The consideration of power of a clinical trial to detect the treatment effect is integral in the planning and designing stage of any trial. Recent research however argues that the power of the subsequent evidence synthesis model including the new trial should receive attention in the design stage of any new trial besides the power of the new trial in isolation. This thesis begins with a survey aiming to assess the extent of the use of previous evidence in the design stage of a new trial. The survey concludes that there is a lack of such use of previous evidence, particularly in determining the sample size of the new trial. The findings of the survey set the background and the context of the methodology developed in this thesis. The thesis aims to develop a simulation based methodological framework for designing new trials based on the power of the subsequent evidence synthesis model including the new trial, using several evidence synthesis models. The purpose of this methodology is to offer guidance to researchers in computing the sample size of a new trial on the basis that the new trial will eventually be a part of an evidence synthesis model. The variety of evidence synthesis methods includes standard meta-analysis methods, indirect comparison methods, mixed treatment comparison methods and meta-regression methods. This approach treats the pooled effect size of the initial evidence synthesis model to be the mean of the predictive distribution of the new trial. The predictive distribution of the new trial provides the distribution of an effect size of a new trial that is deemed sufficiently similar to the existing trials to be eligible for the synthesis. Under each evidence synthesis method, we develop various models to design new trials by varying the variance of the predictive distribution. The power of the new trial is shown to increase with increased variance in the predictive distribution. In contrast, the power of the updated evidence synthesis is shown to decrease with the increased variance of the predictive distribution. The new trials designed using fixed effects principles yield the lowest power. However, the updated evidence synthesis model including the new trial designed using the fixed effects principles shows the highest power. This is a common phenomenon noticed in all evidence synthesis methods explored. The framework also includes a component that develops a methodology to design new trials using Bayesian meta-analysis principles. The reasons for the differences found in power results of the Bayesian and frequentist approaches are investigated. The variance of the predictive distribution of a new trial clearly influences both the power of the new trial and the updated evidence synthesis. Trialists are advised to adapt the fixed effects method in designing new trials, whenever the assumption of a common true effect is possible. The Bayesian meta-analysis method developed here does not produce sufficient power in the updated meta-analysis and the methodology requires further refinements.

Licensing and reimbursement decisions on health technologies should be ideally based on randomised controlled trials (RCTs) that report final patient relevant outcomes, such as overall survival or health-related quality of life. However, biomarkers and intermediate endpoints are often used in clinical trials as surrogate outcomes, i.e., as substitutes for final patient-relevant outcomes. Surrogate outcomes may occur faster or may be easier to assess than final outcomes. Nevertheless, relying on surrogate outcomes evidence alone has been shown to lead to inadequate conclusions about the value of new treatments. This PhD thesis by publication explores key issues related to the use of surrogate outcomes in health technology assessment, particularly in the field of oncology. The specific aims of the four component papers are: I. To quantify and compare the treatment effect of RCTs reporting surrogate outcomes versus RCTs using final patient-relevant primary outcomes across a range of diseases; 11. To review the statistical methods used in meta-analyses for validating surrogate endpoints in a specific disease area (i.e., advanced solid tumours) and assess the available level of evidence against current standardised frameworks for surrogate evaluation; Ill. To assess the within-trial surrogate-to-finaI outcome relationship in advanced colorectal cancer, according to different methods and depending on several trial characteristics; IV. To illustrate the use of surrogate end points in a real HTA process (i.e., the technology appraisa l of imatinib, nilotinib and dasatinib as first-line treatment in chronic myeloid leukemia at the National Institute for Health and Care Excellence). In publication I, clinical trials reporting surrogate primary outcomes were found to be more likely to report larger treatment effects (by up to 47%) than clinical trials reporting final patient-relevant outcomes. The review of statistical methods in publication 11 shows that the level of evidence for the use of surrogate outcomes in advanced solid tumours to date is generally poor according to common evaluation tools. In publication IV, I confirm the findings from publication I: the treatment effect observed on the surrogate endpoint appears always to be larger than that observed on the final endpoint, by 3% to 45%. In 4 publication IV, using the case study of chronic myeloid leukemia, the validation of two surrogate outcomes was performed and their link with long-term effectiveness and cost-effectiveness was built for three treatments under comparison. A final overall discussion section brings together the findings of these four publications and identifies practical recommendations and future research implications.

The increasing cost of randomised controlled trials is hindering the rate at which new, effective therapies reach patients. To accelerate drug development, more efficient clinical trial designs are needed. One such design which has had success in speeding up the evaluation of therapies in cancer is the multi-arm multi-stage (MAMS) design. This particular design compares multiple new treatments against a control in a single trial, obviating the need for multiple two-arm studies, and ceases recruitment to poorly performing arms during the study. To further increase efficiency, interim assessments can be based on an intermediate outcome which is on the causal pathway to the primary outcome of the trial, thus allowing phases 2 and 3 of evaluation to be incorporated into a single, seamless design. The MAMS design was initially developed for trials in cancer where time to event outcomes are commonly used. To make it more widely applicable to other disease areas, we first extend the design to other types of outcome measure such as binary. The new designs are then applied to trials in tuberculosis --- a disease area with many new treatments currently in the clinical pipeline and which may therefore benefit from using more efficient trial designs. We then consider more general design issues such as familywise error rate and expected sample size and present calculations of both measures using simulation. Methods are developed for finding designs which have the desired overall operating characteristics and which are the most efficient under particular optimality criteria, known as admissible designs. Guidance is provided for choosing the number of stages and allocation ratio for a particular number of arms and we apply the methods developed in the thesis to existing and hypothetical MAMS trials. Throughout, Stata programs are created and updated to accommodate the use of the methods in practice.

Drug toxicity is usually triggered by the occurrence of a combination of extreme values of laboratory variables that are collected in clinical trials. Drug-induced liver injury (DILI) has been the most frequently related single cause of safety-related drug marketing withdrawals for the past 50 years. The importance of assessing the safety of a drug is illustrated through its pre-marketing evaluation. Safety testing is ubiquitous in all phases of clinical trials and early detection of toxicity is key to preventing severe adverse events as well as to reducing the huge financial cost due to the long-term pre-marketing screening of a new drug. The current applied and methodological interest is in univariate and multivariate extreme value models that are typically fitted to a fraction of the data and form the basis of all subsequent predictions and inferential aspects for the problem under study. Typical challenges that arise in pharmaceutical applications among others are the limited source of information, commonly measured by the sample size, and the accurate estimation of the underlying dependence structure These challenges motivate the present thesis which focuses on constructing and improving extreme value models that have direct potential application to the pharmaceutical industry. In particular, in this thesis we focus on i. providing alternatives to univariate extreme value threshold models that can be fitted to lower thresholds and improve the stability of. the parameter estimates as well as the efficiency of the estimators; ii. introducing additional constraints for, and slight changes in, the model formulation and parameter space of two commonly used multivariate extreme value approaches, namely the conditional extremal dependence model and the component-wise maxima approach. These changes in the method are aimed to overcome complications that have been experienced with using these models in terms of modelling negatively associated random variables, overcoming identifiability problems, and to avoid drawing invalid inferences; 111. extending the conditional extremal dependence model to incorporate subject specific knowledge and a natural ordering between doses in the estimation of the probability of DILI; IV. exploring techniques from multivariate analysis and constructing diagnostic measures for estimating the graphical structure of extreme multivariate events.

No description available.

Randomization schemes for two-treatment clinical trials are studied. Theoretical expressions for the power are derived under both complete randomization and Efron’s biased coin design for normal and binary responses. The better the scheme is at balancing the numbers of patients across treatments, the higher the power is. Efron’s biased coin design is more powerful than complete randomization. Normal approximations to the powers are obtained. The power of the adjustable biased coin design is also investigated by simulation. Covariate-adaptive randomization schemes are analysed when either global or marginal balance across cells is sought. By considering a fixed-effects linear model for normal treatment responses with several covariates, an analysis of covariance t test is carried out. Its power is simulated for global and marginal balance, both in the absence and in the presence of interactions between the covariates. Global balancing covariate-adaptive schemes are more efficient when there are interactions between the covariates. Restricted randomization schemes for more than two treatments are then considered. Their asymptotic properties are provided. An adjustable biased coin design is introduced for which assignments are based on the imbalance across treatments. The finitesample properties of the imbalance under these randomization schemes are studied by simulation. Assuming normal treatment responses, the power of the test for treatment differences is also obtained and is highest for the new design. Imbalance properties of complete randomization and centre-stratified permuted block randomization for several treatments are investigated. It is assumed that the patient recruitment process follows a Poisson-gamma model. When the number of centres is large, the imbalance for both schemes is approximately multivariate normal. The power of a test for treatment differences is simulated for normal responses. The loss of power can be compensated for by a small increase in sample size.

Clinical trials are prospective studies in volunteers to test the safety and efficacy of a drug or intervention in a well-defined, controlled experiment. Pharmaceutical companies spend billions of dollars each year on clinical trials. Yet, despite the rising levels of chronic diseases and evidence suggesting that black patients may respond to treatments differently than their white counterparts, Sub-Saharan Africa is still represented in very few industry-sponsored trials. In addition to any immediate potential therapeutic benefit and the ability to grant patients greater access to drugs that they might not normally be able to obtain, clinical trials may also bring collateral benefits, such as investments in infrastructure and resources. To this end, clinical trials may be useful in helping to address the rising levels of chronic disease in the Sub-Saharan region of Africa. Additionally, it may not always be appropriate to extrapolate data from trials conducted in patients in the West and apply them to patients in other regions of the world, as the literature demonstrates that for certain medicines, treatment effects may differ due to genetic variations between ethnic groups. Aim: The aim of the study was to better understand stakeholder perceptions of the issues associated with the conduct of pharmaceutical industry-sponsored clinical trials in chronic diseases in Sub-Saharan Africa. A further goal was understanding what benefit, if any, conducting such trials could confer to the population and region. Methods: A multi-methods approach was adopted. The first part of the study focused on the use of semi-structured qualitative interviews with various stakeholders to identify the themes most relevant to the research objectives. The contents of the interview transcripts were thematically analysed, and a quantitative online questionnaire was created on the basis of the themes that emerged from the interviews. This questionnaire was then administered to a larger number of similar stakeholders to corroborate the findings from the first part of the study. Results: The interviews identified five main overarching themes. Those themes were as follows: (1) ethical, (2) commercial, (3) medical/scientific, (4) educational, and (5) practical. All five themes are closely related and oftentimes impact one another. The ethical issues largely related to the provision and availability of medicines post-trial and informed consent, as well as to the potential for corruption and fraud by both investigators and pharmaceutical companies operating outside the scope of tightly regulated Western competent authorities and ethics committees. The commercial considerations that were raised primarily centred on the fact that pharmaceutical companies are businesses, many of which have obligations to shareholders, and on the fact that drug development is tremendously expensive. The majority of the profit generated by pharmaceutical companies comes from their sales in the West, which is why their focus remains on that part of the world. The medical and scientific issues were primarily related to the evolution of Sub-Saharan Africa’s disease landscape and pharmaceutical companies’ responsibility to their global patients to ensure a robust understanding of how their drugs affect patients of varying ethnic backgrounds in different parts of the world. The educational issues were mainly linked to public awareness regarding what clinical trials are, as well as to the education of investigators, research staff, and ethics committee members. The final theme to emerge was practical issues raised in relation to a lack of infrastructure and oversight. The results of the questionnaire mostly echoed the findings of the interviews. Through their questionnaire responses, participants indicated that they felt that the pharmaceutical industry does have an ethical and scientific responsibility to do more to ensure that its drugs are tested in developing parts of the world, such as Sub-Saharan Africa. However, respondents indicated that pharmaceutical companies should not conduct trials in regions where they have no intention of selling their products and that the three largest barriers precluding the conduct of clinical trials in that part of the world are a lack of adequate infrastructure, a lack of commercial attractiveness, and concerns around unethical behaviour. Discussion: Although there are inherent risks and disadvantages associated with participating in clinical trials, the benefits are well known and understood for participants in the West. Therefore, most respondents across the stakeholder groups could see the potential benefits of research for Sub-Saharan Africa. However, many within the pharmaceutical stakeholder group exhibited unfamiliarity with the evolving disease landscape and level of infrastructure within Sub-Saharan Africa. The ethical issues and associated practicalities of conducting trials in that part of the world were likewise not well understood. The results of the study suggest that respondents across all stakeholder groups feel that the pharmaceutical industry needs to do more to make drugs available to patients in developing countries, both commercially and through research. As a justification, they pointed to the industry’s ethical and scientific responsibilities to do so. The commercial benefits that the industry could gain from conducting an increased number of clinical trials in Sub-Saharan Africa did not appear to be well understood by the research participants. The results also illustrated that the respondents did not think that chronic diseases should be prioritised over infectious diseases, or vice versa. By carrying out this research, important questions were raised regarding the capabilities of countries within Sub-Saharan Africa, and topics associated with the increasing prevalence of chronic diseases in that region were explored. All stakeholder groups agreed that pharmaceutical companies can play a role in addressing levels of rising chronic disease through the conduct of clinical trials. The findings of this research led to several recommendations, including allowing countries in the region to participate in bridging studies as a starting point, establishing national databases, and revisiting the restrictive wording in certain current ethical regulations.

Im Mittelpunkt dieser kumulativ angefertigten Forschungsarbeit stehen vier prospektive Beobachtungsstudien, die die physischen und psychischen sowie sozial-emotionalen Effekte konventioneller Krebstherapien (Operation, Chemotherapie, Radiotherapie und Hormontherapie) auf Brustkrebspatientinnen in frühen Krebsstadien von der Diagnose über die Behandlung hinweg untersuchen. In der ersten Studie wird die feinmotorische Geschicklichkeit inklusive der Hand- und Fingerfunktion überprüft. Die zweite Studie beschäftigt sich mit individuellen Veränderungen physischer Leistungsfähigkeit und Aktivität, bioelektrischem Phasenwinkel, Symptomen krebsbedingter Fatigue, Angst und Depressivität sowie dem Auftreten von Risikoparametern. Im Fokus der dritten Studie stehen patientenberichtete Endpunkte der gesundheitsbezogenen Lebensqualität und der wahrgenommenen kognitiven Funktion. Ein biopsychosoziales Profil einschließlich klinischer Charakteristika, physischer Leistungsfähigkeit, Phasenwinkel, Angst, Depressivität, Fatigue-Symptomatik sowie gesundheitsbezogener Lebensqualität wird in einer vierten Studie erstellt.:In Kapitel 1 der vorliegenden kumulativen Dissertationsschrift erfolgt die Herleitung der dieser Arbeit zugrunde liegenden wissenschaftlichen Untersuchungen. In Kapitel 2 werden theoretische Grundlagen zur Brustkrebserkrankung erläutert, um dem Leser einen besseren Einblick in die Thematik zu bieten und das Verständnis der eigenen Beiträge zu fördern. Die Publikationen selbst können dem Anhang entnommen werden und stehen als Veröffentlichungen nach Peer-Review-Verfahren in internationalen Fachzeitschriften zur Verfügung. In Kapitel 3 wird das methodische Vorgehen zum Ablauf, Umsetzung und Analyse der Studien beschrieben. In Kapitel 4 werden die einzelnen Studien zur Übersicht zusammengefasst und die wichtigsten Ergebnisse präsentiert. Anschließend erfolgt die Diskussion der gewonnenen Erkenntnisse zu physischen und psychischen sowie sozial-emotionalen Effekten konventioneller Krebstherapien auf Brustkrebspatientinnen (Kapitel 5). Den Abschluss bildet eine kurze Zusammenfassung der Untersuchungen (Kapitel 6).