An oversight process can improve quality

An expert explains how to do this

Investigators and physicians may be experts on research and medicine, but it’s up to the research compliance staff and the clinical trial managers to be experts in the interpretation and application of regulations governing clinical research.

This is one reason some institutions have begun to focus on quality improvement and in-house monitoring of clinical trials.

"When we first set up the research compliance monitoring office, the charge was to go forth and monitor," says Deborah Waltz, MS, CIP, director of the Research Compliance and Quality Improvement Office for Human Research at the University of Pennsylvania School of Medicine in Philadelphia.

It’s not enough to rely on federal monitoring and peer reviews of federally funded research if the goal is to prevent major problems, she notes.

For instance, the National Institutes of Health (NIH) might send a group of oncologists out to review research conducted by other oncologists, Waltz explains.

"Political dynamics and personal relationships come into play," she says. "There’s a code of behavior and conduct in the medical field where physicians are very reluctant to criticize fellow physicians."

While these peer reviewers may catch some important mistakes and will evaluate adverse events, this still isn’t as detailed a review as it could be, Waltz adds.

"Don’t confuse a physician medical review with source data verification and review for research compliance and protocol adherence," she explains.

"In general, peer review and/or medical monitoring is not going to identify potentially important compliance gaps because there is a different focus in the review itself," Waltz says. "This doesn’t mean that someone’s wrong and someone’s right; they are just different disciplines with different focus."

Therefore, it’s a good idea for institutions and clinical trials managers to establish their own monitoring and compliance program, which also could serve as a vehicle for educating clinical trials staff and investigators, Waltz says.

The numbers tell a story

Waltz offers these suggestions for what to include in such a monitoring program:

• Establish a risk rating standard. At the University of Pennsylvania, all centers agreed to a standard for rating risk. They agreed on a rating system that included minimal risk, low risk, moderate risk, and high risk, Waltz says.

"It took an extraordinary effort to get the centers to agree on the language," she adds.

Now, when an investigator proposes what he or she thinks is the risk and the IRB agrees with this, it is entered into a database where the study is stratified according to its risk rating, Waltz explains.

"Being able to stratify research according to risk levels is a powerful tool when trying to maximize the impact of your monitoring program because it allows you to use a risk base strategy in allocating monitoring resources," Waltz says.

• Add another level for review for IND studies. "We also review another element of risk if our investigator is conducting an investigator-initiated trial where he is an IND holder," she says.

"What we have them declare is who is the regulatory sponsor," Waltz says. "What we found to be a problem in many institutions is that investigators didn’t understand the difference between a regulatory sponsor and a funding sponsor."

In other words, investigators sometimes would erroneously believe that the NIH was the regulatory sponsor, when in fact the NIH frequently is only the funding sponsor, and the investigator is expected to fulfill the responsibility of the regulator sponsor, she explains.

"Since the regulatory sponsor of the trial is responsible for ensuring that the trial is conducted in compliance with the protocol and the regulations, if there is not clear understanding — right up front — about where this responsibility for regulatory sponsorship resides, then there is a much greater risk of compliance issues," Waltz says. "It comes down to a matter of ensuring that someone has taken ownership of the regulatory compliance of the trial.

"From the institution’s perspective, it can be a matter of Who’s the one who’s going to be on the headline in the newspaper if you make a mistake? Who’s in control of the study?’" she adds.

• Assess how much research an investigator is conducting. One facet of the monitoring process focuses on the investigator’s combined work, including assessing how many protocols the investigator has and what the enrollment is for these protocols, Waltz says.

"We have encountered investigators with more than 50 studies," she notes. "That’s something we certainly want to take a closer look at."

There may be a reasonable explanation: for example, the investigator may be simply doing blood draw studies, or there may be a number of substudies under one large protocol, Waltz says.

It may be a situation where only two or three are actively enrolling subjects, she notes.

"But it also may be a symptom of an investigator who doesn’t know how to close out a study," Waltz adds. "Within every institution, you will find a couple of well-intentioned investigators who simply submit zero enrollment to the IRB every year because they don’t have the time, resources, or understanding of the regulatory requirements to properly close out a study.

"When you see those things, you want to look closely because that’s a huge risk to have one investigator exposed to that kind of volume of research and patients, unless as an institution you can be sure that he has the proper support system and infrastructure to properly manage it," she says.

"It comes down to a matter of exposure," Waltz says. "Some diseases are so rare that you might find one patient on each of 50 protocols; is that OK? I don’t know; it might be, but it really depends on a number of variables — the point is that we certainly need to take closer look at this."

Look out for noncompliance

• Watch for conflicts of interest. Reviewers will follow the conflict of interest committee’s recommendations for managing conflicts of interest, and they’ll make certain conflicts are managed according to the recommendations, she says.

"If an investigator is a patent holder, and the conflicts of interest committee has recommended they not be directly involved in the research, then we’ll go in and make sure that it’s actually happening," Waltz says.

• Monitor local compliance units. For example, suppose an institution has a cancer center with its own compliance program and local monitoring program, then the key is to evaluate the local monitoring programs as a way to extend the office and to push oversight to the local level, she says.

"When we have investigators processing or manufacturing any of the components of what’s being delivered to the patient, including the blinding of the study drug, then we need to make sure the manufacturing has appropriate controls and standards in place," Waltz says. "We also need to be sure the investigational pharmacy has adequate controls and standards in place if they are managing aspects of the blinding or randomization for the study."

• Look for triggers of other areas of noncompliance. For instance, if an IRB sees something amiss with the documentation supplied by an investigator to the IRB for either initial approval or continuing review, then the IRB will turn it over to the monitoring office for review, she says.

"If an investigator had a total enrollment of 210 patients last year and on this year’s continuing review there are only 180 patients, then that’s a problem," Waltz explains. "IRBs have become more sophisticated and have raised the bar."

IRBs now expect the investigator to submit accurate and complete information or they are not going to grant approval, she notes.

"At the risk of oversimplifying this, it is obvious that someone isn’t paying careful attention to the IRB paperwork, naturally you should be curious about what other aspects of the research might be suffering from lack of careful attention," Waltz says.

What’s next?

• Have a plan for dealing with what you find. For many institutions, implementing an oversight process and quality improvement program amounts to changing standards and expectations around clinical research.

The trouble is that if you raise the bar, then you have to be prepared to deal with the people who are under the bar, Waltz adds.

"One of the first things we did was develop protocols for the management of compliance or serious noncompliance," she explains. "We established what is serious noncompliance and what is important noncompliance that requires serious oversight."

Having policies like this in place ensures the fair and consistent management of compliance issues, Waltz says.

It also lets investigators know ahead of time that the institution takes compliance issues seriously, and if an investigator is the subject of some compliance remediation, the investigator doesn’t feel as though he or she is being singled out or treated unfairly, she adds.

• Note the experience of clinical trials staff and other items. "We look at the staff assigned to a project and their level of experience," Waltz says. "We look at things such as compliance with reporting adverse events to the IRB, the phase of the research and the IND status of the research."

Reviewers also assess protocol performance, rate of accrual, study design, and number of centers involved, she says.

"It raises the risk level if it’s a multicenter trial," Waltz notes. "We also look to see if it has a vulnerable patient population and if there have been previous government inspections or previous inspections from other sources."

• Follow investigators closely if they’ve had past problems: Past performance is considered, and if an investigator has been found to be in need of important improvements in the clinical trials process, then reviewers will monitor that investigator closely to ensure sustained compliance, she says.

"Depending on the nature of specific needs, we may customize the follow-up monitoring, including monitoring of the consent process," Waltz explains. "We evaluate whether they comply with inclusion criteria and whether informed consent of the patients was properly obtained."

Reviewers will return at various intervals to verify the accuracy of the data and case report forms and to make certain source records and data are collected in compliance with the protocol, she says.

"In starting our program, one thing we found was that investigators didn’t have case report forms in a lot of cases, and then we found that if they did have them they’d wait very long to fill them out — not just weeks, but months or even longer," Waltz says. "Investigators are generally well intentioned: they always meant to fill them out, but never got around to it."

This is where investigators can be educated about regulations, compliance, and documentation.

In general, the investigators have come to understand the importance of compliance and the benefit to both in terms of human subject protections and data integrity, Waltz says.

One important aspect of a sound compliance and quality improvement program is that when compliance problems are encountered, the program should provide the strategy, education, and resources to help the investigator achieve sustained compliance, he notes.

"We try to make sure the investigators we’ve worked with are model citizens in terms of data collection, data organization, and understanding what it takes to conduct a study," Waltz says. "These are the people we want to have go out and mentor up-and-coming physicians."