From the Guidelines
Modified intention-to-treat (mITT) analysis in clinical trials is limited by its potential to introduce bias and undermine the benefits of randomization, as evidenced by the most recent and highest quality study 1. The primary limitation of mITT analysis is that it can introduce bias by excluding certain participants after randomization, which compromises the key benefit of randomization in balancing known and unknown confounders between treatment groups. When researchers exclude participants who don't receive treatment or who don't meet specific post-randomization criteria, they risk creating systematic differences between comparison groups that can lead to overestimation of treatment effects.
Key Limitations of mITT Analysis
- Lack of standardization in mITT definitions, with different trials using various criteria for excluding participants, making cross-study comparisons difficult, as noted in 1.
- Reduction in statistical power by decreasing sample size, potentially missing true treatment effects.
- Ethical concerns about excluding data from participants who have contributed to the research.
- Regulatory agencies often prefer the more conservative standard ITT approach that includes all randomized participants regardless of protocol adherence, as it better reflects real-world effectiveness where patient compliance varies, as discussed in 1.
Recommendations for mITT Analysis
- Clearly pre-specify and justify any mITT criteria in the protocol.
- Report both ITT and mITT results for transparency.
- Consider sensitivity analyses to assess the impact of different analytical approaches on the findings, as suggested in 1. By acknowledging these limitations and taking steps to address them, researchers can ensure that their use of mITT analysis is transparent, unbiased, and contributes to the overall quality of clinical trials, ultimately prioritizing morbidity, mortality, and quality of life as the outcome.
From the Research
Limitations of Modified Intention-to-Treat (mITT) Analysis
- The mITT approach can lead to biased estimates of treatment effects if the excluded patients differ from those included in the analysis 2
- The use of mITT can result in an overestimation of efficacy, as seen in chimeric antigen receptor T-cell therapy trials 3
- mITT trials are more likely to report post-randomization exclusions, which can lead to an incomplete picture of the treatment's effectiveness 4, 5
- The descriptions of the mITT approach are often ambiguous, making it difficult to determine the exact methodology used 5
- The use of mITT can be associated with industry sponsorship and authors' conflicts of interest, which can influence the reporting of results 4
- mITT trials may not accurately represent the intention-to-treat principle, which is a key aspect of randomized controlled trials 6, 2
Methodological Limitations
- The mITT approach can lead to a lack of transparency in reporting, making it difficult to identify the exact number of patients who received the treatment 3
- The use of mITT can result in a failure to account for missing data or deviations from protocol, which can impact the validity of the results 5
- The mITT approach may not be suitable for all types of trials, such as those with high rates of non-adherence or loss to follow-up 2
Implications for Clinical Trials
- The use of mITT should be clearly justified and transparently reported in clinical trials 5, 3
- Researchers should consider using alternative analytical approaches, such as intention-to-treat analysis, to provide a more complete picture of the treatment's effectiveness 6, 2
- Regulatory agencies and journals should encourage the use of clear and transparent reporting of analytical methods, including the use of mITT 4, 5