Table 3.

Methodological issues with adaptive design trials in rheumatology

Methodological issues	Dissemination of interim results, especially if not fully blinded or incorporate some subjective element/analyst access to unblinded interim results and how they may influence investigators managing the trial (who must remain unequivocally objective), i.e. operational bias
	Decision-making around early stopping should not be based solely on a statistically significant primary analysis, but should also include results of subgroup analyses and careful assessment of the adequacy of the safety database
	Whether patients who have yet to reach the interim time point should be included in these analyses or not, especially if this influences the potential decision-making
	Results based on P-values alone
	Control of the type I error rate
	Interpretation of study results when the study design has changed as a result of interim analyses
	Rejection of a global null hypothesis across all stages, which may not be sufficient or methodologically sound
	Involvement of sponsor personnel in interim decision-making
	Differential population for recruitment before and after modification, which will affect treatment effect
	Making hypothesis claims from results of interim analyses
	Interim analyses/adaptation choices provide multiple opportunities to show a successful treatment effect (with greater likelihood of doing so than if no such analyses existed), thus introducing inherent multiplicity bias
	The potential to select a modification as a result of an interim analysis that, by random chance, is more favourable than the true value, thus creating bias that will lead to an overestimate of the true treatment effect
	Limiting the opportunity to reflect on the data, including safety issues, and thus limiting the design of future well-thought-through research
	An increase in pressure to make assumptions, even when only limited prior information exists
	Exploratory adaptive design study flaws, which could lead to sub-therapeutic dose selection in subsequent (adequate and well-controlled) trials