Safety analysis of new medications in clinical trials: a simulation study to assess the differences between cause-specific and subdistribution frameworks in the presence of competing events.

Safety is an essential part of the evaluation of new medications and competing risks that occur in most clinical trials are a well identified challenge in the analysis of adverse events. Two statistical frameworks exist to consider competing risks: the cause-specific and the subdistribution framework. To date, the application of the cause-specific framework is the standard practice in safety analyses. Here we analyze how the safety analysis results of new medications would be affected if instead of the cause-specific the subdistribution framework was chosen. We conducted a simulation study with 600 participants, equally allocated to verum and control groups and a 30 months follow-up period. Simulated trials were analyzed for safety in a competing risk (death) setting using both the cause-specific and subdistribution frameworks. Results show that comparing safety profiles in a subdistribution setting is always more pessimistic than in a cause-specific setting. For the group with the longest survival and a safety advantage in a cause-specific setting, the advantage either disappeared or a disadvantage was found in the subdistribution analysis setting. These observations are not contradictory but show different perspectives. To evaluate the safety of a new medication over its comparator, one needs to understand the origin of both the risks and the benefits associated with each therapy. These requirements are best met with a cause-specific framework. The subdistribution framework seems better suited for clinical prediction, and therefore more relevant for providers or payers, for example.

Indirect comparison of vedolizumab and adalimumab for biologic-naive patients with ulcerative colitis.

AIM: Indirect comparison of efficacy and safety of vedolizumab with adalimumab in biologic-naïve patients with moderate to severe ulcerative colitis (UC). METHODS: Vedolizumab is a gut-selective medication for moderate to severe UC. Since no comparative trials are available for direct comparison of vedolizumab vs adalimumab in UC, a systematic review of literature databases was conducted to identify randomized, placebo-controlled trials of the two drugs in patients with moderate to severe UC after failure of conventional treatment. Studies were screened for eligibility by two reviewers based on predefined inclusion criteria. Bucher's adjusted indirect comparison was used to compare vedolizumab and adalimumab indirectly through placebo as common comparator. RESULTS: One vedolizumab study (GEMINI 1) and three adalimumab studies (ULTRA 1, ULTRA 2 and M10-447) met the eligibility criteria. Baseline characteristics of the included populations were similar in biologic-naïve UC patients across study arms. Although no statistically significant differences between treatments were found for induction efficacy endpoints, there was a trend toward a benefit of vedolizumab over adalimumab. There were also no significant differences between treatments for any maintenance efficacy endpoints, with no clear trend favoring either agent. Vedolizumab exhibited statistically superior maintenance safety compared with adalimumab, with significant reductions in risks of adverse events (relative risk 0.67 [95% confidence interval 0.57-0.80]; p < .0001), serious adverse events (0.20 [0.09-0.42]; p < .0001) and adverse events leading to discontinuation (0.14 [0.05-0.43]; p = .0006). CONCLUSION: This analysis indicates that vedolizumab has comparable efficacy to adalimumab with improved safety in biologic-naïve patients with moderate to severe UC.

Impaired serial visual search in children with developmental dyslexia.

In order to test the hypothesis of attentional deficits in dyslexia, we investigated the performance of children with developmental dyslexia on a number of visual search tasks. When tested with conjunction tasks for orientation and form using complex, letter-like material, dyslexic children showed an increased number of errors accompanied by faster reaction times in comparison to control children matched to the dyslexics on age, gender, and intelligence. On conjunction tasks for orientation and color, dyslexic children were also less accurate, but showed slower reaction times than the age-matched control children. These differences between the two groups decreased with increasing age. In contrast to these differences, the performance of dyslexic children in feature search tasks was similar to that of control children. These results suggest that children with developmental dyslexia present selective deficits in complex serial visual search tasks, implying impairment in goal-directed, sustained visual attention.

Do children with developmental dyslexia show a selective visual attention deficit?

The authors investigated the performance of children with developmental dyslexia on a number of visual tasks requiring selective visual attention. Dyslexic children did not show the overestimation of the left visual field (pseudo-neglect) characteristic of normal adult vision. The performance of dyslexic children in texture segmentation and feature search tasks was identical to that of control children matched for age, gender and intelligence. However, when tested on conjunction tasks for orientation and form, dyslexic children showed shorter reaction times and a dramatically increased number of errors. Differences between the two groups decreased with increasing age. These results suggest that children with developmental dyslexia present selective deficits in visual attention.

Children with developmental dyslexia show a left visual "minineglect".

We investigated the performance of children with developmental dyslexia on a visual line bisection task. Dyslexic children did not show the overestimation of the left visual field (pseudoneglect) characteristic of normal adult vision. These results suggest that children with developmental dyslexia present selective deficits in visual attention, probably involving neural structures located in the right posterior parietal cortex.

Hemispheric differences in the recognition of possible and impossible objects.

Three experiments using a visual half-field technique were conducted to address the question of lateralised processing of three-dimensional aspects of visual stimuli. We used drawings of "possible" and "impossible" triangles and quadrilaterals. In one condition subjects had to decide whether these stimuli were possible (i.e., the depicted figures could exist in the three-dimensional world) whereas in the second condition the task was to distinguish between triangular and quadrangular shapes. All experiments revealed an interaction of task and visual field on discrimination indices (d') suggesting a dissociation of the processing of two- and three-dimensional aspects of visual stimuli. These results are discussed with respect to known perceptual differences between the cerebral hemispheres.