Deficient Reporting and Interpretation of Non-Inferiority Randomized Clinical Trials in HIV Patients: A Systematic Review

Adrian V Hernandez,Priyaleela Thota,Jaime A Collins,Abhishek Deshpande,Vinay Pasupuleti,Jose E Vidal,Landon Myer

doi:10.1371/journal.pone.0063272

Abstract

ObjectivesNon-inferiority (NI) randomized clinical trials (RCTs) commonly evaluate efficacy of new antiretroviral (ARV) drugs in human immunodeficiency virus (HIV) patients. Their reporting and interpretation have not been systematically evaluated. We evaluated the reporting of NI RCTs in HIV patients according to the CONSORT statement and assessed the degree of misinterpretation of RCTs when NI was inconclusive or not established.DesignSystematic review.MethodsPubMed, Web of Science, and Scopus were reviewed until December 2011. Selection and extraction was performed independently by three reviewers.ResultsOf the 42 RCTs (n = 21,919; range 41–3,316) selected, 23 were in ARV-naïve and 19 in ARV-experienced patients. Twenty-seven (64%) RCTs provided information about prior RCTs of the active comparator, and 37 (88%) used 2-sided CIs. Two thirds of trials used a NI margin between 10 and 12%, although only 12 explained the method to determine it. Blinding was used in 9 studies only. The main conclusion was based on both intention-to-treat (ITT) and per protocol (PP) analyses in 5 trials, on PP analysis only in 4 studies, and on ITT only in 31 studies. Eleven of 16 studies with NI inconclusive or not established highlighted NI or equivalence, and distracted readers with positive secondary results.ConclusionsThere is poor reporting and interpretation of NI RCTs performed in HIV patients. Maximizing the reporting of the method of NI margin determination, use of blinding and both ITT and PP analyses, and interpreting negative NI according to actual primary findings will improve the understanding of results and their translation into clinical practice.

Highlights

Non-inferiority (NI) randomized controlled trials (RCT) are standard research methodology to demonstrate that a new experimental treatment is not worse than reference therapy in terms of efficacy
There is poor reporting and interpretation of NI RCTs performed in Human immunodeficiency virus (HIV) patients
Maximizing the reporting of the method of NI margin determination, use of blinding and both ITT and per protocol (PP) analyses, and interpreting negative NI according to actual primary findings will improve the understanding of results and their translation into clinical practice

Summary

Introduction

Non-inferiority (NI) randomized controlled trials (RCT) are standard research methodology to demonstrate that a new experimental treatment is not worse than reference therapy (active comparator) in terms of efficacy. Increased efficacy rates of highly active antiretroviral therapies (HAART) have reduced space for newer antiretroviral agents with better efficacies [2], there is need for treatment simplification and newer alternative agents. This has led to a growing number of HIV NI trials in recent years. The extended Consolidated Standards of Reporting Trials (CONSORT) statement of 2006 [3] has updated recommendations to guide the conduct and reporting of NI trials. Other basic requirements of a well-designed NI trial would be sample size calculation taking NI margin into account, a clear description of the use of 1- or 2-sided confidence intervals and both per protocol (PP) and intention-to-treat (ITT) analysis [7]

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