Regarding the IND Safety Reporting final rule, the FDA does not want to be too prescriptive concerning thresholds and approaches; however, they note that these reviews focus on a tiny fraction of AEs. Effective aggregate reviews will include both blinded analyses (likely used to identify possible safety signals) and unblinded clinical reviews. Upfront planning will help maintain trial integrity and protect against false signals. Sponsor’s responsibility to address safety concerns can be accomplished through the Program Safety Analysis Plan (PSAP). Statistics becomes a stronger part of the analysis at the program level; we need to look at events in the whole program, especially rare events. What’s more, visual and exploratory analytics can assist in uncovering issues.
The PSAP facilitates holistic looks at the entire program until clinical studies are complete. It is based upon CIOMS VI – CDER doesn’t guide the PSAP. The FDA feels that industry statisticians have done very good work on incorporating the tenets of the PSAP. The Safety Surveillance Plan (SSP) addresses the IND rule and addresses a specific aspect of the PSAP, a much more narrowly focused look, a tiny fraction of the overall safety analysis and reporting. They don’t have to conflict, but the SSP is a subset of the PSAP. We’re looking at serious anticipated events that may become reportable. Just reporting all of them, without looking, would be bizarre. Should only report events once they pass some threshold, make people nervous.
The PSAP (and CIOMS VI) was developed in an era steeped in the review of blinded information. It was written in an era when we never would have thought we would be looking at any unblinded data. When the new guidance is discussed, unblinded review is critical. The PSAP is consistent with ideas that FDA have been promulgating; however, it’s important to look at all of the data, including unblinded data.
[The Aggregate Safety Assessment Planning (ASAP) process, developed by the DIA–ASA Interdisciplinary Safety Evaluation (DAISE) working group, builds on the PSAP and addresses the IND safety reporting final rule.]
The IND Safety Reporting final rule offers an opportunity for sponsors to partner with the FDA to champion safety issues:
- To protect human subjects participating in clinical trials
- To gain an understanding of the aggregate safety profile of drugs as early in their development as possible
- Avoid premature termination of programs that show promise even in the face of certain risks
- Improve the way we identify patients at higher risk so that we can better position effective medicines
The outcomes will be more advantageous the earlier we get involved in this dialogue.