Pocock SJ, Stone GW. The Primary Outcome Fails – What Next? The New England journal of medicine. 375(9):861-70. 2016. PMID: 27579636 [free full text]
The key questions to ask when the primary outcome is negative:
- Is there some indication of potential benefit?
- Was the trial underpowered?
- Was the primary outcome appropriate (or accurately defined)?
- Was the population appropriate?
- Was the treatment regimen appropriate?
- Were there deficiencies in trial conduct?
- Is a claim of noninferiority of value?
- Do subgroup findings elicit positive signals?
- Do secondary outcomes reveal positive findings?
- Can alternative analyses help?
- Does more positive external evidence exist?
- Is there a strong biologic rationale that favors the treatment?