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A look at the vague but time consuming requirements imposed on sites and efforts to ease the burden.
Serious adverse event (SAE) reporting and to a lesser extent adverse event (AE) reporting have long been time consuming, costly, and often perplexing tasks for investigative sites. Growing worldwide concern about patient safety in clinical trials now seems to be unintentionally adding to the burden—with marginal to no real utility in improving subject protection.
Kenneth A. Getz
Many sponsors have begun seeking definitive answers from investigators about whether or not an AE or SAE is related to a study drug, an opinion that even the most astute clinician will admit comes down to guesswork. Institutional review boards (IRB) are also asserting themselves with information requests connected to protocol deviations and Investigational New Drug (IND) safety reports.
Growing reporting requirements for SAEs and protocol deviations are widely considered by investigative sites to be distracting layers of bureaucracy at a time when they are expected to provide substantially higher levels of efficiency. Most sites believe study conduct performance targets cannot be met unless the burden of safety reporting can be eased.
Sites understand the necessity of AE and SAE reporting and the federal requirements behind it. Investigative sites tacitly submit to the volume of exchanges with study sponsors and IRBs that these requirements require. Nonetheless, safety reporting is a very frustrating task, due in part to poor clarity around the definition of unexpected adverse events; the unpredictable frequency of SAEs; a lack of context with which to place the observed SAEs.
The time investment for investigative sites to meet safety reporting requirements is anecdotally substantial. Study coordinators estimate that AE/SAE reporting consumes between 10% and 20% of their work effort on trials. These back-of-the-envelope estimates vary widely by therapeutic area. Little to no data has been systematically gathered to quantify the magnitude of this burden. But speak with any investigative site, and you'll get an ear full.
Consider the case of the Alaska Clinical Research Center in Anchorage. "We're involved in a large Phase II trial that was supposed to have few side effects and we've had two SAEs so far," says Mary Anderson, RN, study coordinator and regulatory affairs manager. "You just never know when someone is going to have a severe allergic reaction or cardiac rhythm change."
For one of the SAEs that occurred with the current oncology trial, Anderson figures she has spent 20 hours treating and monitoring the subject, scheduling procedures, picking up the patient's records from the hospital, and completing all the requisite paperwork, often in triplicate. The other SAE consumed less than five hours of her time to document, she says, because the subject was acutely ill and died of natural causes.
When an SAE occurs, an initial two to five page SAE form must be filled in and sent to the study sponsor within 24 hours, as required by the FDA, and sites have much of the requested information on hand. But for weeks thereafter, the effected subject requires vigilant supervision. Sponsors also ask for regular updates on the patient's status and follow-up lab work until the SAE is resolved, as well as clarification on anything it deems inappropriate in the initial report.
Although sponsors may be loath to hear it, sites know that accurate and timely reporting isn't always possible. With AEs, reporting is straightforward. It gets listed in a log, indicating when it started and was resolved, what action (if any) was taken, its severity and potential association with the study drug, and the outcome. "It's no problem," says Anderson, "as long as you know the answers. The primary issue is that patients don't always remember the precise day and time their symptoms began."
"Recently, a female subject in a study waited until her 30-day follow-up visit to mention that she experienced hair loss during the entire study. Other times, an AE is discovered only because the complaint was voiced to another doctor and appears as a note on the patient's chart, often devoid of details such as date of the reported illness," she said.
Cancer patients tend to be more conscientious about recording their symptoms, but oncology trials are particularly tricky when it comes to teasing out cause and effect. Overall, Anderson estimates that AE/SAE reporting consumes about 15% of her work hours but nearly a quarter of her time as a study coordinator.
At Jasper Summit Research in Jasper, AL, which primarily conducts respiratory research, study coordinator Becky Thompson, RN, CCRC, says that AE/SAE reporting consumes less than 5% of her time on most studies.
A bigger issue for some sites has been the growing role of IRBs in patient safety reporting over the past several years. Sites are required to report promptly to the IRB all protocol deviations, SAEs, and any other unanticipated problems involving risk to study subjects. Not only do sites face a deluge of reports that must be forwarded to IRBs, there are also no universal standards for reporting.
"Each IRB has its own set of standards about what has to be reported to them," says Phillip D. Toth, MD, FACP, owner and medical director of the Midwest Institute for Clinical Research in Indianapolis, IN. "So sites are in a quandary as to what is reportable, such as when the patient misses a dose or is late by a week for a study visit."
Dr. Toth and other principal investigators (PIs) believe that relative to all other safety-related reporting activities, dealing with protocol deviations represents the largest amount of paperwork with the least amount of clarity about what PIs should be doing. "This is time consuming and it doesn't serve the patient at all," says Toth.
Most investigators believe at the heart of the matter lies the apparent distrust that IRBs have for research centers' ability to determine when a patient's safety is in jeopardy. "But IRBs unreservedly rely on sites' judgment when it comes to deciding if consent forms need amending based on IND safety reports sent out by sponsors," points out Toth.
"Sites are actually solicited by IRBs for advice regarding needed changes to consent forms," says Toth. "When I submit a copy of the IND safety report to the IRB, I routinely ask for its counsel on the matter. But at best, the IRB will say it 'received' the IND safety report. It's rare for the IRB to say it has read the report or that it makes a recommendation regarding edits to the consent form."
With some longer studies now generating as many as 100 IND safety reports, many investigators believe that IRBs are avoiding, even shirking, a major responsibility to ensure the consent form truthfully covers important information—and in plain language—about the clinical trial.
In April 2007, the FDA issued a draft guidance for clinical investigators, sponsors, and IRBs entitled "Adverse Event Reporting—Improving Human Subject Protections." This draft guidance describes how the increasing use of multisite studies and international trials has "complicated the reporting pathways prescribed in regulations." The need for the guidance arose in 2005 due to IRBs complaining that they were receiving an increasingly large volume of individual AE reports often lacking the necessary context and detail for them to adequately address the complaints.
The FDA has proposed more detailed definitions of what constitutes "unanticipated problems" and has recommended steps for study sponsors to aggregate and centralize the AE and SAE reporting process in order to ease the burden on IRBs. It is unclear whether this proposed arrangement will ultimately provide relief for investigative sites. However, at this time many investigators state that only a small number of sponsors are even aware that the now 20-month-old draft guidance is being considered.
Most sites feel helpless to change the situation. A few have reported that they are considering requiring additional compensation from sponsors—between $500 and $750 per safety occurrence, for example—in order to make it easier to tolerate the burden of safety reporting. This is hardly a direction that sponsors would be receptive to given their need for ever-tighter cost controls.
Ongoing patient education about the need to immediately report symptom changes and adverse reactions is a critically important step that can be taken by all study personnel at the outset of clinical trials.
Recently, the Clinical Trials Transformation Initiative (CTTI), a broadly based consortium of stakeholders focusing on improving the trials process, proposed conducting a study designed to gather empirical evidence on the nature and magnitude of the problem and to propose viable relief. Clearly there is a need for such a study to inform sponsors, IRBs, and regulatory agencies about the huge and potentially unreasonable safety reporting burden that they are placing on investigative sites. Ultimately, this burden potentially harms patient safety instead of helping it.
Kenneth A. Getz MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: firstname.lastname@example.org