Statistical Properties of the Design for Simultaneous Global Drug Development Program

ABSTRACTThe primary objective of a multiregional clinical trial (MRCT) is to assess the efficacy of all participating regions and evaluate the probability of applying the overall results to a specific region. The consistency assessment of the target region with the overall results is the most common way of evaluating the efficacy in a specific region. Recently, Huang et al. (2012) proposed an additional trial in the target region to an MRCT to evaluate the efficacy in the target ethnic (TE) population under the framework of simultaneous global drug development program (SGDDP). However, the operating characteristics of this statistical framework were not well considered. Therefore, a nested group sequential program for regional efficacy evaluation is proposed in this paper. It is an extension of Huang’s SGDDP framework and allows interim analysis after MRCT and in the course of local clinical trial (LCT) phase. It is able to well control the family-wise type I error in the program level and enhances the flexibility of the program. In LCT sample size estimation, we introduce virtual trial, which is transformed from the original program by using discounting factor, and an iteration method is employed to calculate the sample size and stopping boundaries of interim analyses. The proposed sample size estimation method is validated in the simulations and the effect of varied weight, effect size of TE population, and design setting is explored. Examples with normal end point, binary end point, and survival end point are shown to illustrate the application of the proposed nested group sequential program.

Uniformly most powerful (UMP) tests are known to exist in one-parameter exponential families when the hypothesis H0 and the alternative hypothesis H1 are given by

Uniformly Most Powerful (UMP) centralized detection for the composite binary hypothesis problem has been well researched. This paper extends the UMP methodology to the parallel distributed detection problem, when the local observations are independently distributed. A collection of general theorems and corollaries define sufficient conditions for the existence of a UMP parallel Distributed Detection (UMP-DD) under one set of fusion rules. These same conditions under another set of general fusion rules result in at least a Locally Most Powerful Distributed Detection (LMP-DD) rule. The subtleties of these conclusions are explored using informative examples that highlight the strengths of this approach and introduce new groups of UMP-DD tests.

In this paper, we study some relationships between the detection and estimation theories for a binary composite hypothesis test <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">H</i> <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">0</sub> against <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">H</i> <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1</sub> and a related estimation problem. We start with a one-dimensional (1D) space for the unknown parameter space and one-sided hypothesis problems and then extend out results into more general cases. For one-sided tests, we show that the uniformly most powerful (UMP) test is achieved by comparing the minimum variance and unbiased estimator (MVUE) of the unknown parameter with a threshold. Thus for the case where the UMP test does not exist, the MVUE of the unknown parameter does not exist either. Therefore for such cases, a good estimator of the unknown parameter is deemed as a good decision statistic for the test. For a more general class of composite testing with multiple unknown parameters, we prove that the MVUE of a separating function (SF) can serve as the optimal decision statistic for the UMP unbiased test where the SF is continuous, differentiable, positive for all parameters under <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">H</i> <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1</sub> and is negative for the parameters under <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">H</i> <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">0</sub> . We then prove that the UMP unbiased statistic is equal to the MVUE of an SF. In many problems with multiple unknown parameters, the UMP test does not exist. For such cases, we show that if one detector between two detectors has a better receiver operating characteristic (ROC) curve, then using its decision statistic we can estimate the SF more ε-accurately, in probability. For example, the SF is the signal-to-noise ratio (SNR) in some problems. These results motivate us to introduce new suboptimal SF-estimator tests (SFETs) which are easy to derive for many problems. Finally, we provide some practical examples to study the relationship between the decision statistic of a test and the estimator of its corresponding SF.

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast‐changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology‐related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China‐specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology‐related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data.

More than 3 million children 10 million child deaths annually throughout the world [World Health Organization (WHO) 2005]. Some factors of susceptibility, including race, ethnicity, and socioeconomic status, are generally not well understood in the context of risk assessment. For children’s environmental health the focus is almost exclusively on age-related differences and exposure hazards, without much discussion of the myriad additional factors including nutritional status, preexisting health status, multiple exposures, and gender differences that can affect the life course of a child.

The Uniformly Most Powerful (UMP) test, which is one with the highest probability of detection over all unknown parameters in a composite hypothesis test, does not exist in the most practical problems. It is common to derive the suboptimal Generalize Likelihood Ratio (GLR) detector, that is shown to perform close to optimal invariant tests in some problems. The Uniformly Most Powerful Invariant (UMPI) test is the one that is used for the performance evaluation of the GLR detector. However, the GLR or UMPI detectors are not simply derivable in many problems. In this paper, we suggest that the problem be transformed to a new space. We derive the conditions of the transformation, such that the detectors for the original problem and the transformed ones become equivalent. In addition, using this method, we discuss two practical problems (one in radar and other in communication) and derive the GLR detectors. We also find the UMPI detectors in these problems to verify the performance of the derived GLR detector.

SUMMARY The use of major genes is a component of livestock improvement. This requires identification of the genotypes of reproducers, in particular progeny-tested sires after mating with homozygous females. Two test statistics derived from the nonnested test of Cox (1961, Proceedings of the Fouirth Berkeley Svmposium on Mathematical Statistics and Probability 1, 105-123; 1962, Journal of the Royal Statistical Society, Series B 24, 406-424) are proposed. For both tests, asymptotic normality is proved algebraically and the speed of convergence is studied through simulations. In the cases where a uniformly most powerful (UMP) test exists, the power of one of the tests is close to the power of that UMP test. Finally, the tests are applied to a population of poultry carrying the dwarf gene.

This letter is focused on the classic problem of testing samples drawn from independent Bernoulli probability mass functions, when the success probability under the alternative hypothesis is not known. The goal is to provide a systematic taxonomy of the viable detectors (designed according to theoretically-founded criteria) which can be used for the specific instance of the problem. Both One-Sided (OS) and Two-Sided (TS) tests are considered, with reference to: ( $i$ ) identical success probability (a homogeneous scenario) or ( $ii$ ) different success probabilities (a non-homogeneous scenario) for the observed samples. As a result of the study, a complete summary (in tabular form) of the relevant statistics for the problem is provided, along with a discussion on the existence of the Uniformly Most Powerful (UMP) test. Finally, when the Likelihood Ratio Test (LRT) is not UMP, existence of the UMP detector after reduction by invariance is investigated.

PurposeThe purpose of this paper is to explore how multinational corporations’ (MNCs’) women leaders in South Korea (Korea) have overcome career challenges in the process of becoming CEOs. The two guiding questions for this study included: what career challenges have MNCs’ women leaders in Korea faced to become CEOs? How have they overcome their career challenges?Design/methodology/approachThe authors used a basic qualitative research design, the goal of which is to understand how people make sense of their lives and experiences. Qualitative data were collected by semi-structured interviews with 15 women CEOs at MNCs in Korea to capture their lived experiences (challenges and strategies) in their careers. The authors used NVivo 11, a qualitative data analysis software, to analyze the interview data.FindingsFrom data analysis, the authors identified five themes including: becoming a CEO, key success factors, MNC culture, career challenges and career development strategies. The authors found that in the process of becoming CEOs, 15 women leaders faced career challenges that are largely generated by traditional culture, work stress and work–life balance. The authors also found that the women leaders became CEOs through diverse on-the-job experiences (e.g. marketing and sales) and positions (e.g. managers, senior managers and regional directors) with organizational support (e.g. supervisor support).Research limitations/implicationsGiven research on organizational support for leadership, human resource practices and working conditions, this study’s findings have qualitatively confirmed the importance of organizational support for women CEOs’ career success. For theory building in women in leadership, the authors suggest that researchers investigate the complex process of becoming women CEOs, including their early experiences in their career in tandem with family background, organizational climate and national culture.Practical implicationsThe study findings on women CEOs’ career strategies can be used as a reference for women in the leadership pipeline who aspire to take leadership positions in organizations. A lack of role models or mentors for women leaders is one of the reasons why women give up on their career. Learning career strategies (e.g. global development programs, mentoring and networks) that women CEOs have employed to overcome their career challenges can help women in the leadership pipeline from their early career on.Originality/valueThe authors found that both internal and external factors combined were instrumental in the women CEOs’ career success. What stood out from this study was that the women’s desirable personality attributes might not have materialized without the MNC culture that has been supportive for these women. The women CEOs shared their company’s values and philosophy that is based on gender equality, received supervisor support that is crucial for their career success, experienced diverse jobs and positions along the way and were recognized for their work ethic. Given research on women leaders conducted largely in western contexts, this qualitative study on the lived experiences of women CEOs in MNCs contributes to emerging non-western research by capturing the importance of culture that is uniquely Korean.

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Review and Prospects of Global Positive Youth Development Programs: A Scientometric Analysis

Cutting edge communication technologies such as smartphones remain far from prevalent in most of the settings with the greatest need for improved health and development programs. As a result, designers of ICT4D initiatives often weigh difficult tradeoffs between the usability of smartphone applications for structured data collection versus the battery life, durability, cost and familiarity of basic phones. However, as this paper and our deployment experiences demonstrate, such tradeoffs are not always necessary. Most mobile network operators in sub-Saharan Africa offer value added services via simple, menu-driven applications that run directly from the SIM card. While conventional SIM applications can only be accessed by mobile network operators, this paper describes the design and implementation of a 'thin SIM' approach that does not require mobile network operator involvement. We have implemented this tool with more than 3,000 health workers and describe particular deployment experiences in Kenya, Benin, Nepal and Guatemala. We then reflect on a number of important limitations of the thin SIM approach, and opportunities for further development and deployment. Ultimately, we argue that there is an important role for SIM applications as one part of a configurable data collection toolkit for supporting global health and development programs.