Format

Send to

Choose Destination
Clin Trials. 2012 Feb;9(1):48-55. doi: 10.1177/1740774511420743. Epub 2011 Sep 23.

Beyond the intention-to-treat in comparative effectiveness research.

Author information

1
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. miguel_hernan@post.harvard.edu

Abstract

BACKGROUND:

The intention-to-treat comparison is the primary, if not the only, analytic approach of many randomized clinical trials.

PURPOSE:

To review the shortcomings of intention-to-treat analyses, and of 'as treated' and 'per protocol' analyses as commonly implemented, with an emphasis on problems that are especially relevant for comparative effectiveness research.

METHODS AND RESULTS:

In placebo-controlled randomized clinical trials, intention-to-treat analyses underestimate the treatment effect and are therefore nonconservative for both safety trials and noninferiority trials. In randomized clinical trials with an active comparator, intention-to-treat estimates can overestimate a treatment's effect in the presence of differential adherence. In either case, there is no guarantee that an intention-to-treat analysis estimates the clinical effectiveness of treatment. Inverse probability weighting, g-estimation, and instrumental variable estimation can reduce the bias introduced by nonadherence and loss to follow-up in 'as treated' and 'per protocol' analyses.

LIMITATIONS:

These analyse require untestable assumptions, a dose-response model, and time-varying data on confounders and adherence.

CONCLUSIONS:

We recommend that all randomized clinical trials with substantial lack of adherence or loss to follow-up are analyzed using different methods. These include an intention-to-treat analysis to estimate the effect of assigned treatment and 'as treated' and 'per protocol' analyses to estimate the effect of treatment after appropriate adjustment via inverse probability weighting or g-estimation.

PMID:
21948059
PMCID:
PMC3731071
DOI:
10.1177/1740774511420743
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center