Do non-inferiority trials of reduced intensity therapies show reduced effects? A descriptive analysis.

Content Provider	Europe PMC
Author	Aberegg, Scott K Hersh, Andrew M Samore, Matthew H
Copyright Year	2018
Abstract	ObjectivesTo identify non-inferiority trials within a cohort where the experimental therapy is the same as the active control comparator but at a reduced intensity and determine if these non-inferiority trials of reduced intensity therapies have less favourable results than other non-inferiority trials in the cohort. Such a finding would provide suggestive evidence of biocreep in these trials.DesignThis metaresearch study used a cohort of non-inferiority trials published in the five highest impact general medical journals during a 5-year period. Data relating to the characteristics and results of the trials were abstracted.Primary outcome measuresProportions of trials with a declaration of superiority, non-inferiority and point estimates favouring the experimental therapy and mean absolute risk differences for trials with outcomes expressed as a proportion.ResultsOur search yielded 163 trials reporting 182 non-inferiority comparisons; 36 comparisons from 31 trials were between the same therapy at reduced and full intensity. Compared with trials not evaluating reduced intensity therapies, fewer comparisons of reduced intensity therapies demonstrated a favourable result (non-inferiority or superiority) (58.3%vs82.2%; P=0.002) and fewer demonstrated superiority (2.8%vs18.5%; P=0.019). Likewise, point estimates for reduced intensity therapies more often favoured active control than those for other trials (77.8%vs39.7%; P<0.001) as did mean absolute risk differences (+2.5% vs −0.7%; P=0.018).ConclusionsNon-inferiority trials comparing a therapy at reduced intensity to the same therapy at full intensity showed reduced effects compared with other non-inferiority trials. This suggests these trials may have a high rate of type 1 errors and biocreep, with significant implications for the design and interpretation of future non-inferiority trials.
Journal	BMJ Open
Volume Number	8
PubMed Central reference number	PMC5855198
Issue Number	3
PubMed reference number	29500210
e-ISSN	20446055
DOI	10.1136/bmjopen-2017-019494
Language	English
Publisher	BMJ Publishing Group
Publisher Date	2018-03-02
Publisher Place	London
Access Restriction	Open
Rights License	This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Subject Keyword	clinical trials bio-creep putative placebo effect non-inferiority trials
Content Type	Text
Resource Type	Article
Subject	Medicine