Docket Management
Docket: 00N-1484 - Safety Reporting Requirements for Human Drug & Biological Products
Comment Number: EC -7

Accepted - Volume 1

Comment Record
Commentor Dr. James Nickas Date/Time 2003-03-19 11:46:26
Organization Genentech, Inc
Category Health Professional

Comments for FDA General
1. General Comments COMMENTS ON INVESTIGATOR REPORTING In pre-marketing clinical trials, it is common practice for sponsors to instruct investigators via the protocol to report and record all treatment emergent adverse events (TEAEs) regardless of causal attribution. The ICH E9 guidance document defines treatment emergent as an event that emerges during treatment having been absent pre-treatment, or worsens relative to the pre-treatment state. This definition would seemingly capture all adverse events potentially related to treatment, and is probably the most appropriate capture definition for the purposes of safety analyses. The Agency is proposing that investigators be required to report to the sponsor any serious SADR (as defined in 312.32(a)) immediately and any other SADR (as defined in 312.32(a))promptly unless the protocol or investigator's brochure specifies a different timetable for reporting the SADR. If the Agency's SADR definition is implemented as proposed, it is conceivable that investigators won't report certain TEAEs (as defined previously) if they feel a casual relationship can be ruled out. Since there are no standard guidelines for ruling out a possible causal relationship, there could be inconsistent causality assessments and adverse event reporting across study sites. The Agency should consider simply requiring investigators to report protocol-defined TEAEs (serious TEAEs expeditiously) and to record their best causality assessment when reporting such events. Upon receipt of reports of serious TEAEs that are deemed possibly related to the study treatment by either the investigator or the sponsor, the sponsor would in turn submit those that are classified as unexpected (per the investigator's brochure) to the Agency and all applicable investigators as expedited safety reports. What is desperately needed is Agency guidance on what should be considered expected for regulatory reporting purposes. If the bar is simply any event listed in the investigator brochure, then sponsors may add long laundry lists of all observed AEs in investigator brochures and classify most events as expected for regulatory reporting purposes. If this is done, the Agency may not receive potentially important safety reports in real time. It would be helpful to provide guidance on what safety information to include in an IB and what subset should be considered expected for regulatory reporting purposes. My bias is that only adverse events that are listed in the investigator brochure for which a causal relationship is suspected, reasonably established or inferred (i.e., evidence-based) should be classified as expected for regulatory reporting purposes.

EC -7