An Audit of Interim Analyses of Randomized Controlled Trials (RCTs) Published in Three High Impact Factor Medical Journals Over a Seven- year Period (2012-2018)

Abstract

Background: Interim analysis is an integral component of clinical research and drug development in particular and helps reduce ‘time to market’ for an intervention or stop further development of unsafe and ineffective interventions. In this audit, we evaluated the extent of use of interim analyses in published RCTs in three leading journals and their impact on regulatory approval. Methodology: RCTs published in JAMA, NEJM and Lancet in the year 2012 to 2018 were extracted. Each RCT was scrutinized using the filter term ‘Interim’. Both descriptive and inferential statistics were used to analyze the data. The factors (therapeutic areas, nature of interventions, source of funding and phases of trials) associated with Interim analysis and its impact on drug approval were analyzed. Results: The majority of RCTs with interim analysis belonged to oncology (27%) and cardiology (17.2%) and were related to drugs (70%). Majority of the RCTs were in phase 3 (56.3%) and funded exclusively by Pharmaceutical industry (36.2%). A total of 2% and 14% studies led to accelerated approval and normal regulatory approval. The choice of alpha spending function was not mentioned in 44.8% studies and 21% studies used O-Brien Fleming method. A total of 18.5% studies were stopped early. The oncology trials, drug as intervention and Phase 3 trials were associated with the conduct of interim analysis which was associated with significantly higher numbers of accelerated and routine regulatory approvals. Conclusion: Majority of the RCTs with interim analysis were from oncology and most did not report a stopping rule. Interventions that were drugs (rather than devices or surgical procedures). and phase 3 trials (relative to other phases of RCTs). were associated with significantly higher number of interim analyses which was also associated with significantly higher number of regulatory approvals.