Risk management making its way into clinical trials

Informed consent, patient safety key areas

Developing and adhering to a solid risk management strategy is an important foundation for preparing for the possibility of clinical trial problems, including those pertaining to patient safety, regulatory issues, and civil suits, experts say.

One of the key issues in the risk management process is informed consent. "It seems to me that the area that people still need to pay attention to is really to have a good informed consent process," says Jeffrey Trunzo, RPh, MBA, CIP, vice president of the Chesapeake Research Review Inc. in Columbia, MD.

While everyone focuses on the informed consent document itself, that’s not the primary informed consent function, he notes.

"The process really is meant to have potential subjects understand that they are in research and to understand what’s going to happen to them," Trunzo says.

The research field is beginning to understand that informed consent is a major factor in risk management, says Allison Weber Shuren, MSN, JD, health care attorney for Arent Fox in Washington, DC.

"People spend a lot of time writing a document, but they’re just beginning to understand that informed consent is not just handing someone a document," she says. "Informed consent is a process of truly educating someone about the risks of a trial and letting them know whether it’s therapeutic or whether there will be any financial gain for their participation."

From a research sponsor’s perspective, patient safety must be adequately managed both on site and through checks and balances, explains Christopher Gallen, MD, PhD, vice president and chief of operations for clinical research and development at Wyeth in Collegeville, PA.

"We have a responsibility within the company," he adds. "We want to check the data very carefully across all patients, as well as look for outliers and high-risk findings in patients."

It’s important for sponsors to work with clinical trials staff and investigators to make certain all medical concerns are addressed and that investigators don’t overlook problems, Gallen notes.

Gallen, Shuren, and Trunzo offer these suggestions for improving risk management of clinical trials:

1. Review your recruitment process. "Subject recruitment is an area where people can get themselves in trouble," Trunzo says. "Almost all clinical trials in the United States don’t make their recruitment timeline."

One of the reasons clinical trials recruitment often is difficult is because the inclusion/exclusion criteria are not designed realistically, the experts say.

"One thing that really makes these unsuccessful is if you have a protocol that is designed for patients who don’t exist in the real world," says Gallen. "Someone — often a less experienced person — will design a trial and will try to exclude everyone who would make any extra difficulty in the trial, so they can get a clean answer."

But by the time potential subjects are checked against the inclusion/exclusion criteria, there are very few subjects left, he adds. "For instance, someone starts out with a combination of criteria that individually can make some sense, but cumulatively excludes everyone," Gallen says.

A solution would be to develop a more realistic way to write inclusion/exclusion criteria, he suggests.

Some programs are aggressive in their recruiting efforts through paying high-dollar compensation to healthy volunteers for phase I clinical studies and paying recruitment bounties to investigators and study coordinators, and sometimes even to patients, Trunzo notes.

However, the truly bad programs are rare, he adds. "There are lots of good recruitment programs that create awareness about diseases, and there’s nothing wrong with providing moderate amounts of monetary awards to compensate people for their time and transportation," Trunzo says. "But when people say they want to stay in a study until the end — even when they’re having bad effects — because they want to collect the payments, then that’s when it turns around into a problem."

One risk management solution would be to spread study visit reimbursement equally as the study progresses, instead of offering subjects a big bonus at the end of the study, he suggests.

"It may not be in their best interest to finish, so just reimburse them up to the time they participated," Trunzo says.

Another risk management strategy is to hire a trials coordinator who is paid to recruit subjects at a rate that fairly reflects the cost of the person’s work, Shuren explains. "As long as that person is a third party who has no incentive for putting people into a trial arbitrarily, then it’s a very good strategy to say that the physician knows his patient population and can say who might be a good candidate for a trial, but to have someone else do the triage for it. The third party could be a trial coordinator."

Financial incentives paid to clinical trials staff and investigators for recruiting subjects can be outrageous and sometimes coercive, she says.

Likewise, if the investigator is the person doing the recruitment, then the financial incentives should be no more than the cost of the investigator’s time, Shuren adds.

Wyeth wants to attract the first-rate investigators to clinical trials so they are paid fairly for their work, Gallen says. "We don’t want to create incentives that lead people to engage in bad behaviors," he adds. "As a consequence, we’re pretty careful to try to be fair and pay a rate that a first-rate person would receive to do the work, but not so much that it becomes a financial coercion to induce people to engage in bad behavior."

"If a person is paid a salary and spends 10 hours per week recruiting patients, then there’s a dollar value to that time," Shuren explains. "Stick to fair market value of the services provided."

2. Run a well-organized trial with timely documentation. Reporting adverse events in a timely manner to the appropriate regulatory agencies is another area that has caused risk management problems for some clinical trials, Shuren notes.

"We’re seeing more focus on this mainly because of big [tort] cases that have come up in the last few years," he says. "Some of these have been adverse events that have not been reported in a timely manner or accurately. If they had been reported correctly then patients might not have been harmed, according to the allegations."

Most of the regulatory problems arise from paperwork problems, Gallen notes.

"The attention to detail when putting a patient into a trial was not as good as we’d like," Gallen explains. "The first sign of defense is to have monitoring follow-through and to highlight problems to be addressed."

When Wyeth reviews audit findings at clinical sites, company auditors often find that a large majority of the problems relate to paperwork for which there are electronic copies in the files, Gallen says.

Items such as IRB approval forms and informed consent documents may be missing information, but these problems could be avoided through an internal, electronic auditing system, he explains. "We can look through the documents and audit them ourselves inhouse to figure out what the problems are and get back to the monitors to correct the problems," Gallen says. "With this policy, we can do — inexpensively — 70% of the audit at 100% of our sites, at our own leisure."

3. Avoid the appearance of a conflict of interest. "One hang-up the industry is struggling with right now is whether or not subjects have the right to know if there’s a conflict of interest on the side of the investigator," Shuren says. "You can have conflicts that interfere with the informed consent in trials."

It’s critical to consider the conflict of having an investigator serve both as a physician to a patient and as a clinical trials researcher for a study in which the patient is enrolled, she notes.

The question that needs to be posed when investigators wear both hats is whether the use of the investigator’s own patient population in a study is so coercive that patients may feel they have no choice but to enroll, Shuren says.

"Some of these contracts are quite lucrative for physicians," she explains.

Besides dealing with the risk of lawsuits, clinical trials staff and investigators who have the appearance of a conflict of interest could run afoul of state and federal kickback and referral laws.

"Contracts to run investigations should be viewed no differently than any other contract with a pharmaceutical or device company," Shuren notes. "In terms of the kickback laws, it should be in a safe harbor if it can be."

The federal government has identified a number of arrangements that technically would violate the kickback rule, but if the arrangements meet the criteria of a safe harbor then the government will not prosecute them, she explains.

For instance, it’s all right for a clinical trials sponsor to pay a physician investigator for his or her time and resources spent recruiting, but if these incentives are much higher than what the physician’s work would warrant, then they may give the appearance of being a way for the sponsor to funnel money to the investigator as a kickback or "thank-you" for other services the investigator has provided, Shuren says.

Sponsors may pay investigators for their clinical trials work and costs, but they can’t use that payment to give the investigator a benefit for other reasons.