Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials

Background Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. Methods Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. Results We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. Conclusions There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers.

Generic construction of monitors for floating point unit designs

This paper proposes a set of well defined steps to design functional verification monitors intended to verify Floating Point Units (FPU) described in HDL. The first step consists on defining the input and output domain coverage. Next, the corner cases are defined. Finally, an already verified reference model is used in order to test the correctness of the Device Under Verification (DUV). As a case study a monitor for an IEEE754-2008 compliant design is implemented. This monitor is built to be easily instantiated into verification frameworks such as OVM. Two different designs were verified reaching complete input coverage and successful compliant results.

Cross-sector surveys assessing perceptions of key stakeholders towards barriers, concerns and facilitators to the appropriate use of adaptive designs in confirmatory trials

Background Appropriately conducted adaptive designs (ADs) offer many potential advantages over conventional trials. They make better use of accruing data, potentially saving time, trial participants, and limited resources compared to conventional, fixed sample size designs. However, one can argue that ADs are not implemented as often as they should be, particularly in publicly funded confirmatory trials. This study explored barriers, concerns, and potential facilitators to the appropriate use of ADs in confirmatory trials among key stakeholders. Methods We conducted three cross-sectional, online parallel surveys between November 2014 and January 2015. The surveys were based upon findings drawn from in-depth interviews of key research stakeholders, predominantly in the UK, and targeted Clinical Trials Units (CTUs), public funders, and private sector organisations. Response rates were as follows: 30(55 %) UK CTUs, 17(68 %) private sector, and 86(41 %) public funders. A Rating Scale Model was used to rank barriers and concerns in order of perceived importance for prioritisation. Results Top-ranked barriers included the lack of bridge funding accessible to UK CTUs to support the design of ADs, limited practical implementation knowledge, preference for traditional mainstream designs, difficulties in marketing ADs to key stakeholders, time constraints to support ADs relative to competing priorities, lack of applied training, and insufficient access to case studies of undertaken ADs to facilitate practical learning and successful implementation. Associated practical complexities and inadequate data management infrastructure to support ADs were reported as more pronounced in the private sector. For funders of public research, the inadequate description of the rationale, scope, and decision-making criteria to guide the planned AD in grant proposals by researchers were all viewed as major obstacles. Conclusions There are still persistent and important perceptions of individual and organisational obstacles hampering the use of ADs in confirmatory trials research. Stakeholder perceptions about barriers are largely consistent across sectors, with a few exceptions that reflect differences in organisations’ funding structures, experiences and characterisation of study interventions. Most barriers appear connected to a lack of practical implementation knowledge and applied training, and limited access to case studies to facilitate practical learning. Keywords: Adaptive designs; flexible designs; barriers; surveys; confirmatory trials; Phase 3; clinical trials; early stopping; interim analyses

Interim analyses and sequential designs in phase III studies

Recruitment of patients to a clinical trial usually occurs over a period of time, resulting in the steady accumulation of data throughout the trial's duration. Yet, according to traditional statistical methods, the sample size of the trial should be determined in advance, and data collected on all subjects before analysis proceeds. For ethical and economic reasons, the technique of sequential testing has been developed to enable the examination of data at a series of interim analyses. The aim is to stop recruitment to the study as soon as there is sufficient evidence to reach a firm conclusion. In this paper we present the advantages and disadvantages of conducting interim analyses in phase III clinical trials, together with the key steps to enable the successful implementation of sequential methods in this setting. Examples are given of completed trials, which have been carried out sequentially, and references to relevant literature and software are provided.

A fuzzy logic controller for intestinal levodopa infusion in Parkinson’s disease

The aim of this work is to evaluate the fuzzy system for different types of patients for levodopa infusion in Parkinson Disease based on simulation experiments using the pharmacokinetic-pharmacodynamic model. Fuzzy system is to control patient’s condition by adjusting the value of flow rate, and it must be effective on three types of patients, there are three different types of patients, including sensitive, typical and tolerant patient; the sensitive patients are very sensitive to drug dosage, but the tolerant patients are resistant to drug dose, so it is important for controller to deal with dose increment and decrement to adapt different types of patients, such as sensitive and tolerant patients. Using the fuzzy system, three different types of patients can get useful control for simulating medication treatment, and controller will get good effect for patients, when the initial flow rate of infusion is in the small range of the approximate optimal value for the current patient’ type.

DC Motor Speed Control via Fuzzy / Pole Placement / PI Controller

This report presents a new way of control engineering. Dc motor speed controlled by three controllers PID, pole placement and Fuzzy controller and discusses the advantages and disadvantages of each controller for different conditions under loaded and unloaded scenarios using software Matlab. The brushless series wound Dc motor is very popular in industrial application and control systems because of the high torque density, high efficiency and small size. First suitable equations are developed for DC motor. PID controller is developed and tuned in order to get faster step response. The simulation results of PID controller provide very good results and the controller is further tuned in order to decrease its overshoot error which is common in PID controllers. Further it is purposed that in industrial environment these controllers are better than others controllers as PID controllers are easy to tuned and cheap. Pole placement controller is the best example of control engineering. An addition of integrator reduced the noise disturbances in pole placement controller and this makes it a good choice for industrial applications. The fuzzy controller is introduce with a DC chopper to make the DC motor speed control smooth and almost no steady state error is observed. Another advantage is achieved in fuzzy controller that the simulations of three different controllers are compared and concluded from the results that Fuzzy controller outperforms to PID controller in terms of steady state error and smooth step response. While Pole placement controller have no comparison in terms of controls because designer can change the step response according to nature of control systems, so this controller provide wide range of control over a system. Poles location change the step response in a sense that if poles are near to origin then step response of motor is fast. Finally a GUI of these three controllers are developed which allow the user to select any controller and change its parameters according to the situation.

Colonial designs: Thomas Karsten and the planning of urban Indonesia

Thomas Karsten (1885 – 1945) is undoubtedly a major figure in the history of architecture and town planning in Indonesia. Between 1915 and 1941 he was involved in town planning in 12 of the 19 municipalities and towns in Java (the most prominent exception being Surabaya) 3 of the 9 towns in Sumatra, and the only town in Borneo This paper does not attempts to investigate or question his importance in this field but to place his architectural and town planning ideas in the context of his broader politico-cultural ideas and activities in the Dutch East Indies between 1914 and 1942, and these, in turn, in the context of an evolving colonialism and colonial discourse.

Research designs and scientific identity in marketing journals: review and evaluation

Purpose - This research is based upon the assumption that the empirical research designs and the scientific identity of a journal are related. The objective is to review and evaluate the empirical research design of papers to determine the scientific identity of a selection of academic marketing journals. Design/methodology/approach – The journal sample consists of the Australasian Marketing Journal (AMJ), the European Journal of Marketing (EJM) and the Journal of Marketing (JM). The review and evaluation considers a six-year period, namely 2000-2005. The content analysis consisted of 811 papers. Findings – The scientific identity of JM may be seen as built upon quantitative research designs and the North American paradigm of research values. The scientific identity of AMJ is based upon a mix of empirical research designs and the Australian paradigm of research values. The scientific identity of EJM is also based upon a mix of empirical research designs, but a multi-continental paradigm of research values. Research limitations/implications – The leading continental journals in marketing maintain a scientific identity based upon the continental paradigm of research values. If it is driven to the extremes, a paradigmatic myopia and inertia of research designs may evolve that limit the scientific identity to be dogmatic and narrow-focused rather than variable and broad-focused. Originality/value – A cross-continental eview and evaluation of research designs and scientific identity of academic marketing journals is presented.

Fuzzy terminal attitude guidance controller with angle only measurements

This paper introduces the concept of terminal attitude guidance as an alternative to precision guidance and uses fuzzy control ideas in designing a control strategy for a pursuer in countering a manoeuvreing target. The fuzzy controller uses only angle measurements in the control strategy and produces satisfactory results in comparison to the LQR or H∞ type guidance controllers, although they were addressed in a precision guidance context. Both 2D and 3D cases have been considered.

The impact of cell formation on layout designs in cellular manufacturing

This paper provides a procedure to address all three phases of the design for cellular manufacturing namely parts/machines grouping, intra-cell and inter-cell layout designs concurrently. It provides a platform to investigate the impact of the cell formation method on intracell and inter-cell layout designs and vice versa by generating multiple efficient layout designs for different cell partitioning strategies. This approach enables the decision maker to have wider choices with regard to the different number of cells and to assess various criteria such as travelling cost, duplication of machines, space requirement against each alternative. The performance of the model is demonstrated by applying it to an example selected from literature.