This quantitative study assessed the association of the design methods used for early phase oncology studies (adaptive versus traditional) and the outcome of late stage clinical trials. Differences by cancer type and by drug classification were also assessed. The theoretical and conceptual frameworks used were the general systems theory and the design and evaluation of complex interventions, respectively. Units of analysis were individual oncology studies in the ClinicalTrials.gov database and Bayesian logistic modeling was applied on a random sample of 381 studies initiated after November 1999 to December 2016. When assessing study design and outcome, there were lower odds of a positive outcome when adaptive methods were used though this association was not statistically significant (OR [95% highest posterior density (HPD)]:0.66 [0.20, 1.21]). Among the different drug types, using adaptive compared to traditional methods was associated with significantly higher odds of a positive outcome for taxanes, OR: 2.75, 95% HPD: 1.01, 5.16) and other, OR: 3.23, 95% HPD: 1.58, 5.46) but no association among studies of monoclonal antibodies or protein kinase inhibitors. Also, there were no significant associations between early phase study design and outcome in late phase studies by cancer type (lung, breast, other). Further research should be conducted using all completed oncology clinical trials in the database to more precisely determine the relationship between adaptive study design in early phase oncology studies and outcomes in late stage studies. Social change can occur through increased uptake of adaptive design methods, which may lead to more efficacious cancer treatment options.

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This thesis focuses on the design, statistical operating characteristics and interpretation of early phase oncology clinical trials. Anti-cancer drugs are generally highly toxic and it is imperative to deliver a dose to the patient that is low enough to be safe but high enough to produce a clinically meaningful response. Thus, a study of dose limiting toxicities (DLTs) and a determination of the maximum tolerated dose (MTD) of a drug that can be used in later phase trials is the focus of most Phase I oncology trials. We first comprehensively compare the statistical operating characteristics of various early phase oncology designs, finding that all the designs examined select the MTD more accurately when there is a clear separation between the true DLT rate at the MTD and the rates at the dose levels immediately above and below. Among the rule-based designs studied, we found that the 3+3 design under-doses a large percentage of patients and is not accurate in selecting the MTD for all the cases considered. The 5+5 a design picks the MTD as accurately as the model based designs for the true DLT rates generated using the chosen log-logistic and linear dose-toxicity curves, but requires enrolling a larger number of patients. The model based designs examined, mTPI, TEQR, BOIN, CRM and EWOC designs, perform well on the whole, assign the maximum percentage of patients to the MTD, and pick the MTD fairly accurately. However, the limited sample size of these Phase I oncology trials makes it difficult to accurately predict the MTD. Hence, we next study the effect of sample size and cohort size on the accuracy of dose selection in early phase oncology designs, finding that an adequate sample size is crucial. We then propose some integrated Phase 1/2 oncology designs, namely the 20+20 accelerated titration design and extensions of the mTPI and TEQR designs, that consider both toxicity and efficacy in dose selection, utilizing a larger sample size. We demonstrate that these designs provide an improvement over the existing early phase designs. / 2019-12-01T00:00:00Z

La prise en compte des enjeux environnementaux est un sujet très présent dans notre société actuelle. Dans le domaine du développement de produits, l'Eco-conception est une démarche qui permet la considération de ces enjeux en proposant de réduire les impacts environnementaux des produits tout au long de leur cycle de vie. La phase d'utilisation du cycle de vie est une étape cruciale puisque le mode d'utilisation des produits peut avoir des conséquences non négligeables sur leur performance environnementale. Nous proposons dans cette thèse d'enrichir la compréhension de cette phase d'utilisation en mettant en évidence les composantes Kansei qui jouent un rôle dans l'interaction de l'utilisateur avec le produit et qui peuvent être intégrées en amont de la conception de produits à faible impact environnemental. Notre démarche permet de mieux renseigner la phase d'utilisation, contribuant ainsi à la maitrise de la performance environnementale des produits. Nous démontrons à travers notre recherche que l'utilisateur peut être défini, non seulement par des informations basiques que nous retrouvons communément dans la Conception Centrée Utilisateur, mais également à partir d'informations subjectives apportées par la dimension Kansei. A travers nos expérimentations, nous mettons en application deux attributs EcoKansei correspondants aux valeurs et aux émotions afin d'illustrer la modélisation utilisateur pour la conception de produits à faible impact environnemental. L'approche que nous proposons vient en complément au projet EcoUse qui vise à développer une méthodologie d'Eco-conception centrée utilisateur. Les apports de notre démarche sont multiples. Du point de vue de la recherche, une mise en relation de l'Eco-conception et du Kansei, qui sont à la base complètement déconnectées entraine un enrichissement mutuel entre ces deux approches. Du point de vue industriel, une démarche d'Eco-conception appuyée par les études Kansei doit permettre la conception de nouveaux produits qui auront l'avantage d'être à la fois mieux acceptés par les utilisateurs car en adéquation avec leur sensibilité environnementale et en même temps moins impactants pour l'environnement. / The consideration of environmental issues is a very strong topic in our society nowadays. In the field of Product Development, Ecodesign is a methodology that allows the consideration of these issues by proposing to reduce the environmental impacts of products throughout their life cycle. The use phase of the life cycle is a critical step as the way how the products are managed can have significant impact on their environmental performance. We propose in this thesis to enrich the understanding of the use phase by highlighting the Kansei Information that can play a major role in the interaction between the user and the product and thus can be integrated in the early phase of the Ecodesign process. Our approach provides a better understanding the use phase, by contributing to the mastery of the environmental performance of products. Our research points out that the user can be defined not only from basic information commonly used in the User Centered Design, but also from subjective information brought by the Kansei dimension. We carry out experiments in which we implement two EcoKansei attributes corresponding to the values and emotions in order to illustrate user modeling for Ecodesign. The approach we propose is a part of EcoUse project that aims to develop a methodology for user-centered Ecodesign. Various contributions of our approach can be pointed out. For the Research, linking Ecodesign with the Kansei studies, which are basically unconnected leads to mutual enrichment between these two approaches. For Industry, an Eco-design approach supported by Kansei Information enables the design of new products which will have the benefits of both providing less impacts to the environment, and at the same time being more accepted by users as these products match with their environmental sensitivity.