Quality of Reporting of Noninferiority and Equivalence Randomized Trials

Institut National de la Santé et de la Recherche Médicale (INSERM) U738, Paris, France.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 04/2006; 295(10):1147-51. DOI: 10.1001/jama.295.10.1147
Source: PubMed


Noninferiority and equivalence trials aim to show that the experimental treatment is not clinically worse than (noninferior) or clinically similar to (equivalent) a control active treatment. These study objectives imply particular planning and analysis.
To assess the methodologic quality of reports of randomized controlled trials of noninferiority and equivalence.
We searched MEDLINE and the Cochrane Central Register of Controlled Trials for reports of randomized controlled trials of noninferiority and equivalence hypotheses published between January 1, 2003, and December 31, 2004.
Data extracted by use of a standardized form involved assessment of choice of noninferiority or equivalence margins, sample size calculation, sets of patients analyzed, method of statistical testing and reporting results, and conclusions.
A total of 162 reports were included in the analysis (116 reports of noninferiority and 46 of equivalence). The margin defining noninferiority or equivalence was described in most reports (156 [96.3%]), with justification of the margin in only 33 (20.4%). Almost one quarter of the reports (35 [21.6%]) did not describe a sample size calculation, and an additional 11 (6.8%) did not take into account a prespecified noninferiority or equivalence margin. Less than half of the reports (69 [42.6%]) described both an intent-to-treat (ITT; all randomized patients are included in the analysis) or modified ITT (patients who never received treatment are excluded) and per-protocol (patients who did not complete the treatment are excluded) analysis, and only about half of those (39 [56.5%]) described both types of results. Results were displayed with confidence intervals in 136 reports (84.0%). Only 33 articles (20.3%) fulfilled reporting requirements specific to noninferiority and equivalence trials, 4 of them (12.1%) with misleading conclusions.
Reporting of noninferiority and equivalence trials has important deficiencies: absence of noninferiority or equivalence margin, only an ITT (or a per-protocol) analysis performed, and results not adequately reported. Moreover, even for articles fulfilling these requirements, conclusions are sometimes misleading.

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Available from: Philippe Ravaud
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    • " coded data were then exported to STATA - 11 ( StataCorp LP , College Station , TX , USA ) for analysis . We analysed data at individual level rather than at cluster level and all analyses were adjusted for clustering . In accordance with recommendations for analysing and reporting equivalence studies , both ITT and PP analyses were performed ( Le Henanff et al . 2006 ; Piaggio et al . 2006 ) . The ITT analyses included all chil - dren enrolled in the study . The PP analyses excluded children who defaulted , transferred out of the pro - gramme , were lost to follow up after inpatient transfer or switched RUTF . Summary enrolment characteristics for each arm were calculated as mean Ϯ standard deviatio"
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    ABSTRACT: Community-based Management of Acute Malnutrition using ready-to-use therapeutic food (RUTF) has revolutionised the treatment of severe acute malnutrition (SAM). However, 25% milk content in standard peanut-based RUTF (P-RUTF) makes it too expensive. The effectiveness of milk-free RUTF has not been reported hitherto. This non-blinded, parallel group, cluster randomised, controlled, equivalence trial that compares the effectiveness of a milk-free soy-maize-sorghum-based RUTF (SMS-RUTF) with P-RUTF in treatment of children with SAM, closes the gap. A statistician randomly assigned health centres (HC) either to the SMS-RUTF (n = 12; 824 enrolled) or P-RUTF (n = 12; 1103 enrolled) arms. All SAM children admitted at the participating HCs were enrolled. All the outcomes were measured at individual level. Recovery rate was the primary outcome. The recovery rates for SMS-RUTF and P-RUTF were 53.3% and 60.8% for the intention-to-treat (ITT) analysis and 77.9% and 81.8% for per protocol (PP) analyses, respectively. The corresponding adjusted risk difference (ARD) and 95% confidence interval, were -7.6% (-14.9, 0.6%) and -3.5% (-9,6., 2.7%) for ITT (P = 0.034) and PP analyses (P = 0.257), respectively. An unanticipated interaction (interaction P < 0.001 for ITT analyses and 0.0683 for PP analyses) between the study arm and age group was observed. The ARDs were -10.0 (-17.7 to -2.3)% for ITT (P = 0.013) and -4.7 (-10.0 to 0.7) for PP (P = 0.083) analyses for the <24 months age group and 2.1 (-10.3,14.6)% for ITT (P = 0.726) and -0.6 (-16.1, 14.5) for PP (P = 0.939) for the ≥24 months age group. In conclusion, the study did not confirm our hypothesis of equivalence between SMS-RUTF and P-RUTF in SAM management.
    Full-text · Article · Jun 2013 · Maternal and Child Nutrition
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    • "With respect to the analysis, the guidelines state that both ITT and PP analysis have equal importance in noninferiority and equivalence trials [5,12] , since both analyses can be biased. However, nearly half of the reports stated the results of both analyses, which is similar to the percentage in the period before publication of the CONSORT extension [10] . Trials published in highimpact journals showed only slightly better results. "
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    ABSTRACT: Background Non-inferiority and equivalence trials require tailored methodology and therefore adequate conduct and reporting is an ambitious task. The aim of our review was to assess whether the criteria recommended by the CONSORT extension were followed. Methods We searched the Medline database and the Cochrane Central Register for reports of randomised non-inferiority and equivalence trials published in English language. We excluded reports on bioequivalence studies, reports targeting on other than the main results of a trial, and articles of which the full-text version was not available. In total, we identified 209 reports (167 non-inferiority, 42 equivalence trials) and assessed the reporting and methodological quality using abstracted items of the CONSORT extension. Results Half of the articles did not report on the method of randomisation and only a third of the trials were reported to use blinding. The non-inferiority or equivalence margin was defined in most reports (94%), but was justified only for a quarter of the trials. Sample size calculation was reported for a proportion of 90%, but the margin was taken into account in only 78% of the trials reported. Both intention-to-treat and per-protocol analysis were presented in less than half of the reports. When reporting the results, a confidence interval was given for 85% trials. A proportion of 21% of the reports presented a conclusion that was wrong or incomprehensible. Overall, we found a substantial lack of quality in reporting and conduct. The need to improve also applied to aspects generally recommended for randomised trials. The quality was partly better in high-impact journals as compared to others. Conclusions There are still important deficiencies in the reporting on the methodological approach as well as on results and interpretation even in high-impact journals. It seems to take more than guidelines to improve conduct and reporting of non-inferiority and equivalence trials.
    Full-text · Article · Nov 2012 · Trials
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    • "Equivalence trials are usually parallel-group trials including a large number of patients (the smaller the margin, the larger the number of patients) and clinical outcomes. Some previous methodological reviews [16], [17] assessed the quality of reporting for noninferiority and/or equivalence trials and showed important deficiencies, but to our knowledge, this is the first review focusing on bioequivalence trials. "
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    ABSTRACT: Generic drugs are used by millions of patients for economic reasons, so their evaluation must be highly transparent. To assess the quality of reporting of bioequivalence trials comparing generic to brand-name drugs. PubMed was searched for reports of bioequivalence trials comparing generic to brand-name drugs between January 2005 and December 2008. Articles were included if the aim of the study was to assess the bioequivalency of generic and brand-name drugs. We excluded case studies, pharmaco-economic evaluations, and validation dosage assays of drugs. We evaluated whether important information about funding, methodology, location of trials, and participants were reported. We also assessed whether the criteria required by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) to conclude bioequivalence were reported and that the conclusions were in agreement with the results. We identified 134 potentially relevant articles but eliminated 55 because the brand-name or generic drug status of the reference drug was unknown. Thus, we evaluated 79 articles. The funding source and location of the trial were reported in 41% and 56% of articles, respectively. The type of statistical analysis was reported in 94% of articles, but the methods to generate the randomization sequence and to conceal allocation were reported in only 15% and 5%, respectively. In total, 65 articles of single-dose trials (89%) concluded bioequivalence. Of these, 20 (31%) did not report the 3 criteria within the limits required by the FDA and 11 (17%) did not report the 2 criteria within the limits required by the EMA. Important information to judge the validity and relevance of results are frequently missing in published reports of trials assessing generic drugs. The quality of reporting of such trials is in need of improvement.
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