Mar. 12, 2001 DURHAM, N.C. -- The current system for protecting people participating in clinical drug trials is outdated and needs to be overhauled, according to an article in Wednesday's issue of the Journal of the American Medical Association (JAMA).
"Serious concerns have been raised regarding the processes by which the safety of participants in clinical trials is currently monitored," wrote senior author Dr. Jeremy Sugarman, director of the Center for the Study of Medical Ethics and Humanities at the Duke University Medical Center. "All the players in the system recognize that patient safety is a critical issue that must be addressed."
While no one knows exactly how many people are harmed from adverse events during clinical trials, Sugarman and Duke co-authors Drs. Michael Morse and Robert Califf said additional steps need to be taken to further safeguard clinical trial participants. Clinical trials are tests in which limited numbers of people use new or experimental medications and medical devices to ascertain their safety and efficacy. Only after the medications and devices are tested can they obtain approval from the federal Food and Drug Administration for broad-based use.
First and foremost, the authors suggest, a formal method of monitoring must be a part of every clinical trial to review and assess adverse events during trials. In large trials that may take place at many locations, data monitoring committees can perform this task. More importantly, they said information obtained by monitoring committees must be rapidly communicated to institutional review boards (IRBs). In addition, there needs to be a way to help IRBs understand whether an adverse event is caused by a problem from the drug under study or was brought about by a natural course of the disease for which the patient is being treated. Institutional review boards have long been the standard for reviewing and approving a study before it begins and then monitoring its progress to ensure patient safety.
"People in clinical trials are generally sick or are already being treated for a disease. The experts on a data monitoring committee must be able to quickly discern between natural occurrences or actual effects of the disease and what is a truly harmful effect of a study drug," Sugarman said.
Data monitoring committees recently have been required in all federally funded late-phase studies. Traditionally, they report each individual adverse event occurring in a clinical trial, but this practice has made it difficult for IRBs to accurately evaluate the events, particularly when the trial is being conducted at multiple sites throughout the country and, even more so, when studies involve international study sites.
"Moreover, IRBs have become inundated with AERs (adverse event reports) with as many as several hundred reports submitted to IRBs. Some of the excessive burden that AERs create for IRBs may be attributed to confusing terminology in the regulations that govern trials, differing requirements of the governmental regulatory bodies involved in ensuring patient-subject safety and inconsistencies in the regulations themselves," Sugarman said.
In certain cases it is not clear precisely what adverse event reports must be reported, how rapidly they must be reported, who shoulders the main responsibility for reporting or to whom completed reports must be submitted, the authors said. Flooded by adverse event reports and poorly positioned to interpret the emerging trial data, IRBs have tended to focus on optimizing regulatory compliance instead of using adverse event reports to determine whether the risk-benefit assessment for locally enrolled patients is affected. Federal regulations lack provisions about how IRBs should handle these reports once they have been received.
"Simply put, communication between all parties involved in clinical trials must be improved," Sugarman said. "Communication must be better between the IRBs, the data monitoring committees and the sponsors of studies. The information must be condensed and better compiled for enhanced communication. Furthermore, sponsors such as pharmaceutical companies often do not disclose to researchers data on the true meaning of adverse events."
Trials sponsors often possess considerable information from other studies about adverse events, the authors said. They said sponsors should compile and maintain up-to-date information with cumulative summary of adverse events so that IRBs can decide on an ongoing basis whether additional safeguards are required.
The authors also said that safety parameters should be established at the outset of each study. They said data monitoring committees should provide a simple, understandable report to each IRB at appropriate and regular intervals indicating that the safety parameters have not been exceeded and that there are no reasons, based on evolving information concerning the risks and benefits, that the study should not continue.
Finally, the authors urged preventing sponsors from being the sole monitor of a trial, thus removing all potential conflicts of interest.
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