Le développement d’un médicament est non seulement complexe mais les retours sur investissment ne sont pas toujours ceux voulus ou anticipés. Plusieurs médicaments échouent encore en Phase III même avec les progrès technologiques réalisés au niveau de plusieurs aspects du développement du médicament. Ceci se traduit en un nombre décroissant de médicaments qui sont commercialisés. Il faut donc améliorer le processus traditionnel de développement des médicaments afin de faciliter la disponibilité de nouveaux produits aux patients qui en ont besoin. Le but de cette recherche était d’explorer et de proposer des changements au processus de développement du médicament en utilisant les principes de la modélisation avancée et des simulations d’essais cliniques. Dans le premier volet de cette recherche, de nouveaux algorithmes disponibles dans le logiciel ADAPT 5® ont été comparés avec d’autres algorithmes déjà disponibles afin de déterminer leurs avantages et leurs faiblesses. Les deux nouveaux algorithmes vérifiés sont l’itératif à deux étapes (ITS) et le maximum de vraisemblance avec maximisation de l’espérance (MLEM). Les résultats de nos recherche ont démontré que MLEM était supérieur à ITS. La méthode MLEM était comparable à l’algorithme d’estimation conditionnelle de premier ordre (FOCE) disponible dans le logiciel NONMEM® avec moins de problèmes de rétrécissement pour les estimés de variances. Donc, ces nouveaux algorithmes ont été utilisés pour la recherche présentée dans cette thèse. Durant le processus de développement d’un médicament, afin que les paramètres pharmacocinétiques calculés de façon noncompartimentale soient adéquats, il faut que la demi-vie terminale soit bien établie. Des études pharmacocinétiques bien conçues et bien analysées sont essentielles durant le développement des médicaments surtout pour les soumissions de produits génériques et supergénériques (une formulation dont l'ingrédient actif est le même que celui du médicament de marque, mais dont le profil de libération du médicament est différent de celui-ci) car elles sont souvent les seules études essentielles nécessaires afin de décider si un produit peut être commercialisé ou non. Donc, le deuxième volet de la recherche visait à évaluer si les paramètres calculer d’une demi-vie obtenue à partir d'une durée d'échantillonnage réputée trop courte pour un individu pouvaient avoir une incidence sur les conclusions d’une étude de bioéquivalence et s’ils devaient être soustraits d’analyses statistiques. Les résultats ont démontré que les paramètres calculer d’une demi-vie obtenue à partir d'une durée d'échantillonnage réputée trop courte influençaient de façon négative les résultats si ceux-ci étaient maintenus dans l’analyse de variance. Donc, le paramètre de surface sous la courbe à l’infini pour ces sujets devrait être enlevé de l’analyse statistique et des directives à cet effet sont nécessaires a priori. Les études finales de pharmacocinétique nécessaires dans le cadre du développement d’un médicament devraient donc suivre cette recommandation afin que les bonnes décisions soient prises sur un produit. Ces informations ont été utilisées dans le cadre des simulations d’essais cliniques qui ont été réalisées durant la recherche présentée dans cette thèse afin de s’assurer d’obtenir les conclusions les plus probables. Dans le dernier volet de cette thèse, des simulations d’essais cliniques ont amélioré le processus du développement clinique d’un médicament. Les résultats d’une étude clinique pilote pour un supergénérique en voie de développement semblaient très encourageants. Cependant, certaines questions ont été soulevées par rapport aux résultats et il fallait déterminer si le produit test et référence seraient équivalents lors des études finales entreprises à jeun et en mangeant, et ce, après une dose unique et des doses répétées. Des simulations d’essais cliniques ont été entreprises pour résoudre certaines questions soulevées par l’étude pilote et ces simulations suggéraient que la nouvelle formulation ne rencontrerait pas les critères d’équivalence lors des études finales. Ces simulations ont aussi aidé à déterminer quelles modifications à la nouvelle formulation étaient nécessaires afin d’améliorer les chances de rencontrer les critères d’équivalence. Cette recherche a apporté des solutions afin d’améliorer différents aspects du processus du développement d’un médicament. Particulièrement, les simulations d’essais cliniques ont réduit le nombre d’études nécessaires pour le développement du supergénérique, le nombre de sujets exposés inutilement au médicament, et les coûts de développement. Enfin, elles nous ont permis d’établir de nouveaux critères d’exclusion pour des analyses statistiques de bioéquivalence. La recherche présentée dans cette thèse est de suggérer des améliorations au processus du développement d’un médicament en évaluant de nouveaux algorithmes pour des analyses compartimentales, en établissant des critères d’exclusion de paramètres pharmacocinétiques (PK) pour certaines analyses et en démontrant comment les simulations d’essais cliniques sont utiles. / Drug development is complex with results often differing from those anticipated or sought after. Despite technological advances in the many fields which are a part of drug development, there are still many drugs that fail in the late stages of clinical development. Indeed, the success rate of drugs reaching commercialization is declining. Improvements to the conventional drug process are therefore required in order to facilitate development and allow new medications to be provided more rapidly to patients who require them. The aim of this Ph.D. project was to explore and propose ways to improve this inefficient drug development process with the use of advanced modeling and clinical trial simulations. For the first part of this research, new algorithms available in ADAPT 5® were tested against other available algorithms in order to determine their potential strengths and weaknesses. The two new algorithms tested were the iterative two-stage and the maximum likelihood expectation maximization (MLEM) methods. Our results demonstrated that the MLEM algorithm was consistently better than the iterative two-stage algorithm. It was also comparable with the first order conditional estimate method available in NONMEM®, with significantly fewer shrinkage issues in the estimation of the variances. Therefore, these new tools were used for the clinical trial simulations performed during the course of this Ph.D. research. In order to calculate appropriate noncompartmental pharmacokinetic parameter estimates during the drug development process, it is essential that the terminal elimination half-life be well characterized. Properly conducted and analyzed pharmacokinetic studies are essential to any drug development plan, and even more so for generic and supergeneric (a formulation similar to the reference product, containing the same active ingredient; however differing from the original reference product it its delivery process) submission where they often are the only pivotal studies that need to be done to decide if a drug product is good or not. Thus, the purpose of the second part of the research was to determine if the pharmacokinetic (PK) parameters obtained from a subject whose half-life is calculated from a sampling scheme duration that is considered too short could bias the bioequivalence conclusions of a study and if these parameters should be removed from statistical analyses. Results demonstrated that subjects with a long half-life relative to the duration of the sampling scheme negatively influenced results when these were maintained in the analysis of variance. Therefore, these subjects should be removed from the analyses and guidelines to this effect are required a priori. Pivotal pharmacokinetic studies done within the drug development process should therefore follow this recommendation to make sure that the right decision be taken on a drug product formulation. This information was utilized with the clinical trial simulations that were subsequently performed in this research in order to ensure the most accurate conclusions. Finally, clinical trial simulations were used to improve the development process of a nonsteroidal anti-inflammatory drug. A supergeneric was being developed and results from a pilot study were promising. However, some results from the pilot study required closer attention to determine if the test and reference compounds were indeed equivalent and if the test compound would meet the equivalence criteria of the different required pivotal studies. Clinical trial simulations were therefore undertaken to address the multiple questions left unanswered by the pilot study and these suggested that the test compound would probably not meet the equivalence criteria. In addition, these results helped determine what modifications to the test drug would be required to meet the equivalence criteria. This research brought forward solutions to improve different aspects of the drug development process. Notably, clinical trial simulations reduced the number of studies that would have been done for a supergeneric, decreased the number of subjects unnecessarily exposed to a drug, lowered costs and helped established new criteria for the exclusion of subjects from analyses. Research conducted during this Ph.D. provided concrete ways to improve the drug development process by evaluating some newly available tools for compartmental analyses, setting standards stipulating which estimated PK parameters should be excluded from certain PK analyses and illustrating how clinical trial simulations are useful to throughout the process.

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Many studies have focused on whether or not different kinds of strategies used towards radical right parties give them more or less electoral support and power. This study, however, sets out to center the MP’s subjective views on how the strategies and different approaches are being used and experienced in parliamentary committees in the Swedish Riksdag. The purpose of the study is to gain new and more detailed information of the motivations used for the strategies from the MPs subjective views of the Swedish Democrats (SD). The different types of strategies studied are excluding strategies such as ignore, cordon sanitaire, demonise and defuse. The including strategies which are examined are adapt and collaborate. Vote technical disidentification is a theoretical contribution to strategies being used from this study and shows how MPs blame other parties for voting more on SD than their own. Semi- structured interviews with MPs from five parties, including SD, in three different parliamentary committees with a total number of 15 participants, which are used as the material. The result of the study suggests that there are some differences in the approaches of the different MPs, and the difference lies mostly in between and within parties and not so much among the different committees. The MPs have some differences in their subjective conception of the SD where some have a tough approach against them while others have a softer understanding to them socially but none except for one MP want formal collaboration with them. In broad terms, the political right has some tendencies to use inclusion strategies and the political left uses the exclusion strategies more broadly and not the inclusion at all, according to the result. Informal approaches to take distance from SD, used more by the political left. The perception of the strategies and approaches being used differs a lot from between the MPs from SD and the rest of the MPs in the study. A more hard, unfair and undemocratic is the perceptions of the MPs from SD of the strategy and approaches while the others do not see them as commonly used.

The aim of the dissertation was to examine the relationship between career adaptability, sense of coherence (SOC) and career decision-making self-efficacy (CDMSE), and whether there were any demographic differences, namely age, gender and race, between the constructs. The Career Adapt-ability Scale South Africa (CAAS-South Africa), Orientation to Life Questionnaire (OLQ-13), Career Decision Self-Efficacy Scale Short Form (CDSE-SF) and a demographical questionnaire were applied in a convenience sample comprising 317 undergraduate students at a residential university in South Africa. The results indicated a moderate positive relationship between career adaptability, and SOC, and a strong positive relationship between career adaptability and CDMSE. CDMSE predicted career adaptability with a variance of 43%. SOC did not emerge as a significant predictor of career adaptability. No gender differences were found. This study makes a valuable contribution to the existing literature and practice, showing that CDMSE and SOC can have an impact on the career adaptability of undergraduate students. / Industrial and Organisational Psychology / M. Com. (Industrial and Organisational Psychology)

The Electric/Electronic architecture of vehicle becomes more complex and costly, self-adaption can reduce the system, enhance the adaptive meanwhile reduce energy consumption and costs. The self-adaption needs the cooperation of both hardware and software reconfigurations, such that after the software is reconfigured the automotive network continues to fulfill the time constraints for time-critical applications. The thesis focuses on the real-time network reconfiguration. It uses EAST-ADL to model a real-time automotive system with timing events and constraints, which conforms to AUTOSAR timing extensions. The network media access is analyzed based on the model and a scheduling algorithm is developed. Then the concept is implemented by a use case, which is transformed from an EAST-ADL model to an executable simulation.

The Electric/Electronic architecture of vehicle becomes more complex and costly, self-adaption can reduce the system, enhance the adaptive meanwhile reduce energy consumption and costs. The self-adaption needs the cooperation of both hardware and software reconfigurations, such that after the software is reconfigured the automotive network continues to fulfill the time constraints for time-critical applications. The thesis focuses on the real-time network reconfiguration. It uses EAST-ADL to model a real-time automotive system with timing events and constraints, which conforms to AUTOSAR timing extensions. The network media access is analyzed based on the model and a scheduling algorithm is developed. Then the concept is implemented by a use case, which is transformed from an EAST-ADL model to an executable simulation.:1. Introduction 2. Research Fundamentals 2.1. AUTOSAR Specifications for Modeling Function Communication 2.2. Media Access Control in Real-time Network 3. Function Communication Model and Determination of Network Configuration 3.1. Function Communication Model 3.2. Scheduling Algorithm for Media Access 4. Implementation of Communication Model and Plugin for Model Transformation 4.1. EAST-ADL Modeling Language 4.2. Implementation of Function Communication Model in EAST-ADL 4.3. Model Transformation Plugin and Simulation Tool Integration 5. Evaluation of the Function Communication Model 5.1. Use-Case Model for Evaluation 5.2. Time Values of Use-Case Model 5.3. Analysis and Evaluation of Simulation Result 6. Conclusion and Outlook 6.1. Conclusion of the Work 6.2. Outlook of the Future Work A. OMNeT++ Simulation Log B. EAST-ADL Model to Artop Model Mapping Bibliography Nomenclature