Non-inferiority trials: methodological and regulatory challenges

This thesis discusses methodological challenges in non-inferiority trials and the role of regulatory guidelines in these trials. From a methodological perspective, non-inferiority trials have special challenges in design and analysis that can influence proper interpretation of results. Most importantly, there are different methods for determining the threshold for saying that one pharmaceutical is not worse than its active comparator (the non-inferiority margin). This choice of method is not guided by clear regulations. This thesis reports that in most cases of previous non-inferiority trials, how non-inferiority margins were established was not clear. In one fifth of the cases, determination of the margin was not supported by a proper clinical or statistical judgment, but based on the subjective judgment of the investigator. We conclude that determination of the non-inferiority margin needs to be improved, for instance by straightforward regulatory guidance on this matter. Better regulations could also guide researchers on questions like when to conduct non-inferiority trials. In addition, non-inferiority trials could benefit from an improved dialogue between researchers and regulators on how to solve specific issues.

Results

• Non-inferiority trials: methodological and regulatory challenges (thesis)
• Wangge G, Klungel OH, Roes KC, De Boer A, Hoes AW, Knol MJ. Interpretation and inference in noninferiority randomized controlled trials in medicine research. In: Clin Pharmacol Ther, 2010; 88(3): 420-3. (journal publication)
• Wangge G, Klungel OH, Roes KC, De Boer A, Hoes AW, Knol MJ. Room for improvement in conducting and reporting non-inferiority randomized controlled trials on medicines: a systematic review. In: PLoS One, 2010; 5(10): e13550. (journal publication)
• Wangge G, Klungel OH, Roes KC, De Boer A, Hoes AW, Knol MJ. Should non-inferiority drug trials be banned altogether? In: Drug Discovery Today, 2013. (journal publication)
• Wangge G, Roes KC, De Boer A, Hoes AW, Knol MJ. The challenges of determining noninferiority margins: a case study of noninferiority randomized controlled trials of novel oral anticoagulants. In: CMAJ, 2013; 185(3): 222-7. (journal publication)