A fine mess: IRBs overloaded with unnecessary adverse event reports
A fine mess: IRBs overloaded with unnecessary adverse event reports
Federal guidance fails to clear confusion
It's a constant refrain: IRBs are overburdened by adverse event reports (AERs) — many of which are unnecessarily reported to them and which they often lack the information to properly analyze.
This problem has been the subject of journal articles, conferences and two government guidance documents — one in 2007 by the Office of Human Research Protections (OHRP) and one released earlier this year by the Food and Drug Administration (FDA).
So why does the problem persist? Those who have studied it have a range of different answers. Some say the government entities released conflicting advice that muddies the waters and causes defensive over-reporting. The Infectious Diseases Society of America recently appealed to the FDA to ask for clarifications to its guidance.
Others blame IRBs, saying they ask for unnecessary reports, leery of trusting others to determine when AERs are a sign of a larger problem with a study. Stephanie Zafonte, MSN, RN, CCRP, CQA, RAC, nurse researcher for the Department of Defense's Defense Centers of Excellence, says she encountered that attitude at a conference a few years ago.
"We were sitting in a session on serious adverse events and there were between six and 10 IRB chairs in the room," Zafonte says. "And they were just militant that they needed to see not only the serious (AERs) that are possibly related to the research, but even the other ones.
"In order to respond to the pressure of liability, you have IRBs who are choosing to say 'I need to see more; I need to review it.'"
Role for data monitoring panels
But Marjorie Speers, PhD, executive director of the Association for the Accreditation of Human Research Protection Programs, says that in the past several years, the IRBs with whom she works have become more comfortable having adverse event reports reviewed by data monitoring committees and sponsors' coordinating centers.
Speers says IRBs realize that viewing every report is not only time-consuming but ultimately unproductive, because IRBs usually lack the information necessary to know whether an individual event is part of a larger trend, particularly in a multisite study.
She says the problem is that sponsors and investigators continue to send those reports to IRBs.
"I think where the change needs to occur is with sponsors taking more responsibility for reviewing adverse events, because they can review across all of the trial sites," Speers says. "When you send all of those adverse event reports to the IRBs, essentially you're asking the IRBs to be data monitoring committees and the IRBs can't do that."
Both Zafonte and Speers say it's going to take more time and an industry-wide shift in thinking to solve the problem. Zafonte says it also requires the cooperation of various government entities, which have different reporting requirements.
"Why can't we agree on a centralized document that says this is what we're going to do with information that changes the risk-benefit ratio?" Zafonte asks. "Until you do that, I don't know how the IRBs can really do anything that's going to impact change at that level to alleviate this burden."
Guidance critiqued
Guidance released by OHRP and the FDA was supposed to help clarify matters. But some think they've confused things further.
When the Infectious Diseases Society of America released a report earlier this summer on reducing regulatory burden (See IRB Advisor, September 2009, p. 103.), the group singled out adverse event reporting for criticism and recommendations. In September, the IDSA wrote to the FDA, asking for changes to its guidance.
The IDSA noted that both the FDA and OHRP have agreed that reporting offsite adverse events to IRBs in a multisite study is wasteful and fails to protect subjects. But it said the FDA guidance still suggests reporting certain individual offsite events — those indicating an increase in frequency of AERs, for example, or a single instance of an uncommon event that is strongly associated with drug exposure — to all the IRBs in a multisite study.
"In contrast, the OHRP guidance document suggests that local IRBs only be notified if there is a finding by the sponsor or the independent data monitoring committee regarding patient safety," the IDSA states in its letter to FDA. "IDSA supports OHRP's approach towards adverse event reporting and analysis for multicenter clinical trials and recommends that FDA issue guidance consistent with OHRP's guidance."
William Burman, MD, an associate professor in the Division of Infectious Diseases at the University of Colorado at Denver, was the lead author on the IDSA's report. He says IRBs should have no role in the review of offsite adverse event reports and that the OHRP guidance makes this clear.
"I wish the FDA would have said something that simple," he says.
Speers says OHRP's guidance is more direct than the FDA's. "The OHRP guidance says any unanticipated event that's related to the research and involves risks to subjects or others is an unanticipated problem involving risks to subjects or others and has to be reported."
But she says the FDA guidance is helpful in that it assigns sponsors the responsibility for reviewing adverse events and determining whether they are unanticipated problems involving risks to subjects or others.
"The reason the FDA says that is that it is the sponsor or the data coordinating committee that has the information about the adverse events across all the trial sites," she says.
Zafonte notes that OHRP and the FDA use different nomenclature in describing events and have different reporting timelines.
"It absolutely is a mess," she says. "And if you bring in the Department of Defense — which is a big funder of clinical research — their regulations are again different. It really is something that should be addressed in a centralized guidance."
In the meantime, local IRBs can try to cut through the noise of so many adverse event reports by asking the sponsors of studies for summaries of adverse events that have occurred and for summaries of unanticipated adverse events that involved increased risk and are related to the study, Speers says.
"That is the practice that we encourage IRBs to use when they are conducting the continuing review of a study," she says. "That way, the local IRB can conduct a much more informative review of the trial."
Zafonte asks IRBs to consider the reporting they're requesting of investigators with an eye toward whether it is really useful information that helps protect participants.
"Step outside the box and start looking at your overall processes and programs," she says. "Take a hard look: Are they effective and efficient? Are your policies meeting the regulation or are they overkill? And are they really making a difference in the risks for your participants?"
[Editor's note: The OHRP's "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events" is available at: http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm.]
The FDA's "Guidance for Investigators, Sponsors and IRBs: Adverse Event Reporting to IRBs — Improving Human Subject Protection" is available at: http://www.fda.gov/downloads.
It's a constant refrain: IRBs are overburdened by adverse event reports (AERs) â many of which are unnecessarily reported to them and which they often lack the information to properly analyze.Subscribe Now for Access
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