Best Practices Spotlight

Give IRB staff & members Rules of Review refresher

Discuss nuances of each rule

IRB offices might improve their staff and IRB members' training and education if they provide an occasional refresher course on the National Institutes of Health (NIH) Guidelines for the Conduct of Research Involving Human Subjects, also known as the Rules of Review.

These guidelines provide the basis for IRB review consideration and discussion, but they provide room for flexibility and common sense, an expert says.

For instance, the first rule asks IRBs to minimize risk, but this is not a mandate to prevent all imagined possible risks.

"I think IRBs need to realize they can't think of every potential bad thing that could go wrong," says Susan Kornetsky, MPH, director of clinical research compliance at the Children's Hospital of Boston (MA).

IRBs should not reject a research protocol based on a very small chance that something of minor risk might occur, she notes.

The seven rules are published online at the website: http://ohsr.od.nih.gov/guidelines/GrayBooklet82404.pdf

Kornetsky offers these suggestions for how to discuss and train staff and IRB members on the NIH Rules of Review:

1. The proposed research design is scientifically sound & will not unnecessarily expose subjects to risk.

"You should think about physical, psychological, economic, and social risks," Kornetsky suggests. "And make certain the study's scientific design meets the aims of the protocol and that there is an important scientific question that the protocol will address."

For example, IRBs should ask themselves if the protocol outlines preliminary data, qualified staff and resources, and discusses minimizing risks to research participants.

If the study involves socio-behavioral or socioeconomic research, these issues are more problematic, she notes.

"Social and economic types of risks do not necessarily happen immediately, and they're not always clear," Kornetsky says. "So I think IRBs spend a lot of time with what-if scenarios while with medical risk protocols you can look for concrete things."

IRBs sometimes spend too much deliberation time on rare minimal risks, she adds.

"You can build things into the protocol so those risks are minimized if done by the appropriate people or staff," she says.

For instance, if a study involves an in-person questionnaire, then the IRB can check to make sure the investigator employs qualified people to conduct the interview, Kornetsky explains.

"Give study participants resources or hotline information," she adds. "Someone might not exhibit distress during the interview, but later they could go home and think about it."

2. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of knowledge that may reasonably be expected to result.

This rule pertains to risk-benefit assessments.

"At least in medical research if you can combine research procedures with other clinical oriented procedures you could reduce risk," Kornetsky says.

With socio-behavioral research, IRBs could get caught up in trying to improve risks that already are minimal, she notes.

"Recognize that for behavioral and social research, if something starts with minimal risk then you don't have to tweak it so much," she adds. "If it's minimal risk, then you can move on."

3. Subject selection is equitable.

The IRB's review of inclusion/exclusion criteria focuses on safety issues, considering pre-existing conditions, Kornetsky says.

"The IRB looks at inclusion/exclusion criteria to make sure it meets the need of the research design, and they look at whether potential populations are vulnerable to coercion or undue influence," Kornetsky says.

IRBs should review the study site's screening procedures to determine whether they are justified, she adds.

Sometimes the criteria are so narrow that study sites have difficulty enrolling participants.

"IRBs respond to what investigators and sponsors propose, so many times they make the criteria so narrow that we'll see after a month or two that a study is open that they'll expand the criteria," she explains. "We see this all the time."

Investigators sometimes will approach the IRB to see if the IRB will grant them an exception for enrolling a subject who does not meet the criteria, but is otherwise eligible, Kornetsky notes.

"We say, 'You might want to consider expanding the criteria,'" she adds.

4. Additional safeguards required for subjects likely to be vulnerable to coercion or undue influence.

IRBs need to review study recruitment procedures to make certain they're acceptable, Kornetsky says.

"IRBs will spend a lot of time looking at recruitment, including the setting, timing, and making sure recruitment activities are well defined," she adds.

When investigators fail to include this information in their protocols, it takes the IRB longer to complete the review, she notes.

IRBs do not necessarily have to review an exact script the study site's recruiters will use, but any details about how, when, and where the recruitment encounters will occur are helpful, she says.

"This information gives the IRB a good chance to understand the nature of what the discussion is," Kornetsky says. "They should have a general idea of what is said during recruitment."

5. Informed consent is obtained from research subjects or their legally authorized representative(s).

IRBs typically spend a considerable amount of time reviewing informed consent documents and learning more about how the study site will conduct its informed consent process.

But they also should consider all initial encounters between potential study subjects and their legal guardians and the study team, Kornetsky says.

The recruitment encounters between potential study participants and investigators or study staff are important and the beginning of the informed consent process, she says.

6. Risks to subjects are minimized.

"When we consider risks we make sure they are adequately described in the protocol and informed consent form," Kornetsky says. "Here's where you want to put the risks into some type of context."

IRBs also might ask investigators to discuss their plans for sharing some study findings with subjects, she suggests.

For example, if the study includes a physical assessment that turns up some potentially important clinical information for a subject, then the study site should have a process in place for handling that information.

In addition to minimizing risks, IRBs could suggest ways that sites could maximize benefits, and sharing pertinent information is one way of doing so, Kornetsky says.

"If you are doing cognitive testing or other types of assessments, then share these with the family so they can use it as a potential benefit," she suggests. "Not everything has potential benefit, but sometimes we overlook the small things we can do to maximize personal benefit."

However, if the informed consent document states there are no personal benefits, then the IRB shouldn't try to find one, she adds.

7. Subject privacy & confidentiality are maximized.

"Privacy and confidentiality are two different concepts," Kornetsky notes. "Investigators spend a lot of time on confidentiality, but privacy also is what participants expect."

Privacy is one's concept of one's self, she explains.

The goal is to keep study data confidential, and this can be handled through electronic and physical data protection protocols and procedures.

Kornetsky adds an eighth rule, pertaining to monitoring data and managing risks involved with this process.

"If a study really has minimal or no risk, then you don't want to spend a lot of time monitoring data for safety," she says.

For studies that involve significant risk, then the IRB will want to see a plan on how data and safety are monitored, she adds.

These are some questions to ask of investigators:

— How frequently are data monitored?

— What type of data analyses are conducted during a trial?

— Are there rules for stopping the trial?

— What is the plan to detect unexpected harms or increases in the severity or frequency of harms?

— Is there an adequate plan to stop the protocol if benefits outweigh harms or if harms outweigh benefits?

"Some trials want data safety monitoring boards (DSMBs), and others rely on independent people and investigators," Kornetsky says. "It's important that every trial involving risk to subjects has a plan, and the IRB doesn't need to see every single event, but they need to know there is a plan embedded in the protocol, and someone is looking at it."