Background

This project was initiated in 2009, prior to the FDA’s issuance of the new premarketing safety rule on September 29, 2010 (effective September 28, 2011).  The CTTI project focused on sponsors’ reporting of individual expedited case reports to investigators in multicenter trials.  Investigators have reported receiving large numbers of individual expedited case reports, including reports arising from studies in which the investigators are not participating but which involved the same investigational product.  Frequently, the expedited reports of serious adverse event (SAEs) arise from blinded studies, and the investigators are not told whether the patient had received placebo or a standard comparator rather than the experimental agent. Interpretation of such expedited reports is challenging because the investigators have no empirical base from which to place the SAE in context: they do not know the numerators and denominators to deduce whether the event is related to the experimental treatment; they do not know the details of the protocol for the trials in which they are not participating; and they do not even know whether a given event occurred in a subject actually receiving the experimental treatment.

This CTTI project sought to provide empirical evidence about the system for reporting expedited SAE information to investigators conducting research under an IND and to consider potential modifications that would more efficiently communicate useful information to investigators to enable optimal care of study participants.  The issuance of the new premarketing safety rule makes this study a useful benchmark of the system in place just prior to the new rule.

Goal

Generate empirical evidence about the current U.S. system for reporting unexpected serious adverse events (SAEs) to investigators conducting research under an investigational new drug application (IND), and to consider potential modifications of the current system to more efficiently and effectively inform investigators of these events.

Objectives

• Document the current range of practices for safety monitoring and reporting of unexpected SAEs to investigators (Workstream 1)
• Quantify resources required to manage individual expedited safety reports and assess investigators’ perceptions regarding the value of this information (Workstream 2)
• Compare current practice of submitting individual SAEs with an alternative approach based on the European Commission's guidance (Workstream 3)
• Explore patients' expectations for how investigators should monitor and communicate information about product safety during the conduct of a clinical trial, and explore current practice on how safety monitoring efforts are being conveyed to research participants in the informed consent document (Workstream 4)
• Integrate results of all workstreams and recommend ways to optimize reporting of SAEs to investigators while ensuring human subjects protection (Workstream 5)

 

Methods and Results

Workstream 1

Workstream 2

Workstream 3

Workstream 4

Workstream 5

 

CTTI Recommendations

Team Organization

Funding and Other Support

Financial support was provided by the CTTI general project fund and grant U19 FD003800 from the U.S. Food and Drug Administration (FDA). Volunteer time and donated resources were provided by Accurate Clinical Trials Inc., American College of Clinical Pharmacology, Amgen Inc., Bristol-Myers Squibb, Duke Clinical Research Institute, FDA, Genentech, a member of the Roche group, ICON Clinical Research, Pfizer Inc., PharmaNet Development Group Inc., Roche, sanofi-aventis U.S. LLC, Treatment Action Group, and University of Pennsylvania.

 

Contact Information

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