Non-inferiority trials: determining whether alternative treatments are good enough.

New treatments that are potentially as effective as existing treatments are increasingly being developed, some of which may be preferred because of lower cost, fewer side effects, easier administration or less harm. Non-inferiority trials attempt to establish whether or not a new treatment -- drug or non-drug -- is no worse than an established treatment for which efficacy has been determined in placebo-controlled trials. Critical issues in the design and conduct of non-inferiority trials include: defining the acceptable margin of adverse events that, if exceeded, will render the new treatment inferior to the standard treatment (the non-inferiority margin); calculating the sample size needed to demonstrate non-inferiority; assessing the robustness of results in terms of absolute versus relative effects, intention-to-treat versus per-protocol analyses, one-sided versus two-sided statistical tests, and observed versus expected event rates for standard treatment; evaluating all relevant outcomes, including harm; and stating conclusions that are consistent with aims and results. Many non-inferiority trials fail to meet basic quality criteria, report biased and misleading conclusions, and are unduly influenced by commercial sponsors, with some commentators going so far as labelling them unethical. Clinicians and trial investigators need to exercise caution when interpreting results of non-inferiority trials which, because they lack a placebo group, can only provide an indirect assessment of the efficacy of a new treatment compared with an existing standard, and where the choice of non-inferiority margin can be highly subjective.