Gaps in Publicly Funded Non-Inferiority Trials Highlighted in UK Review

A review of 114 publicly funded non-inferiority (NI) trials in the UK indicates inconsistent adherence to established best practices, particularly in justifying the non-inferiority margin (NIM). The study, published in Trials, underscores the necessity for enhancing the design and reporting of NI trials to bolster their clinical relevance.

Non-Inferiority Trial Design and Challenges

NI trials have gained traction, especially within the National Health Service, as they allow for comparisons of treatments without placebos, focusing on benefits like safety and cost-effectiveness. However, the design introduces complexities, notably in determining the NIM, which defines the acceptable difference between treatments for the novel therapy to be deemed non-inferior.

"Publicly funded NI trials are increasing in popularity and therefore ensuring the guidelines (created with a focus on industry NI trials) are being suitably followed is important to ensure best practice," the study authors wrote.

The investigators found that while NIM reporting was high, justification often lacked statistical evidence, relying more on clinical importance. According to the study, the median NIM was defined at 8% (IQR: 3%-10%) for risk differences and 0.35 (IQR: 0.26-0.43) standardized mean difference for continuous outcomes.

Justification and Analysis Methods

The study revealed that justifications for the chosen margin were more commonly based on clinical relevance (49/62) than statistical considerations (13/62). Furthermore, the primary analysis population was often solely on an intention-to-treat (ITT) basis (49/114). The authors also noted that treatment superiority, though well-described, was not always included as an outcome, being powered for in only about one-third of cases.

Implications and Recommendations

The researchers highlight that the success of a trial should not solely depend on the primary NI outcome but also on confirming secondary outcomes like improved safety. They suggest that improvements in NI trial design and reporting are crucial for identifying innovative treatment alternatives with clinical value.

"By not powering for the superiority outcome, it implies that the success of the trial (and therefore the evaluation of the new treatment) is not dependent on a secondary outcome being declared superior as well as the primary NI outcome being declared non-inferior," the study authors concluded. "Although this will be true for some treatments which are deemed to be more convenient for the patient, benefits such as improved safety (the most commonly used justification for completing a non-inferiority trial) should be confirmed within the trial to demonstrate the new treatment is a worthwhile alternative for use in practice."