You say UP, I say UE: What's the new government guidance all about?

OHRP and FDA offer new language, definitions

Now that IRBs have both the final guidance on unanticipated problems and adverse events from the Office for Human Research Protections (OHRP) of Rockville, MD, and the draft guidance from the Food and Drug Administration (FDA), their duties in handling these issues should be clear, right?

Well it's not so, say government research experts, who also have to abide by these guidelines.

"There is a tremendous struggle right now, especially with multi-site trials, regarding IRB approvals and subsequent IRB communications when it comes to adverse events (AEs) and serious adverse events (SAEs)," says Stephanie J. Zafonte, BSN, RN, CCRP, CQA, RAC, senior extramural regulatory analyst (quality assurance) with the Office of Clinical Research, National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, MD.

OHRP prefers to use the term "unanticipated problems" (UP), and defines these separately from the more commonly used term "adverse events." The FDA's draft guidance uses both of those terms plus the additional term for device studies for "unanticipated adverse device effect" (UADE). And NHLBI uses the term "unexpected events" (UE).

"We revised out serious adverse event policy and call it 'reportable events,'" Zafonte says.

After OHRP issued its final guidance, Zafonte's office did a significant revision of its reportable events policy to incorporate the concept of unanticipated problems into reportable events, she says.

"I made the decision that we did not want to separate into policies the two types of events: unanticipated problems and adverse events, so we made one policy that speaks for both of them," she adds.

"The staff I work with have had a tough time wrapping their heads around adverse events versus unanticipated problems," Zafonte says.

"The FDA and OHRP guidance are steps in the right direction, but in my personal opinion I think everyone needs to sit down, at the same table, and get this all hashed out," says Patricia Sweet, RN, MSN, CCRP, CIP, a nurse consultant in the Office of Clinical Affairs for NHLBI.

"I think it's harder for [IRBs] when you have all of these different institutions developing policy, and they don't use the same terminology," Sweet says.

Until the FDA guidance is finalized, Sweet's office will continue to follow its institutional policy, which more closely follows the FDA's current regulations than OHRP's guidance, she notes.

"OHRP's guidance is confusing to people," Sweet says. "It would be nice if it would have simple definitions."

As it is, IRBs are the filter for all gray-area decisions, she notes.

"The IRB sometimes is the filter for a lot of things, and people will think, 'Oh send it back to the IRB and let them make the decision,'" Sweet adds.

"Part of the problem is that historically a lot of events that should be classified as unanticipated problems are reported as protocol violations or AEs, for lack of a better way to report them," Zafonte adds.

"IRBs are struggling and insisting on over-reporting of research teams because they're afraid that something is going to be missed," Zafonte says. "So it's a very difficult environment, and, unfortunately, OHRP and FDA are not helping."

While OHRP and FDA made some effort to use the same terms in their guidance, what would have been most helpful to IRBs and researchers is if they had produced a single statement, co-endorsed to the research community, Zafonte says.

"Instead of going together as a united front, we're taking two steps backwards," she adds. "It creates more confusion for the research community and IRBs, and it leads to over-reporting."

Despite the FDA's attempt to incorporate unanticipated problems in its draft guidance, it appears that the agency still is more interested in adverse events, while with OHRP, the opposite is true, Zafonte says.

"IRBs will have to read the FDA's guidance and then look at OHRP's guidance — both side by side — to see if they've covered all bases," Zafonte suggests.

In general, it's helpful to think of unanticipated problems as encompassing a broader picture than adverse events, Zafonte says.

"An adverse event is a particular event related to a product, device, biologic in a study," she explains. "The unanticipated problem is looking at a much broader picture, and it's looking at something that impacts someone's participation in research."

OHRP's final guidance states that unanticipated problems must meet three criteria, including being unexpected in nature, severity, or frequency, possibly related to participation in research, and places, subjects, or others at greater risk than was previously known.

For instance, an unanticipated problem could breach a study's security, such as a laptop being stolen or broken, Zafonte says.

"It's something that's directly related to someone's participation, as opposed to an event related to a product," Zafonte says. "That's where the two are different."

If a research participant accidentally is given an inaccurate dose of the study drug, but has no adverse effect from the incident, then that would be classified as an unanticipated problem, Zafonte says.

"The incident does impact the person's participation and risk, but it's different from an adverse event, and it requires a different view of the problem," she adds.

As it stands, IRBs and institutions will continue to be cautious, and this creates volumes of paperwork, which was one of the problems the OHRP guidance noted when it was released in January 2007.

"There was a goal to try to alleviate some of the burden IRBs are experiencing in over-reporting, but I don't think that was successful," Zafonte says.

"OHRP guidance is leaning toward reporting only those things that are unexpected, which is certainly understandable," Sweet says.

"OHRP, with the word 'unanticipated,' absolutely does muddy the waters," Sweet says. "We have 'expected' and 'unexpected.'"

IRBs will continue to require reporting of most AEs out of concern that the one they miss would not pass the Washington Post test, Sweet says.

In other words, does a particular institution/IRB want to be the one that let's an adverse event slide that later might end up making headlines and resulting in bad publicity for the research program?

The NHLBI IRB that Sweet works with meets every two weeks. Several years ago, the IRB handled about two AE reports per meeting, Sweet says.

"Now we get 12 to 15 per meeting," she adds. "Our IRB is much more conservative than most."

The increase is due to better investigator and research/IRB staff education, she says.

"We've really made an effort in the past two to three years to educate and say, 'You need to make sure that if something like that occurs, you let the IRB know," Sweet explains. "On a rare occasion, it happens that something is reported that doesn't need to be."

The IRB looks closely for trends, Sweet notes.

"Some of our studies are bone marrow transplant studies, dealing with graft-host disease, and there are certain IND studies with new treatments for fighting infection and aplastic anemia," Sweet explains. "Someone with severe aplastic anemia is prone to opportunistic infection, so you're giving them a compound that will for a while lower their immune system and compromise them."

While the compound is expected to help the person in the long run, it's a dilemma for IRBs when there's an adverse event because they have to determine whether it was caused by the treatment or the underlying disease, she adds.

Sweet's office is involved with research that is funded and conducted by NHLBI staff and investigators. Zafonte's work at NHLBI is with outside research institutions that have received federal funding for research of interest to NHLBI.

"NHLBI has just revised our policy on reportable events, and we only want to see what's unexpected and definitely related," Zafonte says. "Expected events can be reviewed by a monitoring committee or research team, and they can be reported in an aggregated format."

Another issue IRBs will need to deal with involves standard operating procedures (SOPs), Zafonte says.

OHRP's new guidance requires IRBs to review their SOPs and continuing review behaviors, and this could have a ripple effect on IRBs, she says.

"IRBs have to go back and make sure they have processes in place so that unanticipated problems are adequately thought about, reviewed, and handled," Zafonte says. "And now they have to review the FDA guidance and make sure there isn't anything they've missed."

The OHRP and the FDA had to write their guidance documents as broadly as possible to cover a wide range of studies, Zafonte says.

"And so a lot of times they lack the specificity that's needed to implement them," he says. "That's where you end up with people individually having to interpret the guidelines and be comfortable with what they have developed for their own policies and procedures."

One solution is for institutions to better utilize data safety monitoring (DSM) plans within the IRB-approved protocols, Zafonte suggests.

The DSM plan will handle the expected events, whether they are serious or not, and this will leave for the IRB the unexpected events and trends, which will significantly cut down on what is reported to the IRB, she explains.

"If an institution empowers the data safety monitoring entity to look at the aggregate data and the expected events on a regular basis, then that entity can report back to the IRB, and it will provide a more meaningful review for IRBs," Zafonte says.

"Every protocol has a data safety monitoring plan to it, and in that plan you delineate who will monitor what and how," Zafonte says. "And if we hold those entities and research teams accountable for that monitoring, then that's where the ongoing safety monitoring should happen, instead of at the IRB."

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