Changing endpoints

Imagine we are playing monopoly. When it is my turn I roll the die five times in a row then choose the roll I prefer, the one which places my piece on a winning square. Wouldn’t you tell me I cannot do that, accuse me of cheating and walk off? It stands to reason that we should not tolerate the equivalent, the changing of endpoints to gain better results, in clinical trials.

What are “endpoints”?
Before a clinical trial is conducted, endpoints should be specified. These are the outcome measures of interest, for example in a trial of a smoking cessation therapy the primary endpoint would be smoking status and a secondary endpoint might be a reduction in the number of cigarettes.

What is wrong with changing endpoints?
Changing from the pre-specified endpoints once a trial has begun can introduce bias. As in the monopoly analogy, if the endpoints of interest are changed to get ‘better’ results, i.e. more ‘significant’ or publishable results, the trial will produce biased results which do not inform research. This includes the selection of new endpoints which display a trend towards ‘significance’ or endpoints that have been investigated but not reported because they fail to display the desired trend. This increases the chance of false positive (type 1) errors.

Further discussion of problems created by changing endpoints can be found in the very clear and helpful essay by Scott Evans. Also discussed are the reasons why changing endpoints may be appropriate, for example if more accurate biomarkers or outcome measures are discovered which could contribute more up-to-date knowledge. Scott Evans proposes a series of issues that need to be considered in order to assess and handle changes in endpoints in clinical trials.

Are many trials guilty?
Chan et al. assessed the selective reporting of outcomes in 102 trials and, through comparing the published results and their protocols, found that 62% of trials had at least one primary outcome that was changed, introduced or omitted without explanation. Furthermore, Chan et al. sent a questionnaire to the lead investigators and found that 86% (42 out of 49 who responded) denied the existence of unreported outcomes despite evidence otherwise.

This, plus evidence from other reports and examples, suggests that many clinical trials are guilty of changing endpoints during a trial without justification.

What can be done?
Any changes in endpoints should be declared and explained to the registry of the trial and to any journals that manuscripts are submitted to. Some measures are already in place. For example, some journals now require the protocol to be submitted along with the manuscript, but we need more. This should be better ‘policed’, perhaps with people who are employed solely to investigate the selective reporting in trials.

Researchers and trialists should be made more aware of the dangers of changing endpoints. We should all be better informed of the problems that can arise and of the few situations where changing endpoints can be appropriate.

Please read Scott Evans’ short article to further your awareness of why changing trial endpoints is problematic.

See here for definition of Medical Statistics.