Compliance Corner

Follow an expert’s advice in reporting to regulators

A clearly defined process is place to start

Clinical trial sites and institutions could improve compliance if they have a clearly defined process for reporting to regulatory authorities, an expert says.

"It sounds simple and obvious, but it’s not always simple and obvious," says David L. Wynes, PhD, an associate vice president for research and an institutional official for Federal Wide Assurance for the university’s human subjects program at the University of Iowa in Iowa City.

"Many institutions spend a great amount of time working out the standard operating procedures (SOP) on how an IRB reviews protocols," Wynes notes. "But they need to think about the back end of the process and recognize that, inevitably, there are going to be unanticipated problems that occur, including new adverse events, previously unreported, and there may be situations of noncompliance."

Since institutions are becoming more active in post-approval monitoring and, as a result, they are more likely to find any existing noncompliance, it’s extremely important to have a well-documented process on how to handle these situations, Wynes says. Wynes offers these suggestions for details to include in the process:

• Know what to report.

"While there’s some guidance in the regulations, there also has to be some determination within the institution and IRB of what constitutes a reportable incident," Wynes says.

For example, the University of Iowa defines serious adverse events in an 89-page "Investigator’s Guide to Human Subjects Research," which is available on the institution’s Web site. The institution’s definition is as follows:

"A serious adverse drug event is any adverse drug experience (associated with the use of the drug), occurring at any dose that results in any of the following outcomes:

— death,

— life-threatening adverse drug experience,

— inpatient hospitalization or prolongation of existing hospitalization,

— a persistent or significant disability/incapacity,

— a congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug event when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed above."

Among the other terms that the institution will need to define include the following:

— unanticipated problems,

— unexpected adverse events,

— noncompliance.

"It’s my experience in talking with colleagues at other institutions that when you’re confronted with a situation or problem, and you’re engaging in a dialogue with a regulatory agency, you have a much stronger basis for your actions if you’re operating off clear definitions and clear procedures," Wynes says. "You and the agency may disagree slightly on how you define serious adverse event, for example, but it’s clear that you have a definition and are applying the definition and using it consistently."

The institution that does not have a definition may find that the regulatory agency contends that they are reporting SAEs inconsistently and without established criteria, he notes.

"Something else to remember is that in many cases where you have an unanticipated problem, adverse event, or something, the institution or IRB can get caught up in addressing the problem," Wynes says. "And if you don’t have a clear process for reporting as you are required to under regulations, then that piece can get lost because you’re so focused on a resolution."

So part of any compliance policy should include a process that describes how and to whom reports are made, he adds.

Know the best approach for reporting.

Institutions may not have a written policy or procedure for this aspect of reporting, but it’s important to also know the best approach for reporting and making initial contact with a regulatory agency, Wynes says.

"In many ways that changes depending on the circumstances," Wynes says.

For instance, some regulations use the term of reporting in a timely manner. An institution will need to define "timely manner" and stay consistent within that definition, he says.

Besides reporting in a timely manner, an institution may need to take the report from the investigator or IRB monitor and review and resolve it, Wynes says.

Also, if a site has a serious adverse event that results in serious injury or death to a participant or involves a grievous case of noncompliance then it may be wise to make a verbal report to the regulatory agency, Wynes suggests.

"You might go on an accelerated time frame to give initial notification, saying, We don’t have any more details, but we wanted to let you know that something serious has occurred at our institution,’ and then you start a dialogue on what the process will be," Wynes says.

If the initial report is made verbally, then perhaps the site could follow up with an email, he notes.

"What’s important is that you give the information they need when they need it," Wynes says. "In a worst-case scenario, the regulator will hear of the incident from a third party, whether it’s the news media or another research institution, and the agency would know nothing about it."

This prompt verbal notice helps with the partnership that is formed between regulators and research sites, Wynes says. "Recognize that regulators are a partner in this process and make sure you’re working with them in that way," Wynes says.

At the University of Iowa, the standard operating procedures (SOPs) say the IRB chair will do the formal notification and provide a copy to an institutional official, Wynes says. The chair is notified by principal investigators, research participants, or others.

"We have a post-approval monitoring program where monitors meet with investigators to review procedures and ensure compliance," Wynes says. "And in that process, something could be identified."

At the University of Iowa, the IRB’s standard operating procedures require the human subjects office to compile a monthly report of all unanticipated problems involving risks to subjects or others and to forward the report to the Office of Human Subjects Protection (OHRP) and the Food and Drug Administration (FDA).

• Have a process for evaluating the report.

It’s important for an institution to have definitions and processes for reporting to an IRB and providing evaluations by the IRB, Wynes says.

Definitions should include the significance of the information, as well whether the incident meets the institution’s reporting criteria, he adds.

Every aspect of reporting an incident should be spelled out in the policy, and the reporting process will need a paper trail, Wynes says.

"In the end everything should be in writing," he says. "Whether you make the call and follow-up five minutes later with an email or with a Fed-Ex delivery, you need to make those kinds of decisions and have them in the policy."

• Know how to make a corrective action plan.

"I like to be an optimist and hope that most of what we’re encountering can be resolved through some sort of corrective action," Wynes says. "If there has been some serious experience or unanticipated problem in research that has to be reported, the question is, Can that be corrected?’"

For example, if there’s a problem with a device, the institution will look to the principal investigator, the manufacturer, and others to tell the IRB what can be changed to ensure this sort of thing doesn’t happen again, Wynes explains.

Or if it’s the type of incident that likely will happen again, then the site needs to factor that possibility into the risk-benefit analysis reported to the IRB and decide how to describe this risk to research participants, he adds.

"Can we minimize it? And what kind of information do we need to provide to participants so they can recognize that there’s a new risk, previously undetermined?" Wynes says.

This type of response is one kind of corrective action, he says.

"A different response might be where you find some sort of noncompliance by a research team," Wynes says. "Depending on the nature of the noncompliance, the response might be better education."

In most cases, noncompliance is a paperwork problem, and a corrective action plan could improve the situation with better education and, possibly, additional monitoring, he notes.

"Once you know employees have additional information, then make sure they’re complying with expectations," Wynes says. "You could evaluate the department to make sure resources are adequate for that clinical research program."