Optimizing Expedited Safety Reporting for Drugs and Biologics Subject to an Investigational New Drug Application

Abstract

In September 2010, the US Food and Drug Administration (FDA) published a final rule governing the requirements for expedited safety reporting for products subject to an investigational new drug application. The rule clarified the types of safety information that qualify for expedited reporting. Its intent was to improve the overall quality of safety reporting by reducing the number of uninterpretable individual reports sent to the FDA and clinical investigators. In December 2011, we surveyed pharmaceutical and biotechnology sponsors regarding their safety reporting practices. We convened a group of experts and a biostatistics work group to review the survey results and identify gaps between current practice and the final safety reporting rule. Most sponsors had not changed their approach to expedited reporting of serious adverse events. We devised recommendations to help sponsors optimize their premarket safety systems to reduce the number of uninformative expedited reports and ensure recognition of important safety issues for an investigational drug as early as possible in development.

The FDA's Final Rule on Expedited Safety Reporting: Statistical Considerations

“…The recommendations here are slight modifications of the ones listed in Archdeacon et al (2014). Some of these are included, at least in part, in the December 2012 Guidance (U.S. Department of Health and Human Services and Food and Drug Administration 2012).…”

“…Pharmaceutical sponsors typically record serious adverse events in both a clinical trial database and a global safety database for the purpose of regulatory reporting (Archdeacon et al 2014). They add these events to the global safety database as soon as the investigator reports them to the sponsor.…”

“…Following the meeting, the Biostatistics Working Group was asked to confer among themselves to provide statistical advice to CTTI concerning implementation of the Final Rule. Archdeacon et al (2014) described the survey, the expert meeting, and the formation of the Biostatistics Working Group.…”

The Majority of Expedited Investigational New Drug Safety Reports Are Uninformative

“…Over 5 years after publication of the final rule, the majority (86%) of expedited safety reports are uninformative. Barriers to the adoption of new procedures for optimal management of IND safety reporting by commercial sponsors have been examined by the Clinical Trials Transformation Initiative (5). Perceived barriers of sponsors include lack of international harmonization for reporting rules, liability risks, and lack of clarity of threshold rules for aggregate reporting.…”

Methods for safety and endpoint ascertainment: identification of adverse events through scrutiny of negatively adjudicated events

“…Study personnel and sponsors fulfill this responsibility by reporting certain types of AEs to experimental products to regulatory authorities promptly [7]. However, reactions to investigational products require knowledge of treatment assignment [8]. The need for both blinded physician adjudication of trial endpoint events and unblinded safety data reporting, a more rapid turnaround time for reporting safety events compared with COEs, and the need for committee review of COEs but not safety events, has therefore resulted in separate processes for COE adjudication and safety monitoring in most cases.…”