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A sequential bioequivalence design with a potential ethical advantage.

ABSTRACT: This paper introduces a two-stage approach for evaluation of bioequivalence, where, in contrast to the designs of Diane Potvin and co-workers, two stages are mandatory regardless of the data obtained at stage 1. The approach is derived from Potvin's method C. It is shown that under circumstances with relatively high variability and relatively low initial sample size, this method has an advantage over Potvin's approaches in terms of sample sizes while controlling type I error rates at or below 5% with a minute occasional trade-off in power. Ethically and economically, the method may thus be an attractive alternative to the Potvin designs. It is also shown that when using the method introduced here, average total sample sizes are rather independent of initial sample size. Finally, it is shown that when a futility rule in terms of sample size for stage 2 is incorporated into this method, i.e., when a second stage can be abolished due to sample size considerations, there is often an advantage in terms of power or sample size as compared to the previously published methods.

SUBMITTER: Fuglsang A

PROVIDER: S-EPMC4070248 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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A sequential bioequivalence design with a potential ethical advantage.

Fuglsang Anders A

The AAPS journal 20140529 4

This paper introduces a two-stage approach for evaluation of bioequivalence, where, in contrast to the designs of Diane Potvin and co-workers, two stages are mandatory regardless of the data obtained at stage 1. The approach is derived from Potvin's method C. It is shown that under circumstances with relatively high variability and relatively low initial sample size, this method has an advantage over Potvin's approaches in terms of sample sizes while controlling type I error rates at or below 5% ...[more]

PMID: 24871343

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Project description:Differences between autistic and nonautistic people are often framed as deficits. This research considers whether some of these differences might actually be strengths. In particular, autistic people tend to be less sensitive to their social environment than nonautistic people who are easily influenced by the judgments, opinions, beliefs and actions of others. Because autistic people are less susceptible to social influence, as employees they are more likely to take action when they witness an operational inefficiency or an ethical problem in the organization. By reporting problems, autistic employees may contribute to the introduction of innovations and improvements in organizational processes and effectiveness that result in superior performance. This paper considers whether and the extent to which these differences between autistic and nonautistic employees are moderated by "moral disengagement," a set of interrelated cognitive mechanisms that allow people to make unethical decisions by deactivating moral self-regulatory processes. While previous research has shown that moral disengagement is related to unethical decisions, there is no research on whether and the extent to which autistic people are vulnerable to moral disengagement. Thirty-three autistic employees and 34 nonautistic employees completed an on-line survey to determine whether differences between autistic and nonautistic employees with regards to (1) likelihood they would voice concerns about organizational dysfunctions, and (2) degree to which they were influenced by the presence of others when deciding to intervene, are moderated by individual differences in moral disengagement. As predicted, autistic participants scored lower on moral disengagement than nonautistic participants. In terms of the moderating effects of moral disengagement, the results are mixed. Although moral disengagement reduced intervention likelihood, there was not a difference between autistic and nonautistic employees in the degree to which intervention likelihood was changed by an individual's level of moral disengagement. However, there was a difference between autistic and nonautistic employees in the extent to which acknowledging the influence of others was affected by moral disengagement. These findings suggest that autistic adults are not just more likely to intervene when they witness dysfunction or misconduct in an organizational context; they are also less likely to engage in unethical behavior in general due to lower levels of moral disengagement. The reduced susceptibility to the bystander effect evidenced by autistic adults in the workplace may be accounted for, in part, by their lower levels of moral disengagement compared with nonautistic adults.

Project description:Pilot bioavailability/bioequivalence (BA/BE) studies are downsized trials that can be conducted prior to the definitive pivotal trial. In these trials, 12 to 18 subjects are usually enrolled, although, in principle, a sample size is not formally calculated. In a previous work, authors recommended the use of an alternative approach to the average bioequivalence methodology to evaluate pilot studies' data, using the geometric mean (Gmean) ƒ2 factor with a cut off of 35, which has shown to be an appropriate method to assess the potential bioequivalence for the maximum observed concentration (Cmax) metric under the assumptions of a true Test-to-Reference Geometric Mean Ratio (GMR) of 100% and an inter-occasion variability (IOV) in the range of 10% to 45%. In this work, the authors evaluated the proposed ƒ2 factor in comparison with the standard average bioequivalence in more extreme scenarios, using a true GMR of 90% or 111% for truly bioequivalent formulations, and 80% or 125% for truly bioinequivalent formulations, in order to better derive conclusions on the potential of this analysis method. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling, accounting for different IOV levels. A redefined decision tree is proposed, suggesting a fixed sample size of 20 subjects for pilot studies in the case of intra-subject coefficient of variation (ISCV%) > 20% or unknown variability, and suggesting the assessment of study results through the average bioequivalence analysis, and additionally through Gmean ƒ2 factor method in the case of the 90% confidence interval (CI) for GMR is outside the regulatory acceptance bioequivalence interval of [80.00-125.00]%. Using this alternative approach, the certainty levels to proceed with pivotal studies, depending on Gmean ƒ2 values and variability scenarios tested (20-60% IOV), were assessed, which is expected to be helpful in terms of the decision to proceed with pivotal bioequivalence studies.

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A sequential bioequivalence design with a potential ethical advantage.

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A sequential bioequivalence design with a potential ethical advantage.

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