Non-inferiority trials: design concepts and issues - the encounters of academic consultants in statistics

Ralph B D'Agostino, Joseph M Massaro, Lisa M Sullivan
Statistics in Medicine 2003 January 30, 22 (2): 169-86
Placebo-controlled trials are the ideal for evaluating medical treatment efficacy. They allow for control of the placebo effect and are most efficient, requiring the smallest numbers of patients to detect a treatment effect. A placebo control is ethically justified if no standard treatment exists, if the standard treatment has not been proven efficacious, there are no risks associated with delaying treatment or escape clauses are included in the protocol. Where possible and justified, they should be the first choice for medical treatment evaluation. Given the large number of proven effective treatments, placebo-controlled trials are often unethical. In these situations active-controlled trials are generally appropriate. The non-inferiority trial is appropriate for evaluation of the efficacy of an experimental treatment versus an active control when it is hypothesized that the experimental treatment may not be superior to a proven effective treatment, but is clinically and statistically not inferior in effectiveness. These trials are not easy to design. An active control must be selected. Good historical placebo-controlled trials documenting the efficacy of the active control must exist. From these historical trials statistical analysis must be performed and clinical judgement applied in order to determine the non-inferiority margin M and to assess assay sensitivity. The latter refers to establishing that the active drug would be superior to the placebo in the setting of the present non-inferiority trial (that is, the constancy assumption). Further, a putative placebo analysis of the new treatment versus the placebo using data from the non-inferiority trial and the historical active versus placebo-controlled trials is needed. Useable placebo-controlled historical trials for the active control are often not available, and determination of assay sensitivity and an appropriate M is difficult and debatable. Serious consideration to expansions of and alternatives to non-inferiority trials are needed.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"