The role of a research administration program in adverse event reporting.

Introduction

Clinical research has endured remarkable and beneficial expansion in the past 25 years, although this growth has resulted in an unprecedented increase in workload for the human research protection system. Most of the expansion in clinical research has been in the form of multicenter trials, which present significant challenges for a local institutional review board (IRB). The dramatic increase in the number of multicenter clinical trials over the past two decades coincides with a tremendous influx of clinical trial funding from industry, which has resulted in the exposure of inadequacies in human subject protection programs developed to manage clinical trials on a smaller scale, usually at single sites (Morse, Califf, & Sugarman, 2001).

One of the leading challenges facing Human Research Protection Programs (HRPPs) is the volume of AE reports that sponsors and clinical investigators file with IRBs. The current process is burdensome, inefficient, and fails to provide IRBs with meaningful information needed to fully ensure the safety of human research participants. The federal Office for Human Research Protections (OHRP) has estimated that approximately 5% of all AEs reported to IRBs actually warrant some level of review; 70% have little or no impact or concern resulting in meaningful action(s) taken by an IRB, and only 25% require resources for assessment or further consideration by an IRB (Weschler, 2004). The current challenge is how to triage the 70% efficiently and address the remaining 30%, while dedicating resources toward action on the small percent of that latter group where an impact can be made. IRBs have a greater responsibility and ability to evaluate AEs at the sites over which they have purview.

As noted by Burman, Reves, Cohn, & Schooley (2001), additional trends include a recent major change in federal oversight that resulted in a three-fold increase in regulatory actions against local IRBs, with a marked increase in regulatory actions against the IRBs of academic medical centers (l in 1997 compared with 14 in 1999). Inadequate review of safety reports was among the list of reasons for regulatory actions by both OHRP and the U.S. Food and Drug Administration (FDA). Recent reviews by the Office of the Inspector General (OIG) of the Department of Health and Human Services (DHHS) and the National Institutes of Health (NIH) concluded that the continuing review process should be reevaluated and that local IRBs should not be required to review off-site (external) safety reports (OIG, 1998; NIH, 1999). On the basis of a series of reports, the OIG concluded that IRBs are now forced to "review too much, too quickly, with too little expertise," and with inadequate resources (OIG, 1998). A major contributing factor to this dismal outlook for HRPPs is the volume of AEs submitted to IRBs for review.

Background

A key factor in the current crisis in the function of local IRBs is the escalation of multicenter clinical trials as the consistent method for the performance of clinical research. Though Data and Safety Monitoring Boards (DSMBs) have become commonplace in multicenter trials, federal rules and regulations concerning human subject protections require that local IRBs bear the fundamental responsibility of research oversight (Morse et al., 2001). Current rules encourage researchers and sponsors to report all unexpected, serious, or related AEs to a number of parties, including IRBs, FDA, and other regulatory and research agencies in the United States.

One AE alone can result in a multitude of reports to various organizations, which in turn must be assessed by the IRB (Weschler, 2005). For multicenter clinical trials, an IRB receives individual external AE reports. The receipt of reports that are not aggregated and that come from disparate sources contributes to confusion and an added workload for the IRB. More importantly, the format of the reports jeopardizes the IRB's ability to make an informed judgment on the appropriate action, if any, to be taken. According to Burman, et al. (2001):

Local IRBs were not designed to handle the initial evaluation and ongoing review required by the rapidly increasing number of multicenter clinical trials. Furthermore, local IRB review of the thousands of safety reports from multicenter clinical trials monopolizes resources without promoting patient safety. (p. 152)

These policies were effective when the majority of clinical studies were conducted at a single site; however, they are producing chaos with the increase in multi-center trials involving multiple researchers and numerous participants. There is certainly a need for IRB review of multicenter trials, but it is not clear that patient safety is enhanced by duplicating this process at the IRB of every study site. AE reporting ideally should provide useful information regarding safety in a clinical trial. The DSMB is chartered to review such duplicate reports of a single AE, while the local IRB's responsibilities should focus only on those AEs involving human subjects of its own institution's studies and continued review of the DSMB's findings (Levine, 2001).

Morse et al. (2001) stated:

Some of the excessive burden that adverse event reports (AERs) create for IRBs may be attributed to following: 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. The FDA requires the investigator to "promptly report to the IRB all unanticipated problems involving risk to human subjects or others". HHS regulations require prompt reporting to the IRB of "any unanticipated problems involving risks to subjects or others". In contrast to myriad requirements for reporting AEs, US regulations lack provisions about how IRBs should handle these reports once they have been received. Flooded by AERs and poorly positioned to interpret the emerging trial data, IRBs have tended to focus on optimizing regulatory compliance instead of using AERs to determine whether the risk-benefit assessment for locally enrolled patients is affected. When the prospect of many individual IRBs in large studies all attempting to replicate an assessment of the safety and efficacy of the therapy of interest is considered, the implications are magnified. At the same time, the enormous amount of work performed by IRB administrators and members to complete these functions is likely to be costly. (p. 1203)

Morse et al. (2001) further observes that

IRBs do not have sufficient statistical or clinical expertise or access to appropriate information to allow them to evaluate properly the issues of safety and benefit that arise in the course of a trial. As a result of these factors, IRBs frequently are unable to translate observations regarding individual AEs into a coherent assessment of the overall risks and benefits for a trial. (p. 1203)

To conduct a valid assessment of an AER, it is necessary to have information beyond that contained in the report itself, such as the number of patients in the study as a whole, the expected frequency of the AE reported, and, in a blinded study, information about whether the patient-subject in questions is receiving the test agent. Information on efficacy is also necessary to weigh risks and benefits. (p. 1202)

When AEs are reported accurately, their potential importance may not be fully recognized if they are not reviewed and classified in a comprehensive and systematic fashion. Such activity would most likely fall under the charter of a DSMB and he arm's length from the IRB. Given the lack of harmonization of guidance on AE reporting policies and the trend towards increased IRB workload and burden, the research administration staff of the Center for Clinical Research at University Hospitals of Cleveland (UHC), developed a systematic process to address the issue of AE reporting and created a strategy for educating the research community.

Purpose

Evaluation and revision of event reporting policies and procedures by a research administration program are completed with the intent to improve the effectiveness and efficiency of the IRB in the protection of human research participants. The goals of the research administration program aim to interpret policy guidelines in compliance with current regulations, assess the impact of a revised event reporting policy on the quality and quantity of review, and develop a pilot collaborative educational strategy between the research administration office and the research community with regards to event reporting.

Design and Methods