PEDIATRICS Vol. 122 No. 3 September 2008, pp. 676-677 (doi:10.1542/peds.2008-0578)
LETTER TO THE EDITOR |
Ciclesonide Noninferiority to Placebo on Growth Velocity
Behrouz Kassai, MD, PhDINSERM, CIC201
UMR 5558
Université de Lyon
Lyon F-69003, France
Université Lyon 1
Faculté de Médecine Lyon Nord
Hospices Civils de Lyon
Lyon F-69008, France
Paediatric Clinical Research Unit (EPICIM)
Hôpital Femme Mère Enfant
Bron F-69677, France
Michel Cucherat, MD, PhD
UMR5558
Université de Lyon
Lyon F-69003, France
Gabriel Bellon, Prof. MD
Université de Lyon
Lyon F-69003, France
Université Lyon 1
Faculté de Médecine Lyon Sud
Hospices Civils de Lyon
Lyon F-69600, France
Department of Pediatric Pneumology
Hôpital Femme Mère Enfant
Bron F-69677, France
To the Editor.—
The use of noninferiority trials is an uncommon but possible way of testing safety. In their recent study, Skoner et al1 assessed the noninferiority between inhaled ciclesonide and placebo on growth velocity after 1 year's follow-up. This noninferiority could be deemed justified only if the efficacy of ciclesonide was warranted in the trial conditions. In case of underuse of the studied treatment, a better safety was obviously achieved. It is not clear from their report, however, whether pulmonary function measured by forced expiratory volume in 1 second (FEV1) had been improved with ciclesonide. Skoner et al stated that FEV1 was maintained in all groups during the study period with similar mean changes from baseline to study end, but they did not clearly indicate whether or to what extent ciclesonide had done better than placebo.
Moreover, in their trial, safety demonstration depended on intention-to-treat analysis, which is biased toward no effect in case of frequent treatment withdrawals. In the Skoner et al trial, 18.1% of the patients in the CIC40 (ciclesonide 40 µg/day) group and 14.2% in the CIC160 (ciclesonide 160 µg/day) group had discontinued double-blind treatment. Per-protocol analysis is guarded against this bias. To adequately interpret their results, we need to have both intention-to-treat and per-protocol analyses. Finally, we do not know whether the use of concomitant treatments was similar between the 2 groups during the study. For instance, if concomitant treatments were used more often in the placebo group and if they decreased the growth, the results may be biased toward noninferiority.
Because the method of noninferiority trials is of delicate use and leads commonly to a false claim of noninferiority2 and relevant questions for patients are mostly answered by superiority trials, the ethics of noninferiority trials have been questioned.3 Skoner et al should follow recommendations for reporting the analysis of data from noninferiority trials and report clinical outcomes relevant for patients and physicians such as the number of daytime and nocturnal symptoms, the need for relief or rescue treatment in each group, and, if available, the quality of life of children who have participated in this study.
REFERENCES
- Skoner DP, Maspero J, Banerji D; Ciclesonide Pediatric Growth Study Group. Assessment of the long-term safety of inhaled ciclesonide on growth in children with asthma. Pediatrics. 2008;121 (1). Available at: www.pediatrics.org/cgi/content/full/121/1/e1
- Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of reporting of noninferiority and equivalence randomized trials.
JAMA. 2006;295
(10):1147
–1151
[Abstract/Free Full Text] - Garattini S, Bertele V. Non-inferiority trials are unethical because they disregard patients' interests. Lancet. 2007;370 (9602):1875 –1877[Medline]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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