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Yes / The exponential growth of the Internet of Things (IoT) has paved the way for safety-critical cyber-physical systems to enter our everyday activities. While such systems have changed the way of our life, they brought new challenges that can adversely affect our life and the environment. Safety and security are two such challenges that can hamper the widespread adoption of new IoT applications. Due to a large number of connected devices and their ability to control critical physical assets, intended attacks on them and/or unintended failure events such as mechanical failure of devices, communication failure and unforeseen bad interactions between connected devices may cause an IoT-based system to enter into unsafe and dangerous physical states. By considering the importance of safety and security of IoT systems, in this article, we present a security-enabled safety monitoring framework for IoT-based systems. In the proposed framework, we utilise design-time system analysis to create an executable monitoring model that enables run-time safety assurance provision for a system via collecting and analysing operational data and evidence to determine the safety status of the system and then taking appropriate actions and securely communicating the safety status and recommended actions to the system users to minimise the risk of the system entering into an unsafe state.

Background and Objectives: Sharing of interim results by the Data Safety Monitoring Board (DSMB) with non-DSMB members is an important issue that can affect trial integrity. The objective of this dissertation was to determine the views of the stakeholders on what kind of interim results can or should be shared by the DSMB, why, and with whom among those responsible for the conduct of a trial. Methods: We first conducted a systematic search of the literature to assess views and current evidence on sharing interim results. Secondly, we conducted two cross-sectional surveys aimed at those involved in trials to solicit their views on what type of interim results should be shared by the DSMB with non-DSMB members, with whom and under what circumstances. Thirdly, we assessed for any potential association of demographic factors with the sharing of certain interim results and their perceived usefulness, using regression analysis. Results: Mixed views exist in the literature on interim result sharing practices. Evidence from the surveys conducted resulted in the following findings. What to share: Based upon the survey results from our cross-sectional survey (Chapter 4), the interim control event rate (IControlER), the adaptive conditional power (ACP) and the unconditional conditional power (UCP) should not be shared. Most respondents from this survey thought the interim combined event rate (ICombinedER) could be shared provided proper conditions and provisions are in place. However, based on our cross-sectional scenario-based survey (Chapter 3), it was demonstrated that the ICombinedER, when shared at interim, is compatible with three possible interim results (Drug X doing better than placebo, worse than placebo or performing the same as placebo). Why share or not share: Respondents indicate that the ICombinedER can be shared because it does not unmask relative effects between groups, and keeps the steering committee (SC) informed about the trial’s progress; however, with the condition that sharing this type of result should be specified a priori including for what purpose and be at the DSMB’s discretion, especially if the control group rate is known from the literature. However, it is important to note that the ICombinedER, demonstrated with evidence from our cross-sectional scenario-based survey (Chapter 3), is compatible with three possible interim results and should not be shared because it has low usefulness and is flawed due to multiple interpretations. The IControlER and the ACP should not be shared because they are unmasking of interim results. It was mentioned that ICombinedER is usually known by the SC and sponsor making it easy to determine group rates if the IControlER is known. The UCP should not be shared because it is a technical measure that is potentially misleading of interim results. With whom to share: Survey results from Chapter 4 indicated that the ICombinedER can be shared with the SC and that the IControlER, the ACP, and the UCP should not be shared with any non-DSMB members by the DSMB. However, evidence from Chapter 3 also indicates that the ICombinedER should not be shared with any non-DSMB member. Factors associated with sharing: Having experience with greater than 15 trials with private industry sponsorship was found to be associated with not sharing the IControlER and an increase in perceived usefulness in sharing the ACP. Though some other demographic factors were found to be associated with sharing the ICombinedER and the UCP, they were sensitive to missing data upon our sensitivity analysis and will require more validation. Conclusions: Though mixed views exist within an extensive literature review on interim result sharing practices, survey evidence from this dissertation suggests that the ICombinedER, IControlER, the ACP and the UCP should not be shared with any non-DSMB member. The IControlER and ACP can be unmasking of interim results and the UCP is a technical measure that is potentially misleading. We agree with this reasoning. The majority of respondents from the survey in Chapter 4 indicated that the ICombinedER can be shared with the SC because it does not unmask relative effects between groups, however it was also stipulated that sharing this measure should be specified a priori and for what purpose and be at the DSMB’s discretion, especially if the control group rate is known from the literature. Even though the majority from our second survey in Chapter 4 indicate sharing the ICombinedER with the SC, we do not recommend sharing the ICombinedER at interim with any non-DSMB member because, as demonstrated with evidence from our cross-sectional scenario-based survey in Chapter 3, this measure is compatible with three possible interim results potentially leading to the introduction of trial bias at interim by those privy this interim measure and their interpretation. Based on the findings from the survey from Chapter 4, there appears to be a lack of awareness in how sharing the ICombinedER is flawed, of low usefulness, and potentially dangerous. The perceived desire to have this measure shared seems misguided. Experience with greater than 15 trials with private industry sponsorship was found to be associated with not endorsing the sharing the IControlER and an increase in perceived usefulness in sharing the ACP by the DSMB at interim. In regards to implications for future research, this characteristic should be further evaluated to see if this subgroup has insight into interim trial management practices that protect from trial bias. Results from this research have implications for practice and guidelines concerning trial design and protocols, and DSMB charters. These results can also help assess the need for proper safeguards around sharing an interim result when deemed appropriate by the DSMB and under their discretion, that prevent the introduction of bias that could alter the final trial results generated. / Thesis / Doctor of Philosophy (PhD)

Les traitements en cancérologie sont soumis au même risque de non-adhérence que les autres traitements ambulatoires au long cours. Ce travail de thèse a pour objectifs : i) d'étudier les facteurs de risque de dis-adhérence ; ii) de développer un programme d'éducation du patient (PEP) permettant d'améliorer l'adhérence des patients. La première étude étudie les facteurs de risque de non adhésion liés à l'interaction avec le système de soin ; les pratiques des oncologues français relatives à la prescription, la surveillance et l'accompagnement des patients ne sont pas suffisantes actuellement pour assurer un bon niveau de sécurité et d'adhérence des patients sous anticancéreux oraux. Les facteurs de risque de non adhésion liés au patient et au traitement sont étudiés dans la deuxième étude, chez des patients traités par capécitabine pour cancer du sein ou du côlon. Les patients actifs avec un niveau éducatif élevé seraient moins adhérents que les 2 autres. L'ensemble des patients sous capécitabine ont des comportements de sur-adhérence qui mettent en péril leur vie à cause des toxicités induites. La troisième étude présente l'évaluation d'un PEP construit selon une méthodologie standardisée. Ce programme démontre une efficacité dans l'amélioration des connaissances des patientes et de la confiance dans le traitement. Cette étude pilote a permis de modifier ce programme pour qu'il soit plus efficace. Identifier les facteurs de risque de non adhérence aux traitements anticancéreux oraux, à l'aide de méthodologies valides et adaptées au contexte, permet de construire des stratégies d'amélioration de l'adhérence ciblées et efficaces, en faisant levier sur ces facteurs / Non-adherence to oral chemotherapies can lead to lowered efficacy and increased risk of adverse events. The objective of this PhD work was twofold : i) to identify dis-adherence risk factors ii) to develop and test the feasibility of a validated, tailored therapeutic educational program with the aim of improving adherence to oral endocrine adjuvant chemotherapy in breast cancer. A survey was carried out to collect information on drug prescription, administration and surveillance, in order to identify non- adherence risk factors related to health professional behaviors : the majority of prescribers followed no standards in prescription writing, safety monitoring, toxicity prevention and patient education. A cohort study was carried out to identify adherence profiles among patients treated with capecitabine, using a mixed method. A profile of low adherence appeared (highly educated patients, with an irregular active life, with occupied relatives) and absolutely all patients showed an over-adherence profile (with a high risk of toxicity). The pilot study assessing the development and the feasibility of an educational program tailored to patients’ needs led to the improvement of the program : an extra session dealing with anxiety was built, and a new recruitment method was developed. Otherwise, the program succeeded in improving knowledge and trust in the treatment. This PhD work succeeded in identifying new dis-adherence risk factors, thanks to qualitative-quantitative methods. Those risk factors were incorporate in the development process of an educational program, in order to tailor it to the targeted population. This method should guarantee the efficacy of the program on patient’s adherence