Regulatory assessment of drug dissolution profiles comparability via maximum deviation.

In drug development, comparability of dissolution profiles of 2 different formulations is usually assessed using the similarity factor f2 . In practice, the drug dissolution profiles are deemed similar if the f2 exceeds 50, which occurs when a 10% maximum difference in the mean percentage of the dissolved drug at each time point between test and reference formulation is obtained. According to the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) use of the f2 is however restricted by a set of validity conditions. If some of these conditions are not satisfied, the f2 is not considered suitable, and alternative statistical methods are needed. In this article, we propose an inferential framework based on the maximum deviation between curves to test the comparability of drug dissolution profiles. The new methodology is applicable regardless whether the validity criteria of the f2 are met or not. Contrary to the f2 , this approach also integrates the variability of the measurements over time and not only their average. To benchmark our method, we performed simulations informed by 3 real case studies provided by the European Medicines Agency and extracted from dossiers submitted to the Centralised Procedure for Marketing Authorisation Application. In the scenarios of the simulation study, the new method controlled its type I error rate when the maximum deviation was greater than the similarity acceptance limit of 10%. The power exceeded 80% for small values of the maximum deviation, while the test was more conservative for intermediate ones. Our results were also very robust to sampling variations. Based on these positive findings, we encourage applicants to consider the new maximum deviation-based method as a valid alternative to the f2 , especially when the validity criteria of the latter are not met.

The diagnostic value of computed tomography in delayed complications after cochlear implantation.

BACKGROUND: Delayed complications after cochlear implant (CI) surgery can result in the need for revision surgery. Temporal bone computed tomography (tCT) is frequently used in the diagnostic work-up for these patients. AIMS/OBJECTIVES: We aimed to test for the value of tCT in delayed complications after CI surgery. MATERIAL AND METHODS: Retrospective chart review including all patients with CI who were consecutively enrolled in our academic tertiary care centre and received a tCT due to delayed complications between January 2008 and December 2017. RESULTS: A total of 85 patients with a mean age of 28 years at CI surgery were identified. Mean time between CI and tCT was 4.3 years. Reasons for performance of tCT were device malfunction (20%), cephalgia (20%), scalp hematoma/seroma (15.3%), device failure (11.8%), vertigo (10.6%), local infection (7.1%), trauma (5.9%), meningism (3.5%), tinnitus (3.5%) and facial palsy (2.4%). No abnormalities in tCT were detected in 82.4%. However, an abnormal tCT was a predictor for surgical therapy (p < .001). CONCLUSIONS AND SIGNIFICANCE: We recommend the performance of tCT in CI patients with delayed complications to identify or rule out pathology in order to choose the most ideal and relevant individual treatment.