The European Medicines Agency Review of Crizanlizumab for the Prevention of Recurrent Vaso-Occlusive Crises in Patients With Sickle Cell Disease.

Crizanlizumab is a monoclonal antibody that binds to P-selectin. On October 28, 2020, a conditional marketing authorization valid through the European Union (EU) was issued for crizanlizumab for the prevention of recurrent vaso-occlusive crises (VOCs) in patients with sickle cell disease aged 16 years or older. Crizanlizumab was evaluated in a phase 2, double-blind, placebo-controlled randomized multicenter trial comparing high-dose (5 mg/kg) crizanlizumab, low-dose (2.5 mg/kg) crizanlizumab and placebo in patients with a history of 2-10 VOCs in the previous year. Patients who were receiving concomitant hydroxycarbamide (HC) as well as those not receiving HC were included in the study. The primary endpoint of the trial was the annual rate of sickle cell-related pain crises as adjudicated by a central review committee. High-dose crizanlizumab led to a 45.3% lower median annual rate of sickle cell-related pain crises compared to placebo (P = 0.010), with no statistically significant difference for the low dose. Treatment with high-dose crizanlizumab led to similar incidences of adverse events (AEs), grade 3 AEs, and serious AEs compared to placebo. Most frequently observed AEs that occurred more often in the crizanlizumab arm compared to placebo were infusion related reactions (34.8% versus 21%), arthralgia (18.2% versus 8.1%), diarrhea (10.6% versus 3.2%), and nausea (18.2% versus 11.3%). The aim of this article is to summarize the scientific review of the application leading to regulatory approval in the EU.

Positive central lymph-nodes are underdiagnosed in patients with Bethesda V cytology in an endemic goiter region.

BACKGROUND: Fine needle aspiration (FNA) is a significant diagnostic procedure for detecting malignancy in patients with nodular thyroid disease. A high proportion of patients with cytological diagnosed follicular neoplasia (Bethesda IV and V) ultimately have thyroid cancer. The aim of this study was to evaluate the incidence of preoperatively undiagnosed central lymph node metastasis in patients with multinodular goiter (MNG). METHODS: Patients who underwent FNA and were classified as Bethesda IV/V were included. Applying a radical approach, all patients underwent (hemi)thyroidectomy and prophylactic unilateral central neck dissection. RESULTS: During our study period 2009-2013, 60 patients (19.7%) were classified as Bethesda IV and 21 (6.9%) Bethesda V. Final histopathological results revealed malignancy in 35 (43.2%) of 81 Bethesda IV/V nodules. Of the nodules classified as Bethesda IV, 20 (33.3%) showed malignancy in the final histology. Ten patients (16.7%) had papillary micro-carcinoma (mPTC, <10 mm), 4 (6.6%) PTC and 6 (10%) follicular thyroid cancer. Fifteen of 21 (71.4%) Bethesda V nodules were revealed as PTC of whom seven (33.3%) patients also had lymph-node metastases. CONCLUSIONS: While 33.3% of the patients with PTC, preoperatively classified as Bethesda V, had previously undetected positive lymph-nodes, only one patient with Bethesda IV had lymph-node metastasis.

Comparison of Spectralis and Cirrus spectral domain optical coherence tomography for the objective morphometric assessment of the neuroretinal rim width.

PURPOSE: The assessment of cup-disc ratio as a surrogate parameter for the neuroretinal rim width (NRW) of the optic nerve is well established, but prone to human error and imprecision. Objective assessment of the NRW is provided by spectral domain optical coherence tomography (SD-OCT). This study is the first to systematically compare NRW measurements acquired with the Carl Zeiss Meditech Cirrus HD-OCT 5000 and the Heidelberg Engineering Spectralis SD-OCT. METHODS: In this cross-sectional study, 20 eyes of each 20 glaucoma patients and 20 age-matched healthy controls underwent ophthalmic examination, SD-OCT imaging, and computer perimetry. Regression analyses were performed for the NRW comparability and the effect of the rotational alignment disconcordance (RAD), receiver-operating characteristics (ROC) for NRW-based healthy glaucoma discrimination capability, and Pearson's correlation for covariate association. RESULTS: Mean NRW differences were 8 ± 48 µm (p = 0.4528), 91 ± 80 µm (p < 0.01), and 49 ± 77 µm (p < 0.001) in the glaucoma, healthy, and whole group. On average, the Cirrus showed higher NRW values (+ 50 µm) than the Spectralis, this difference increased with values starting with 159 µm. Discrimination ROC were 1.0 (Spectralis) and 0.9675 (Cirrus). RAD showed very little effect on NRW (R2 = 0.9661, p < 0.001). NRW-covariate correlation was highly significant (p < 0.001) with both devices for clinical cup/disc ratio, calculated rim width, visual field mean, and pattern deviations. CONCLUSIONS: Our results suggest to only cautiously compare Spectralis and Cirrus NRW measurements only in patients with morphologically manifest glaucoma. For morphological progression analysis, we recommend the continuous usage of the same device.

Methods for the analysis of multiple endpoints in small populations: A review.

While current guidelines generally recommend single endpoints for primary analyses of confirmatory clinical trials, it is recognized that certain settings require inference on multiple endpoints for comprehensive conclusions on treatment effects. Furthermore, combining treatment effect estimates from several outcome measures can increase the statistical power of tests. Such an efficient use of resources is of special relevance for trials in small populations. This paper reviews approaches based on a combination of test statistics or measurements across endpoints as well as multiple testing procedures that allow for confirmatory conclusions on individual endpoints. We especially focus on feasibility in trials with small sample sizes and do not solely rely on asymptotic considerations. A systematic literature search in the Scopus database, supplemented by a manual search, was performed to identify research papers on analysis methods for multiple endpoints with relevance to small populations. The identified methods were grouped into approaches that combine endpoints into a single measure to increase the power of statistical tests and methods to investigate differential treatment effects in several individual endpoints by multiple testing.

Applicability and added value of novel methods to improve drug development in rare diseases.

BACKGROUND: The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. METHODS: The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. RESULTS AND DISCUSSION: Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. CONCLUSION: Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes.