," he says.
"Often if you respond to the 483 aggressively from the standpoint of making sure you’re really responding to the FDA’s concerns, then that may be the end of it," Swit says. "But if the violations are serious enough, the FDA may think your system problems are so extensive that patient safety is an issue, and then the FDA may issue a warning letter."
Occasionally, the FDA will include a concern that is not valid. Perhaps the FDA has misread something or has based the concern on old information, he notes. You should respond to those charges as well.
• Warning letters: Unlike the 483 form, which are available to whoever requests it, but are not made readily available on the FDA’s web site, the warning letters are made public, Swit says.
"If you receive a warning letter, the FDA posts that on the web site within a week or two of when it was issued," he says.
Even the 483 forms could have some impact on a clinical trial site’s ability to recruit new trials, but typically the FDA will provide the site with an opportunity send in a detailed response, and then will give the site a verbal "OK," Swit says.
"You can try to get some input from the agency that you can communicate to others, but you typically don’t receive a formal letter," he explains. "If you get a 483, that’s fairly innocuous and you can turn it over to the sponsor and say, These are minor issues; here’s our response,’ and many times it’s all right."
However, any responses from the FDA regarding a warning letter is put in writing and will have repercussions, Swit says.
"If you get a warning letter, that changes the public complexion of it," he says. "There have been warning letters issued on occasion that go out before a site has been able to respond to the 483, and that’s when the FDA is not happy with what they found."
In other instances, there might have been an inspection that found some problems, and the warning letter was issued 3½ years later, Swit says.
When there are warning letters, the repercussions can be severe, such as the FDA disqualifying a clinical investigator from doing clinical trials or conditions being placed on how a site can conduct clinical trials, he notes.
• Responding to warning letter: "You have to provide a detailed response and make sure the allegations in the warning letter are true," Swit says.
"If you’re a very small operation you may have direct knowledge of whether it’s true or not, and there may be things that are not accurate," he adds. "Particularly if there’s a delay between the inspection and the warning letter, you may have corrected the violation."
It’s important to send the FDA a carefully worded but comprehensive response that addresses each one of the matters raised in the warning letter thoroughly and appropriately, Swit says.
"Many times what people will do is bring in an outside consultant and law firm to help them address the issues and to work with them to make sure the necessary procedures are put into place," he explains.
Clinical trial administrators also can request to meet with the FDA to discuss the situation, Swit notes.
• Preventing enforcement problems: "What I say to any institution regulated by the FDA is the mnemonic: Please Teach Risk Avoidance," he explains. "The P’ stands for procedures that are designed to address FDA compliance," Swit says.
"The T’ is for training employees on those procedures; the R’ is for recording the results because procedures and training don’t do any good if you don’t have good records that are designed well and are faithfully used."
Often when there’s a failure to record a significant action, it’s because a site might have the best procedures in place but lack good record keeping, he notes. "If it’s not written down, it didn’t happen, and the procedure won’t defend you from a violation," Swit adds.
And the "A" stands for audit, meaning clinical trial sites should conduct their own audits to make certain they are following the best procedures and record keeping, he says.
"If you don’t occasionally audit and make sure all the stuff is being done, you could begin to be out of compliance," Swit says.
Small mistakes sometimes can lead to a worst-case scenario in which a subject dies because someone wasn’t paying enough attention during the inclusion/exclusion process and didn’t document a subject’s hypertension, which should have excluded the person from the trial, he says.
"Remember one significant issue: Good clinical practice is an evolving standard," Swit says. "What exists in the FDA regulations is the minimum standard, and the FDA also has a guidance document that goes into more detail about how we expect people to implement various requirements in the regulations."
While the FDAs enforcement efforts in the clinical trial industry has not changed much over the years, one reality remains: Many clinical trial site staff and administrators do not fully appreciate the consequences of noncompliance, an FDA enforcement expert says.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content