More from the FDA Focus Group I attended in 2016, regarding how companies become aligned with the spirit of the IND Safety Reporting final rule…
There is a preference, mostly driven by current operational issues, for developing and using a Safety Assessment Committee (SAC) for program-level safety assessments and not a traditional Data Monitoring Committee (DMC). Blinded analyses are not discouraged; however, effective review of possible safety signals should be performed on unblinded data by clinical experts. There was agreement on challenges in developing appropriate thresholds; however, the FDA emphasized that clinical judgment, not statistical significance, should drive the reviews. Again, trial integrity is of critical importance.
- DMCs don’t meet often enough, though they could.
- They don’t have all of the necessary expertise; if they did, it would be appropriate.
- They are focused on a particular trial, making assessments based on that one trial; the SAC should be responsible for the whole program (if a company had several similar molecules, an SAC could oversee all of that).
- Stopping or continuing or modifying a trial is different at Phase 2, more similar in Phase 4 – when you are doing comparative effectiveness; answer is different based on the type of trial you are doing and where you are.
- Sometimes it may be appropriate to use a DMC.
A DMC is not the recommended team to be utilized in aggregate program-level safety assessments. DMCs do not usually have enough regularly scheduled meetings and likely lack the clinical expertise required (such as toxicity expertise or product specific knowledge). Another limitation is that they are usually study specific and not reviewing across the compound, unlike the SAC which would perform reviews at a program level. However, if they were to be appropriately resourced it could be a possible approach [this is clarified in the new draft DMC guidance].