Here are examples of best practices in drug safety

Drug safety group can be helpful

Clinical trial sites and research institutions could save time and improve reporting efficiency by working with a drug safety group, experts say.

In the past, clinical trial teams often would handle their own drug safety work, and clinical research organizations would process such reports, notes Esther King, safety surveillance associate III of the Duke Clinical Research Institute (DCRI) at Duke University in Durham, NC.

Now Duke University studies have the benefit of an on-site drug safety group's assistance, King adds.

"We try to get involved at the stage where the protocol is being written," King says. "If our input is not needed, then we at least review the protocol and make sure there's a solid safety section in there."

DCRI studies make drug safety a major priority in other ways, as well.

"One thing we do here at DCRI with our larger trials is we have adverse event and serious adverse event (SAE) reporting through an electronic data capture mechanism," says Peggy Arias, project leader at the DCRI.

"That gets the information out immediately," Arias adds. "And that's been one of our safety surveillance focuses over the last couple of years."

This change was the result of greater vigilance paid to drug safety issues and to the need for real-time information on drug safety, Arias says.

"We always have a safety surveillance component in the trials that we manage here, when it's appropriate," Arias says. "We're always working with Esther's group, and her group is always available to us."

King elaborated on four advantages sites and sponsors have when working with a drug safety group.

1. Evaluate safety issues of study.

Study protocols include definitions of the anticipated adverse events and SAEs. It's a good idea to evaluate the SAE form for drug safety issues, King says.

"We have a medical monitor who is a licensed medical doctor do the review," King explains.

These questions should be asked:

  • Has the site investigator reported the causality and documented it on the form?
  • Is the causality associated or not associated; related or not related?
  • Has anyone died who was on the study, and was the death due to this event?

"If the principal investigator thinks it's possibly related, then that's one criterion we're looking for," King says. "We say that's something we have to send to the Food and Drug Administration (FDA) quickly."

Next the medical monitor reviews the event for expectedness.

"We use the investigator's brochure to see whether the event was expected or not," King says. "If it's not listed in the investigator's brochure then it's considered unexpected."

If the event is listed and if it occurred at the severity listed in the brochure, then it's an expected event, she adds.

2. Follow regulatory reporting requirements.

If the event is unexpected and related to the study drug, then the next step is to follow standard reporting regulations under 21CFR 312.32 for the investigational new drug (IND) safety report, King says.

After the medical monitor makes his or her assessment, then the information is faxed to the sponsor.

"If the sponsor disagrees and maybe interprets the event differently, then they provide their documentation," King says. "It's their final call."

Whoever holds the IND is responsible for the reporting.

"The only time the site would do IND safety reporting is if the site has a single trial, and the PI holds the IND," King says. "Usually sponsors are holding the IND, and we have had studies where the National Institutes of Health (NIH) is the sponsor and holds the IND."

If the sponsor has contracted with the drug safety group to handle regulatory reporting, then the drug safety group will take care of the reporting, she notes.

The key is having an expert decide whether the event was both associated with the study drug and unexpected, she explains.

"You could have an event that is related, but expected, or we have lots of events that are unrelated," King says. "The site principal investigator will say the patient has metastatic cancer and they expected him to die due to disease progression, but that's unrelated to the study drug."

Typically only a small percentage of events that occur in the study are reported to the FDA quickly, King adds.

3. Work with a data safety monitoring board and trial team.

The data safety monitoring board (DSMB) looks at study information at least monthly, and it helps to have a drug safety group assist with providing information to the DSMB.

"We work out a process with the trial statistician to provide information to the DSMB," King says. "The DSMB is not part of our group, but we collect information and clean it so it's there for them to review at scheduled points in the study."

The safety board also works closely with the clinical trial team, including clinical research associates and research monitors, King notes.

The board answers their questions about whether a particular event is an adverse event and needs to be reported, she says.

"We base every decision on the IND safety regulations and on being compliant with what's in the protocol," King says.

"And sometimes for larger or late-phase studies we'll work out a streamline reporting process that makes it easier on sites and is less effort for them to report information," King says. "Maybe we'll report less information or the same information, but not so quickly."

This is because some studies have very sick populations with patients who are expected to die before the study ends.

"We had one study where we expected 60% of the patients to die from cardiogenic shock," King recalls. "So we used a streamlined approach so if the patient had arrhythmia, the site would log those on a case report form and send them within a scheduled time, such as 30 days."

If the site was asked to send out a separate form each time there was an incident of arrhythmia, then there might have been 10 SAEs reported for each patient, King adds.

"We have smart ways to collect information so we have all that we need for a study and we're not making it overbearing for the site," King says.

4. Educate investigators and staff about drug safety issues.

"In addition to processing events as they come in, we go to investigator meetings when a new study starts and we present the safety section of the protocol," King says. "All site investigators and coordinators are in attendance."

The drug safety group also trains clinical research associates and trial teams so they will know what type of events to look for and so they can help the coordinators, she adds.

"Usually the sponsors ask for us to make the presentation, but if the sponsor doesn't ask for us, then we ask the project leader to do the presentation," King says. "We go through the safety processes."