Preregistration of study design and non-inferiority margin

Abstract

www.thelancet.com Vol 381 January 12, 2013 115 an active comparator with respect to change in HbA1c (in addition to showing superiority over placebo in separate studies). Furthermore, we also disagree that a non-inferiority trial cannot show any additional value of a new drug, since this design does not preclude explor ation of other potential benefi ts via secondary endpoints. In fact, the EMA guidance describes the importance of balancing the margin of potential inferiority against possible clinical advantages, including tolerability and cardiovascular risk profi le—outcomes which we assessed in our study by doing prespecifi ed inferential statistical analyses of hypoglycaemia, bodyweight, and cardio vascular events. Indeed, the cardiovascular hazard ratio for linagliptin versus glimepiride in our study provided a hypothesis-generating signal, which is currently being tested in a large cardiovascular outcomes study (CAROLINA; NCT01243424). Van Hateren and colleagues incorrectly imply that the non-inferiority design and study endpoints were not prespecifi ed. The full study protocol— including a complete description of the non-inferiority design and margin, and all the study endpoints (primary, secondary, and exploratory)—was fi nalised in October, 2007, after review and approval by regulatory authorities, and the fi rst patient was subsequently enrolled in February, 2008. It is clear from the FDA’s publicly available medical review of linagliptin that our study’s protocol was prespecifi ed and approved by regulatory authorities. Moreover, the study protocol was submitted to The Lancet together with our paper and was available for peer review. ClinicalTrials.gov provides summary detail rather than a complete repository of all information pertaining to clinical studies, and there is no place to capture the element of non-inferiority design. Indeed, a preliminary search of safety, and tolerability of linagliptin compared with glimepiride. Neither the non-inferiority design, nor the margin of 0·35%, was mentioned. Moreover, of the 27 secondary outcome measures, 26 were added to ClinicalTrials.gov on Feb 17, 2012, whereas the trial took place between Feb 12, 2008, and Dec 12, 2010. In our view, it is essential to prespecify the exact study design and the non-inferiority margin, and to publish that information, preferably before the study starts. When this information is not in the trial registry, the study protocol should be published and referred to in the paper.