Outcome pre-specification requires sufficient detail to guard against outcome switching in clinical trials: a case study.

BACKGROUND

Pre-specification of outcomes is an important tool to guard against outcome switching in clinical trials. However, if the outcome is not sufficiently clearly defined, then different definitions could be applied and analysed, with only the most favourable result reported.

METHODS

In order to assess the impact that differing outcome definitions could have on treatment effect estimates, we re-analysed data from TRIGGER, a cluster randomised trial comparing two red blood cell transfusion strategies for patients with acute upper gastrointestinal bleeding. We varied several aspects of the definition of further bleeding: (1) the criteria for what constitutes a further bleeding episode; (2) how further bleeding is assessed; and (3) the time-point at which further bleeding is measured.

RESULTS

There were marked discrepancies in the estimated odds ratios (OR) (range 0.23-0.94) and corresponding P values (range < 0.001-0.89) between different outcome definitions. At the extremes, differing outcome definitions led to markedly different conclusions; one definition led to very little evidence of a treatment effect (OR = 0.94, 95% confidence interval [CI] = 0.37-2.40, P = 0.89), while another led to very strong evidence of a treatment effect (OR = 0.23, 95% CI = 0.11-0.50, P < 0.001).

CONCLUSIONS

Outcomes should be pre-specified in sufficient detail to avoid differing definitions being analysed and only the most favourable result being reported.

TRIAL REGISTRATION

Clinical Trials.gov, NCT02105532 . Registered on 7 April 2014.