KEY POINTS FOR CLINICIANS
- Including all randomized subjects when analyzing randomized controlled trials—the “intention-to-treat” principle—is an important factor in minimizing bias.
- Studies have found that fewer than half of randomized controlled trials reported intention-to-treat analysis.
- Among studies reporting intention-to-treat analyses, fewer than half actually analyzed all randomized subjects.
The randomized controlled trial (RCT) has become the most important test of therapeutic benefit.1 When evaluating an RCT, readers should determine whether the analysis was by intention to treat (ITT).1-4 ITT analysis, often described as “once randomized, always analyzed,”5 is the practice of attributing all participants to the group to which they were randomized, regardless of what subsequently occurred.2,6,7 ITT analysis avoids the problems created by omitting dropouts and noncompliant patients, which can negate randomization, introduce bias, and overestimate clinical effectiveness.2,8
Surveys of the literature found that ITT analysis was reported in 7% to 48% of RCTs8-10; however, reporting ITT analysis does not guarantee that the analysis was conducted properly or that the results promoted by the authors were derived from the ITT analysis. For articles reporting ITT analysis of an RCT, we specifically examined which participants were included in the analysis.
Methods
We searched MEDLINE for abstracts that included the text words “intention to treat” or “intent to treat,” limiting the results to randomized controlled trials published in English during 1999. We entered the resultant studies in a database (FileMaker Pro 4.0; FileMaker, Inc., Santa Clara, CA), ordered them using the database’s random number function, and reviewed the first 100 eligible studies.
Two of us (in a rotating fashion cycling through each pair-wise combination of the 6 authors) were systematically assigned to review each article. We used a structured form (available on request from the authors) to evaluate each article for the number of subjects randomized, the number in the ITT analysis, the number in the primary analysis, which categories of subjects were in the ITT analysis, and where ITT was defined within the article. We defined the primary analysis as the most prominently featured outcome in the abstract. Two of us (R.L.K., J.J.S.) independently assessed whether articles contained a diagram showing the flow of participants through each stage, a feature strongly recommended in the Consolidated Standards of Reporting Trials (CONSORT).3 All coauthors discussed discrepant results and made final determinations using majority voting. We conducted all analyses using SAS software (SAS system for Windows, Release 8.0; SAS Institute, Cary, NC).
Results
The MEDLINE search identified 335 studies. We reviewed 129 articles to obtain 100 eligible studies (Figure). We excluded articles for the following reasons: the words “intent” or “intention” and “treat” did not refer to a method of analysis (14); the study was not an RCT (5); the study involved randomized groups (eg, villages or hospitals) rather than individuals (4); the study presented a secondary analysis of a previously published study (4); the study used a crossover design (1) or described a trial protocol without results (1). The paired reviewers agreed on all abstracted data elements for 83 articles; there was a disagreement on one or more items for the remainder, which were determined by committee.
Of 100 studies selected, 42 included all randomized subjects in the ITT analysis (Table). Among those studies that excluded randomized patients from analysis, the most common reasons given were that the patients received no follow-up after randomization (16) or received none of the allocated treatment (14). For 13 studies, we could not determine which categories of participants were excluded from the ITT analysis.
We used the number of subjects randomized, the number in the ITT analysis, and the number in the primary analysis to determine the proportion of randomized subjects in both the ITT and primary analyses. Ideally, 100% of randomized subjects should be included in the ITT analysis. The proportion of randomized subjects included in the ITT analysis could be determined for 92 studies, and ranged from 69% to 100%, with a median of 99%. Nineteen of the 92 studies (21%) excluded more than 5% of randomized participants from the ITT analysis, while 10 studies (11%) excluded more than 10%.
We could determine the proportion of randomized participants in the primary analysis in 93 studies; it varied from 49% to 100%, with a median of 98.7%. Ten of the 93 studies (11%) excluded more than 20% of participants from the primary analysis. In 16 of the 93 studies (17%), a non-ITT analysis (eg, “per protocol”) was presented as the primary analysis. In these studies, an average of 80.1% (median, 82.4%; range, 49.0% to 92.4%) of randomized patients were included in the primary analysis.