Developing, Planning and Conducting an Interim Analysis: Lessons From the DEVOTE Cardiovascular Outcomes Trial (Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events).

BACKGROUND: In 2013, a randomized, double-blind, active comparator-controlled, event-driven cardiovascular outcomes trial (DEVOTE) was initiated to compare the cardiovascular safety of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes at high risk of cardiovascular events. The FDA agreed that an interim analysis could form the basis for an early regulatory approval. We report here the operational model developed to support the DEVOTE interim analysis and the results. METHODS: The interim analysis model was designed to reduce the risk of any confidentiality breaches. The Data Access Management Plan comprehensively described the interim analysis operational processes and procedures to maintain the integrity of the ongoing trial while the interim analysis was conducted, submitted, and acted upon by the FDA, and also until completion of the full trial. Most importantly, those who were unblinded to the interim results were limited to a team of 14 members. RESULTS: A total of 150 first major adverse cardiovascular events were recorded at cut-off for the interim analysis. The estimated hazard ratio was 0.92 (95% CI 0.67, 1.27) and non-inferiority to glargine U100 was confirmed as the upper bound of the confidence interval was below 1.8, as prespecified. Based on these results, the FDA approved the use of degludec and degludec/insulin aspart (IDegAsp) in the United States in 2015 before trial completion. CONCLUSIONS: The DEVOTE interim analysis succeeded as a model by which to conduct an interim analysis and submit confidential data for regulatory review and action while continuing the trial to address a primary hypothesis.

Challenges of defining reliable clinical surrogate end points in haemophilia trials: a critical review.

The success of a treatment in haemophilia patients experiencing a bleeding episode is very difficult to define. A variety of efficacy assessment tools have been developed in an effort to better assess when haemostasis has been achieved. These assessment tools are particularly important for the evaluation of the efficacy of therapeutic agents whose mechanism of action is based on pharmacological activity in haemostasis rather than upon the principle of 'replacement therapy'. This review focuses on a number of efficacy measures, summarizing their methodology and discussing their validity. In addition, future developments and requirements in order to evaluate the effectiveness of haemostatic treatment are discussed. The majority of end points used for evaluation of haemostasis relate to the relief of symptoms arising from bleeds. The results of this review highlight that several efficacy end points are frequently combined in order to provide a more comprehensive assessment of efficacy. Key limitations of current methodology are the subjectivity of assessment by either the patient or clinician, and the incomparability of results between trials.