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I argue for two main theses that are at odds with the positions of many clinical researchers and philosophers who write on the ethics of clinical research. The first is that certain types of clinical trials, namely, randomized clinical trials with double or triple blinding and a placebo group are generally necessary to establish that a medical intervention is effective in treating a certain type of disease or disorder. The second main thesis is that such trials are generally not ethically impermissible. My minimalist defense of clinical trials differs from most defenses of clinical trials found in the literature. I feel that the ethical permissibility of clinical trials can be judged by answering yes to the following questions: 1) Is the potential experimental subject competent to exercise his autonomy and his right of self determination in order to enroll in the clinical trial? 2) Is the potential experimental subject informed about the nature of risk and benefit involved in his participation in the clinical trial? 3) Is the trial scientifically/ epistemically valid? 4) Will the trial attempt to answer a scientific question or questions of value? I argue that competent persons have the right to enroll in scientifically valid clinical trials so long as they are informed and consent to participate.

It is of crucial importance to identify and disseminate effective treatments for paediatric obsessive-compulsive disorder (OCD). OCD is time-consuming and distressing, and can substantially disable functioning at school, at home, and with peers (Piacentini, 2003). Children who do not receive treatment are at risk of psychological difficulties in adulthood, including continued OCD, clinical anxiety and depression, personality disorders, and social maladjustment (Wewetzer et al., 2001). Two-thirds of adult cases of OCD develop in childhood, and adults with OCD have lower employment, poorer academic achievement, and lower marital rates compared to non-OCD adults (Hollander et al., 1996; Koran, 2000; Lensi et al., 1996; Steketee, 1993). The distressing nature of OCD in childhood, accompanying psychosocial impairment and risk of future psychopathology, underscore the need to identify effective treatments. The primary aim of this thesis was to expand knowledge of evidence-based treatments for paediatric OCD. A mixed-methodology approach was employed to examine key issues in this area. The first study used meta-analytic methodology to determine the evidence supporting available treatments for paediatric OCD. An extensive literature search revealed over 100 published reports of treatments, encompassing a broad array of theoretical approaches and treatment strategies. Examples of treatments used for paediatric OCD included psychodynamic therapy, pharmacotherapy, cognitive-behavioural therapy (CBT), hypnosis, family therapy, immunotherapy, and homeopathy. / Study 1 comprised the first known meta-analysis of randomised, controlled treatment trials (RCTs) for paediatric OCD. Included studies were limited to RCTs as they are the most scientifically valid means for determining treatment efficacy and provide a more accurate estimate of treatment effect by removing error variance associated with confounding variables. The literature search identified 13 RCTs containing 10 pharmacotherapy to control comparisons (N = 1016) and 5 CBT to control comparisons (N = 161). Random effects modelling yielded statistically significant pooled effect size (ES) estimates for pharmacotherapy (ES = 0.48, 95% CI = 0.36 to 0.61, p < .00001) and CBT (ES = 1.45, 95% CI = 0.68 to 2.22, p =.002). The results support the efficacy of CBT and pharmacotherapy, and confirm these approaches as the only two evidence-based treatments for paediatric OCD. Implications and suggestions for future research are discussed. The effectiveness of CBT provided impetus to further examine this treatment. Group CBT is an understudied treatment modality among children with OCD. It was hypothesised that group CBT would possess efficacy because of the effectiveness of individual CBT for children with OCD, the demonstrated effectiveness of group CBT among adults with OCD, the practical and therapeutic advantages afforded by a group treatment approach, and the embeddedness of the approach in robust psychological theory. The aim of the second study was to evaluate the efficacy of group CBT. The study comprised the largest known conducted randomised, placebo-controlled trial of group CBT for paediatric OCD. / Twenty-two children and adolescents with a primary diagnosis of OCD were randomly assigned to a 12-week program of group CBT or a credible psychological placebo. Children were assessed at baseline, end of treatment, and at 1 month follow-up. Outcome measures included the Children’s Yale-Brown Obsessive-Compulsive Scale, global measures of OCD severity, Children’s Depression Inventory, and parent- and child-rated measures of psychosocial functioning. An intention-to-treat analysis revealed that children in the group CBT condition had statistically significantly lower levels of symptomatology at posttreatment and follow-up compared to children in the placebo condition. Analysis of clinical significance showed that 91% of children that received CBT were ‘recovered’ or ‘improved’ at follow-up, whereas 73% of children in the placebo condition were ‘unchanged’. Effect size analysis using Cohen’s d derived an effect of 1.14 and 1.20 at posttreatment and follow-up, respectively. These effects are comparable to results from studies of individual CBT. This study supported group CBT as an effective treatment modality for paediatric OCD and demonstrated that the effect extends beyond placebo and nonspecific treatment factors. In addition to treatment efficacy, the inherent worth of a treatment lies in its adoption by the relevant clinical population. Children with OCD are known to be secretive and embarrassed about symptoms, and there is often a long delay between onset of symptoms and treatment-seeking (Simonds & Elliot, 2001). An important observation during the course of conducting the RCT was that a high rate (39%) of eligible families declined participation. / This led to the question, "What barriers prevent participation in group CBT for paediatric OCD?" Qualitative methodology was employed to address this research question. Eligible families that had declined participation in the RCT were contacted and invited to participate in semi-structured interviews that explored reasons for non-participation and positive and negative perceptions of group CBT. The average time between non-participation and interview was 1.33 years (SD = 3 months). Data were collected from nine families and thematic analysis methodology was utilised to identify emergent themes. Failure to participate was predicted by practical and attitudinal barriers. Practical barriers included a lack of time, distance, severity of OCD symptoms, financial, and child physical health. Attitudinal barriers included child embarrassment about OCD symptoms, child belief that therapy would be ineffective, fear of the social aspect of the group, lack of previous success with psychology, lack of trust in strangers, parental concern about the structure of the group, denial of a problem, and ‘not being ready for it’. Attitudinal barriers more frequently predicted treatment non-participation. Positive and negative perceptions of this treatment modality were informative. Parents showed no differences in preference for individual or group CBT. An important finding was that 56% of the children had not received treatment since parental expression of interest in the group CBT program. Application of the findings to methods that promote service utilisation is discussed.

Background and Objectives Oral anticoagulants (OACs) are among Canada's most frequently prescribed drugs and a top cause of medication-related serious harm leading to emergency department visits, hospitalizations, and fatalities. During the preparation to launch a Canadian Institutes of Health Research (CIHR)-funded randomized controlled trial (RCT) called "Improving Anticoagulant Safety at Hospital Discharge: A Randomized Trial," we faced some issues. First, as the RCT addresses OAC management, we needed to determine the barriers and facilitators for optimal OAC management, which were not identified in our literature search. Second, there is no core outcome set (COS) specific for OACs and the choice of outcomes and their measurement for the trial was not obvious. Finally, the drug-drug interactions between the OACs and other medications are not fully understood, particularly with regards to important clinical outcomes. Identifying the interacting medications and their interaction effect size, is vital to guarantee the safety of patients. To address these issues, the objectives of this thesis were: (1) to determine the barriers and facilitators for optimal OAC management, (2) to define the potential list for the COS of OACs, and (3) to explore the drug-drug interaction of OACs. Methods Several research approaches, including a systematic review, a systematic survey, a scoping review, a population-based retrospective cohort study with time varying methods, and a qualitative study were applied in this thesis. First, we applied both a synthesis review and qualitative research to explore the barriers and facilitators for OACs management to guarantee the evidence's robustness. Next, we used a systematic survey to address the lack of consensus on outcomes used and their v definitions for OAC treatment clinical trials. Finally, we used a systematic review and planned a population-based study to address drug-drug interaction related to OACs. Methodologic challenges and innovation In the scoping review (Chapter 2: Barriers and facilitators to optimal oral anticoagulant management: a scoping review) and the focus group study (Chapter 3: Perceptions on patient education to improve oral anticoagulant management) we employed a qualitative approach. The main methodological challenge for both the scoping review and the focus group focused on the rigorous way to synthesize the themes. In Chapter 4, we used a systematic survey to explore the outcome list for OAC management research. The primary methodological challenge referred to the outcome reporting in the included studies. Not all outcomes performed in the trials can be reported for the space limitation or potential publication bias. In Chapters 5 and 6, a systematic review with meta-analysis and an observational protocol were used to explore the drug-drug interaction for OACs. The main methodological challenge for Chapter 5 was how to evaluate the drug-drug interaction (DDI) evidence systematically. The main methodological challenge for Chapter 6 is to address confounding and bias in a population-based protocol on DOACs drug-drug interaction. Conclusion In summary, this standard thesis describes five different background projects to prepare for an OAC management RCT. The papers contribute to the literature by using several research methodologies to provide useful evidence for OAC management and OAC research. / Thesis / Candidate in Philosophy / Oral anticoagulants (OACs) (blood thinners) are among Canada's most frequently prescribed drugs and a top cause of severe medication-related harm. The objectives of this thesis include (1) to determine the barriers and facilitators for optimal OAC management, (2) to define a potential list for the core outcome set of OACs, and (3) to explore the drug-drug interaction of OACs. First, we applied a scoping review and a qualitative study to explore the barriers and facilitators for OACs management. Then we conducted a systematic survey to address the lack of consensus on outcomes and their definitions for OAC treatment clinical trials. Finally, we used a systematic review and planned a population-based study to address drug-drug interaction related to OACs. Different research approaches, including a systematic review, a systematic survey, a scoping review, a population-based study, and a qualitative study, were involved in this thesis.

<p><strong>Background:</strong> A better application of evidence-based available therapies and optimal patient care are suggested to have a positive association with patient outcomes for cardiovascular disease (CVD) patients. Electronic integration of care tested in the Computerization of Medical Practices for the Enhancement of Therapeutic Effectiveness (COMPETE) Π study showed that a shared electronic decision-support system to support the primary care of diabetes improved the process of care and some clinical markers of the quality of diabetes care. On the basis of COMPETE Π trial, COMPETE Ш study showed that older adults at increased risk of cardiovascular events, if connected with their family physicians and other providers via an electronic network sharing an intensive, individualized cardiovascular tracking, advice and support program, enhanced their process of care – using a process composite score to lower their cardiovascular risk more than those in conventional care. However, results of the effect of intervention on composite process and clinical outcomes were not similar – there was no significant effect on clinical outcomes.</p> <p><strong>Objectives:</strong> Our objectives were to investigate the robustness of the results based the commonly used statistical models using COMPETE III dataset and explore the validity of the surrogate process composite score using a correlation analysis between the clinical outcomes and process composite score.</p> <p><strong>Methods:</strong> Generalized estimating equations (GEE) were used as a primary statistical model in this study. Three patient-level statistical methods (simple linear regression, fixed-effects regression, and mixed-effects regression) and two center-level statistical approaches (center-level fixed-effects model and center-level random-effects model) were compared to reference GEE model in terms of the robustness of the results – magnitude, direction and statistical significance of the estimated effects on the change of process composite score / on-target clinical composite score. GEE was also used to investigate thecorrelation between the clinical outcomes and surrogate process composite scores.</p> <p><strong>Results:</strong> All six statistical models used in this study produced robust estimates of intervention effect. No significant association between cardiovascular events and on-target clinical composite score and individual component of on-target clinical composite score were found between the intervention group and control group. However, blood pressure, LDL cholesterol, and psychosocial index are significant predictors of cardiovascular events. Process composite score can both predict the cardiovascular events and clinical improvement, but the results were not statistically significant- possibly due to the small number of events. However, the process composite score was significantly associated with the on-target clinical composite score.</p> <p><strong>Conclusions:</strong> We concluded that all five analytic models yielded similar robust estimation of intervention effect comparing to the reference GEE model. The relatively smaller estimate effects in the center-level fixed-effects model suggest that the within-center variation should be considered in the analysis of multicenter RCTs. Process composite score may serve as a good predictor for CVD outcomes.</p> / Master of Science (MSc)

Yes / We thank Professors Evans and Wilkins for their interest in our systematic review.(1) We have reached the same conclusion as previous systematic reviews published in 2008(2) and 2014(3) and a review prepared for the New Zealand Ministry for Health in 2009.(4) Even the ‘alternative systematic review’ prepared by Professors Evans and Allen about which we have significant misgivings concludes that ‘larger and rigorous randomised controlled trials of interventions for visual stress are required’.(5) / A response to Professors Evans and Wilkins regarding the systematic review: Griffiths PG, Taylor RH, Henderson LM and Barrett BT (2016) The effect of coloured overlays and lenses on reading: a systematic review of the literature. Ophthalmic & Physiological Optics. 36: 519–544.

Yes / We read with interest the review written by Evans and Allen, and published in the Journal of Optometry, in July, 2016.

Les essais randomisés split-mouth, sont fréquents en médecine buccodentaire. Cependant, certains auteurs ont suggéré que les effets traitement estimés différaient de ceux fournis par les essais en bras parallèles. Par ailleurs, l'enregistrement prospectif des essais est actuellement la meilleure solution pour lutter contre le biais de publication. Premièrement, nous avons comparé les effets traitement estimés entre essais split-mouth et en bras parallèles par une étude méta-épidémiologique. Nous n'avons pas mis en évidence de différence statistiquement significative dans l'estimation de l'effet traitement entre essais randomisés split-mouth et en bras parallèles à question clinique identique. Ces résultats suggèrent que les auteurs de revues systématiques devraient exploiter toutes les preuves disponibles, et qu'en particulier les essais randomisés split-mouth devraient être inclus dans les méta-analyses avec une analyse appropriée.Deuxièmement, nous avons évalué l'enregistrement prospectif sur des registres publics des essais randomisés split-mouth et en bras parallèles publiés en 2013 dans un échantillon de revues de médecine bucco-dentaire. Sur un échantillon de 317 essais randomisés, nous avons montré que seuls 23% des essais étaient enregistrés. Parmi les essais enregistrés, 91% étaient enregistrés rétrospectivement. Nous n'avons pas mis en évidence de différence statistiquement significative entre essais split-mouth et essais en bras parallèles.En conclusion, nous avons proposé des recommandations relatives à l'intégration des essais randomisés split-mouth au sein de la recherche, tant du point de vue du chercheur que de celui des éditeurs de revue médicale. / Split-mouth RCTs are common in oral health medicine. However, some authors have suggested that intervention effect estimates from split-mouth and parallel-arm RCTs may differ. Besides, prospective registration of RCTs is currently the best solution to reporting bias. First, we performed a meta-epidemiological study to compare intervention effect estimates between split-mouth RCTs and parallel-arm RCTs. There was no sufficient evidence for a difference in intervention effect estimates derived from split-mouth and parallel-arm RCTs investigating the same clinical question. Our results support the use of all available evidence in systematic reviews, including that from split-mouth and parallel-arm RCTs, and authors should consider including split-mouth RCTs in their meta-analyses with suitable and appropriate statistical analysis. Second, we assessed how many split-mouth and parallel-arm RCTs with results published in 2013 in a sample of oral health journals had been prospectively registered in trial registries. Of 317 identified RCTs, we showed that only 23% of RCTs were registered. Among those, 91% were registered retrospectively. We did not find any statistically significant difference between split-mouth and parallel-arm RCTs. In conclusion, we have proposed recommendations regarding the integration of splitmouth RCTs in research, from the point of view of researchers and of medical journal editors.