Ep 84 - Critical Appraisal Nugget 4: Intention to Treat

Understanding Intention to Treat in Clinical Trials: A Key Concept for Critical Appraisal Welcome to the St Emlyns podcast! In this episode, Simon Carley and Rick Bodey delve into an essential topic for anyone interested in critical appraisal and clinical trials—Intention to Treat (ITT). This principle is a cornerstone in the analysis of randomized controlled trials (RCTs), crucial for ensuring the validity and applicability of study findings. What is Intention to Treat (ITT)? ITT is a methodological principle used in the analysis of data from RCTs. It requires that participants be analyzed in the groups to which they were originally randomized, regardless of whether they adhered to the treatment protocol. This approach helps maintain the benefits of randomization, such as comparability between groups, and provides a more conservative and realistic estimate of a treatment's effectiveness. The ITT principle is essential because it preserves the randomization process's integrity, ensuring that the groups remain comparable. This comparability helps minimize bias, allowing researchers to attribute differences in outcomes to the interventions rather than to other confounding factors. Importance of ITT in Clinical Trials The ITT principle plays a critical role in RCTs by ensuring that the analysis reflects real-world scenarios where patients may not perfectly adhere to treatment regimens. For example, in a trial comparing a new anticoagulant, Carleyoxaban, to warfarin, ITT analysis would include all participants, even those who did not complete the treatment due to side effects. This comprehensive approach provides a more accurate reflection of the treatment's potential benefits and risks in everyday clinical practice. By including all participants as originally allocated, ITT analysis helps prevent bias introduced by excluding participants who experience adverse effects or switch treatments. This is vital for obtaining a realistic estimate of the treatment's effect, considering real-world complexities such as patient non-compliance. Challenges and Considerations While ITT is the gold standard for RCT analysis, it does come with challenges. One significant challenge is that it can obscure the reasons why participants dropped out or switched treatments. These reasons can provide valuable insights into the treatment's tolerability and feasibility. For instance, in the hypothetical trial with Carleyoxaban, understanding why 50% of participants dropped out could highlight serious side effects that might not be evident from an ITT analysis alone. In some cases, a per-protocol analysis, which includes only those participants who fully adhered to the treatment protocol, can offer additional insights. This type of analysis can help distinguish between a treatment's efficacy (its effect under ideal conditions) and effectiveness (its effect in a typical clinical setting). However, per-protocol analysis can introduce bias by including only those who were more likely to tolerate and benefit from the treatment. ITT vs. Per-Protocol Analysis Per-protocol analysis is particularly valuable in certain situations, such as non-inferiority trials. These trials aim to show that a new treatment is not worse than an existing one. In such cases, per-protocol analysis can provide a more conservative estimate, ensuring that observed differences are not due to adherence variations between groups. For example, in a trial evaluating a new protocol for early discharge of patients with suspected pulmonary embolism, ITT might show no difference in outcomes if many participants did not follow the new protocol. However, a per-protocol analysis could reveal whether the protocol, when followed, led to improved outcomes or safety concerns. Similarly, in trials assessing new medications, ITT can provide a realistic estimate by accounting for dropouts due to side effects. This is crucial for understanding the medication's overall safety and effectiveness in t