Clinical trials are generally considered the foremost authority for generating robust medical evidence because of their methodological strengths relative to other clinical research designs. However, they are susceptible to substantial challenges, such as enrollment barriers, low participation rates, high operational costs, and limited results generalizability, to name a few. A promising resource to address these challenges is real-world data (RWD), generally defined as routinely collected data during the delivery of healthcare. Database-specific RWD – such as electronic health records (EHRs), administrative claims, and clinical registries – is of particular interest for their richness and volume. However, coordination between the primary data collection actions of clinical trials with the secondary collection nature of RWD, while also accounting for data fitness-for-use considerations, persists as a prominent challenge. This dissertation aims to advance the sciences of using RWD to enhance clinical trials, specifically from two perspectives: (1) a trial design perspective; and (2) a results interpretation perspective. It first reviews relevant literature about RWD uses for clinical trial conduct. It then seeks to address two research questions focused on using RWD to improve clinical trials, with particular emphasis on clinical trials that evaluate medications: (1) how do eligibility criteria, both individually and in combination, affect patient safety and recruitment pool size; and (2) how representative of real-world patients are enrolled trial participants. The utility of RWD in investigating these questions is tested using two aims. Aim 1 examines the impact on hospitalization risk and eligible patient pool size of different eligibility criteria combinations across a variety of disease domains. Aim 2 clinically characterizes trial participants for generalizability assessments. The primary innovations of this dissertation include (1) supplementing a RWD source with trial enrollment data, thus creating a novel combination for enriched evaluations; and (2) developing innovative approaches, both across sets of clinical trials and within individual trials, for generalizability assessments. Ultimately, the findings of this dissertation demonstrate how clinical trial design, and the interpretation of their results, can be enhanced through the use of RWD in order to strengthen clinical research pursuits in study design and results interpretation.

Benefits are measurable improvements that result from project outcomes. There is an emphasis in clinical trials literature that clinical trial benefits must always outweigh the risks yet there is limited clarity on processes to manage and ensure delivery of those benefits. With uncertainty around the delivery of clinical trial benefits, it is worth adopting a balanced management approach. This study looked to establish whether there were any comprehensive benefits management processes in HIV clinical trials and compared these practices to those described in the literature. Methods: To assess the current benefits management practices used to manage HIV clinical trials, a cross-sectional study used a critical review of clinical trials guidelines and publications as well as an online survey that was distributed to stakeholders in clinical trials management. Results: The critical review of the guidelines and literature revealed a high emphasis on risk benefit assessment, but very limited mention of the processes used for the assessment and management of those risks and benefits. The diverse group of clinical trials managers that responded to the online survey were involved at the strategic level of their respective clinical trials and 74% of them had never heard of Benefits Realization Management (BRM) and BRM processes. The respondents however, acknowledged that their lack of awareness did not necessarily mean lack of existence of BRM or BRM processes in HIV clinical trials. There were aspects of benefits management practices in clinical trials that were found to be similar to those in literature and other industries such as benefits planning, benefits identification, benefits review, setting time scale to benefits realization and allocating benefits champions. Even though there was confidence from the respondents in how clinical trial benefits were managed and in clinical trials delivering their promise, the respondents still believed there was room for improvement in the current BRM processes. Conclusion: BRM processes are not readily visible or documented in HIV clinical trials. There is a management bias towards safety and ethics in clinical trials which seems to have resulted in limited focus on benefits management. Compared to other industries, there appears to be more room and opportunity to implement published BRM processes. The findings from this study will serve as a starting point for future studies on how BRM can be incorporated into current management practices in order to achieve the most out of clinical trials.

Submitted in partial fulfilment of the requirements for the degree of Master of Public Health, in the field of Social and Behaviour Change Communications, in the University of the Witwatersrand, Johannesburg, 2012 / The Good Participatory Practice Guidelines recommend that research results are made available to a broad range of stakeholders, including policy makers and trial participants, yet there is little guidance on how this may be achieved. The Microbicides Development Programme (MDP301 trial) was a large scale clinical trial that took place at thirteen clinics in South Africa, Tanzania, Uganda and Zambia between 2004 and 2009. The results of this trial were released in late 2009 and a comprehensive, multi-method results dissemination plan was implemented to communicate the research findings to policy makers, key stakeholders, research staff, Community Advisory Boards and trial participants between December 2009 and November 2010. This study was a retrospective analysis which included a process evaluation (and costing) of the implementation of the results dissemination plan for the MDP301 trial and an analysis of how the incorporation of telephonic unblinding potentially benefited the research community.

Background and Objectives We investigate three statistical and methodological issues within the context of non-inferiority randomized controlled trials (RCTs), specifically those of radiotherapy regimens for the prevention of local recurrence in patients with early stage breast cancer who have undergone breast conserving surgery. These issues are: (1) the analysis of multiple time-to-event outcomes in non-inferiority RCTs; (2) the interim analysis of a binary outcome that is repeatedly assessed at pre-specified times; and (3) determining the optimal analysis population for dealing with crossovers in non-inferiority RCTs. Methods Issue 1: We investigated and compared the properties of four statistical models (proportional hazards model, competing risk model, marginal model and frailty model) for analyzing radiotherapy non-inferiority RCTs of patients with early stage breast cancer who are at risk for and may experience multiple failure types. We applied the four methods to data from an existing trial in which subjects with breast cancer could experience local recurrence (the primary outcome), distant recurrence, death, or a combination of these events. In addition, we compared these models using simulated examples of similar non-inferiority trials with varying hazards of each failure type. Issue 2: We investigated and compared the properties of three methods for estimating the event proportions for an interim analysis in RCTs with a binary outcome that is repeatedly assessed at pre-specified times. Generally, interim analyses are performed after half or more of the subjects have completed full follow-up. However, depending on the duration of accrual relative to the length of follow-up, this may be inefficient, since there is a possibility that the trial will have completed accrual prior to the interim analysis. We focussed our simulations on situations where delaying the interim analysis until half or more of subjects have completed full follow-up is an inefficient approach. The methods include: 1) estimation of the event proportion based on subjects who have been followed for a pre-specified time (less than the full follow-up duration) or who experienced the outcome; 2) estimation of the event proportion based on all available data from subjects randomized by the time of the interim analysis; and 3) the Kaplan-Meier approach to estimate the event proportion. We varied the risk of the outcome, the treatment effect and the probability of an event occurring at each pre-specified time. We compared the three methods in terms of overall type I and II errors, as well as the probability of stopping early for benefit. Issue 3: We explored the effect of subject crossover from the experimental to the standard radiotherapy arm prior to treatment initiation on the intention-to-treat, per-protocol, as-treated and combined intention-to-treat and per-protocol analysis in non-inferiority RCTs of radiotherapy for the prevention of local recurrence in patients with early stage breast cancer. We varied the non-inferiority margin, the percent of subjects who cross over and evaluated random and non-random crossover. The main comparison of the methods was done using overall type I error. In addition, we compared the methods based on estimate bias and standard error of the estimate. Results and Conclusions Issue 1: All four models produced similar results for the existing trial (i.e. non-inferiority was observed regardless of the method used). Simulations showed that the event-specific methods yielded contrasting results when the distribution of distant recurrence or death differed between treatment groups. We conclude that multiple models should be used as part of a comprehensive analysis. Issue 2: We showed that conducting an interim analysis when a considerable number of subjects have completed a portion of their full follow-up duration is an efficient approach under certain scenarios where event distribution probabilities are similar between treatment groups. Under these specific scenarios, all three methods preserved the type I and II errors. In these cases, we recommend using the Kaplan-Meier method because it incorporates all the available data and has greater probability of early stopping. Issue 3: The as-treated analysis had the best performance in terms of type I error rate. However, it can be recommended only in scenarios where crossover is random. It performed poorly in scenarios with greater than 2% non-random crossover. The intention-to-treat and per-protocol analysis performed poorly under both random and non-random crossover scenarios. / Thesis / Doctor of Philosophy (PhD)

This thesis develops two semiparametric methods for censored survival data when the covariates involved are time-dependent. Respectively in the two parts of this thesis, we introduce an interquantile regression model and a censored quantile regression model that account for the commonly observed time-dependent covariates in survival analysis. The proposed quantile-based techniques offer a greater model flexibility comparing to the Cox proportional hazards model and the accelerated failure time model. The first half of this thesis introduces a censored interquantile regression model with time-dependent covariates. Conventionally, censored quantile regression stipulates a specific, pointwise conditional quantile of the survival time given covariates. Despite its model flexibility and straightforward interpretation, the pointwise formulation oftentimes yields rather unstable estimates across neighbouring quantile levels with large variances. In view of this phenomenon, we propose a new class of censored interquantile regression models with time-dependent covariates that can capture the relationship between the failure time and the covariate processes of a target population that falls within a specific quantile bracket. The pooling of information within a homogeneous neighbourhood facilitates more efficient estimates hence more consistent conclusion on statistical significances of the variables concerned. This new formulation can also be regarded as a generalization of the accelerated failure time model for survival data in the sense that it relaxes the assumption of global homogeneity for the error at all quantile levels. By introducing a class of weighted rank-based estimation procedure, our framework allows a quantile-based inference on the covariate effect with a less restrictive set of assumptions. Numerical studies demonstrate that the proposed estimator outperforms existing alternatives under various settings in terms of smaller empirical bias and standard deviation. A perturbation-based resampling method is also developed to reconcile the asymptotic distribution of the parameter estimates. Finally, consistency and weak convergence of the proposed estimator are established via empirical process theory. In the second half of this thesis, we propose a class of censored quantile regression models for right censored failure time data with time-dependent covariates that only requires a standard conditionally independent censorship. Upon a quantile based transformation, a system of functional estimating equations for the quantile parameters is derived based on the martingale construction. While time-dependent covariates naturally arise in time to event analysis, the few existing literature requires either an independent censoring mechanism or a fully observed covariate process even after the event has occured. The proposed formulation extends the existing censored quantile regression model so that only the covariate history up to the observed event time is required as in the Cox proportional hazards model for time-dependent covariates. A recursive algorithm is developed to evaluate the estimator numerically. Asymptotic properties including uniform consistency and weak convergence of the proposed estimator as a process of the quantile level is established. Monte Carlo simulations and numerical studies on the clinical trial data of the AIDS Clinical Trials Group is presented to illustrate the numerical performance of the proposed estimator.

Accelerating regulatory science has become an urgent task due to the ongoing emergence of novel and highly complex diseases, such as coronaviruses and mpox, and the growing real-world evidence and precision medicine paradigms. In research and development, achieving this goal requires the formulation and implementation of innovative clinical trial designs and statistical approaches. Further efforts are needed to devise robust strategies toward expediting the evaluation of drugs and other medical products, which will help to quicken the delivery of safe and effective treatments to individuals in need. One pioneering concept that has greatly contributed to speeding up product assessment is the application of pre-specified adaptations in clinical trials. Adaptive techniques (like early dose or treatment selection and sample size recalibration) are based on participant data collected during the trial, where investigators/sponsors are able to learn from the study population and adjust trial characteristics accordingly without diminishing the integrity of the study. However, adaptations must be employed cautiously; it is essential to ensure that they are both clinically reasonable and statistically sound (in the sense that they will not inflate the nominal type I error rate). The evolution of seamless trial designs has also propelled drug/medical product evaluation. For instance, seamless trials that combine a phase II study (e.g., using a biomarker or short-term intermediate endpoint for early dose or treatment selection) and a phase III study (e.g., using a definitive endpoint for confirming efficacy) have become very popular in practice due to their flexibility and shorter duration compared to running separate studies. In phase II/III seamless trials, a correlation is usually pre-specified between the intermediate and definitive endpoints in order to bridge the phase II and phase III studies and accomplish the overall aims of the intended trial. However, this can be difficult to quantify, especially when the endpoints are non-continuous. An inappropriate or unsubstantiated enumeration of this correlation can yield flawed results and thus misguide approval and labeling decisions, leading to potentially serious consequences. To avert this issue, a three-stage phase II/III transitional seamless trial design was constructed that does not demand prior knowledge of the correlation between the intermediate and definitive endpoints. The design also allows for interim sample size re-estimation according to the accrued intermediate endpoint data. The utility and validity of the design, with and without sample size adaptation, were considered for different types of endpoints. For each, theoretical proofs establish that the design can control the nominal type I error rate while still reaching the targeted power, and simulations reinforce these findings. Therefore, the design exhibits promise in precipitating the assessment of experimental interventions in a wide range of therapeutic areas. This dissertation is organized as follows. First, Chapter 1 presents (1) an introduction to the drug/medical product evaluation process, (2) an overview of adaptive techniques used in clinical trials, (3) a description of seamless trial designs, including a real-world example to demonstrate how they can be applied in different data situations, (4) the research goals, and (5) a display of the proposed three-stage phase II/III transitional seamless trial design and its workflow. Chapters 2-5 lay out the models and procedures for the proposed design when using a continuous intermediate endpoint and a continuous definitive endpoint, a binary intermediate endpoint and a continuous definitive endpoint, and a binary intermediate endpoint and a time-to-event definitive endpoint in the presence and absence of censored observations. This is proceeded by statistical justification and supporting simulations for each procedure. As some authors remain skeptical toward the use of adaptations in clinical trials, Chapter 6 counters an argument posed in the literature. In closing, Chapter 7 summarizes the work and its limitations and provides several additional considerations toward enhancing the proposed design and its generalizability.

This thesis offers insights from knowledge management theory to understand the flow of knowledge across the multiple actors involved in the execution of a clinical trial in Latin America. In the last 12 years, the participation of Latin America in the business of clinical trials has significantly increased, becoming a highly demanded region to implement sponsored clinical research, overtaking regions like Africa, India, Southeast Asia, and Middle Eastern countries. Also, over this period, sponsors have increased the outsourcing of in-house activities such as trial monitoring, pharmacovigilance and regulatory services to Contracted Research Organisations (CROs), shifting the 'two organisations' and bi-directional relationship between the sponsor and the research sites. This change in the clinical trials landscape has also taken place in Latin America, where in addition to the CRO, the figure of Site Management Organisations (SMOs) has emerged to manage multiple research sites over the course of the trial. Therefore, the internationalisation of clinical research, plus the outsourcing of strategic activities, have transformed the implementation of clinical trials in the region. On the other hand, the results of a clinical trial depend strongly on the analytical skills and cognitive capabilities employed by people working on the project. These characteristics make the clinical trial a Knowledge Intensive Project (KIP), where the main project outcomes depend to a large extent on the use of knowledge by the workers, and the transfer of knowledge data and information across the multiple organisations working in the clinical trial. Because knowledge is the primary production factor in a clinical trial, and in the context of Latin America, to my knowledge, there is reduced research about the production of clinical evidence and the role of each one of the actors over the execution, the main research question that this thesis answers is: How does knowledge flow across organisations and is employed by people in their firms to implement the clinical trials and obtain their respective results? To answer this research question, I proposed and evaluated a three-step model to study the flow of knowledge, data and information across multiple organisations being part of the clinical trial and the use of these to produce the knowledge products by the sponsor and the research sites. This model has its roots in the literature of knowledge 'models, work and processes', the concept of interdependence and the literature of knowledge transfer and acquisition in the outsourced project. The model consists of three steps to address, at the inter-organisational level, the transfer and acquisition of knowledge, data and information and the interdependency on results; and at the intra-organisational level, the use of knowledge and storage. The presented model was evaluated and complemented based on the evidence collected through a multi-case study of three multi-organisational clinical trials to evaluate three new vaccine candidates in Colombia, Brazil and Mexico. The findings of this research indicated that the model was robust to study the flow of knowledge, data and information between the sponsor and the research sites, from the design of the protocol to the production of the clinical data. The results also indicate that the presence of intermediaries decreases the transfer of knowledge and information between the parts, and induces the selectivity of the research sites toward one of the sources of knowledge, the Sponsor, the CROs or SMO. The evidence shows that the acquisition of knowledge by physicians demands a knowledge-destruction capability to actively employ the acquired knowledge in the trial and the constant presence of loops to reinforce the knowledge acquisition. The empirical findings of knowledge and data acquisition by the research sites and the sponsor contributed to developing the concept of permeability, contributing to the literature of knowledge acquisition in outsourced projects. This research addresses, for the first time, the implementation of vaccine clinical trials in Latin America countries and the contribution of the local researcher to the project, especially with their knowledge about the communities intervened. But it also highlighted some of the aspects that affect the implementation of clinical trials, such as the labour conditions in academia, which induce turnover, and the lack of harmonisation among clinical trial regulation in the region. In conclusion, the model proposed allowed me to address simply the complexities that take place in the production of knowledge products in multi-organisational clinical trials in Latin America countries.

In received biomedical research wisdom, randomized controlled trials (RCTs) revolutionized post-World War II health research. By blending statistical analysis with the testing of new procedures and interventions, RCTs have enabled investigators to circumvent the influence of a variety of biases on research outcomes so that the effectiveness of interventions can be ascertained with high levels of confidence. While extant literature addresses the epistemological history of RCTs from the scientific community's perspective, the history of public health would be significantly enhanced by a broader, more detailed consideration of social dimensions of RCTs. Similarly, while a plethora of bioethical literature has been written on RCTs and human subject research, we currently lack a historical analysis that considers ethical shifts over time as they relate to RCTs. This dissertation describes the key political, economic, intellectual, and cultural events in the history of RCTs from their origins to 1980 and analyzes how these events influenced RCT norms. I describe the barriers to the implementation of RCTs throughout the late nineteenth and early twentieth centuries--namely the dominance of individualistic ideologies in clinical research and an absence of governmental regulatory or funding structures to require or support RCTs. I then describe how large, multi-site RCTs grew out of a Cold War political environment that supported public investment in scientific structures; how post-WWII research regulations influenced the proliferation of RCTS in the US; how politics and regulations influenced shifts in the demographics of RCT research subjects; and how ethical norms changed over time through interaction with broader ethical shifts and governmental regulations.

Keywords: Non-inferiority Test, Bootstrap, Misclassification, Partially Validated Data. / Moreover, misclassification is frequently encountered in collecting ordinal categorical data. We also consider the non-inferiority test based on the data with misclassification. We have explored two different approaches. The first approach can be applied when misclassification probabilities are known or can be calibrated. The second approach deals with the case when we have partially validated data that provide the information on misclassification. The proposed approaches have wide applications that are not confined to tests in medical research. We design a substantive study to illustrate the practicality and applicability of the proposed approaches. / When a new treatment comes out, it is likely to find benefits of the new one, such as fewer side effects, greater convenience of employment, or lower cost in terms of money and time. Therefore, the more appropriate research question is whether the new one is non-inferior or equivalent to, but not necessarily superior to the reference treatment. Consequently, the non-inferiority test or equivalence test is widely used in medical research, which is oriented towards showing that the difference of effect between the two treatments probably lies in a tolerance interval with the pre-defined lower or upper bounds. In this thesis, we consider non-inferiority tests when the data are ordinal categorical. In particular, we are interested in correlated data. We will develop non-inferiority testing procedures for data that are obtained by the paired design and three-armed design. We take advantage of a latent normal distribution approach to model ordinal categorical data. / Han, Yuanyuan. / Adviser: Poon Wai-Yin. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 114-117). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Bupivacaine ((R, S)-1-butyl-2-piperidylformo-2', 6'-xylidide), an anilide type local anaesthetic is manufactured in the standard racemic form and is widely used in the practice of regional anaesthesia. Despite its popularity as a local anesthetic, it has the potential to produce severe cardiotoxicity. Enantiomers, which are a pair of chiral isomers that are direct, nonsuperimposable mirror images of each other, vary in their chemical, pharmacological and toxicological profiles due to different stereospecific recognition in the body. Single enantiomeric drugs, when compared to racemic drugs, exert similar clinical effects but produce decreased risks of cardiac and neurotoxicity. This has led to the development of the single enantiomeric drugs ropivacaine ((S)-1-propyl-2-piperidylformo-2', 6'-xylidide) and levobupivacaine ((S)-1-butyl-2-piperidylformo-2', 6'-xylidide). Since local anaesthetics are extensively bound (>90%) to plasma protein in blood such as album and alpha1-acid-glycoprotein, it is only the free form of the flowing drug that can exert its pharmacological effects and are believed to be closely related to systemic toxicity. Although the safety and efficacy of these newer local anaesthetics have been ascertained in the literatures, but there are limited data on their pharmacokinetic profiles; thus it is envisioned that further pharmacokinetic trials would be required to elucidate their pharmacological and clinical effects. The aim of this thesis was to develop sensitive, reproducible and reliable methods of local anaesthetic assays to support such clinical trials. / The assays described in the thesis have been applied to numerous clinical research projects. Out of the various studies, the following will be discussed: Ropivacaine undergoes slower systemic absorption from the caudal epidural space in children than bupivacaine; Arterial and venous pharmacokinetics of ropivacaine with and without epinephrine after thoracic paravertebral block; Pharmacokinetics of levobupivacaine after thoracic paravertebral block. / The first method developed is the simultaneous determination of ropivacaine and bupivacaine in human plasma using high performance chromatography (HPLC). Most published methods of determining ropivacaine in human plasma use gas chromatography and a review of literature to date shows no data describing the use of HPLC to simultaneously determine both drugs. This is the first report describing a simple, isocratic, reversed-phase, liquid-liquid extraction procedure of high-performance liquid chromatographic method that allows the simultaneous detection of both local anaesthetics in one single injection. The chromatography was achieved using a reversed-phase chromatographic system with a Waters Novapak C18 column. 0.5 ml plasma was used for the sample preparation procedures. Bupivacaine and ropivacaine concentrations ranging from 10ng/ml to 3000 ng/ml and fixed amounts of pentycaine (internal standard) were spiked into the plasma samples for calculating the calibration graphs. Calibration graphs were linear over the range 10-3000 ng/ml (r=0.9978 for bupivacaine and r=0.9986 for ropivacaine). The within-day (intra-assay) coefficient of variation of the assay varied between 13.84% at 100 ng/ml, 1.84% at 500 ng/ml and 3.34% at 2000 ng/ml for bupivacaine; and 5.29% at 100 ng/ml, 1.38% at 500 ng/ml and 3.93% at 2000 ng/ml for ropivacaine. The between-day (inter-assay) coefficient of variation was 8.43% at 100 ng/ml, 4.06% at 500 ng/ml and 9.15% at 2000 ng/ml for bupivacaine, and 5.66% at 100 ng/ml, 4.40% at 500 ng/ml and 8.14% at 2000 ng/ml for ropivacaine. The limit of detection for both drugs was 10 ng/ml. / The fourth analytical technique describes the successful development of an ultrafiltration protein binding procedure to detect the free levels of the local anaesthetics in human plasma. Sample plasma was deposited in the ultrafiltration apparatus and ultrafiltrate containing the free local anaesthetics was forced thru a membrane under a fixed-angle rotor centrifugal force. Experiments were done to establish the optimum parameters for the ultrafiltration apparatus' binding capacities. The validated procedures use 0.5 ml plasma as the starting volume and it was deposited into the ultrafiltration apparatus. It was then subjected to 1750g centrifugal force for 20 minutes at centrifugal temperature of 37°C. The resultant ultrafiltrate was processed according to the described LC-MS/MS method to detect the free local anaesthetic levels. / The second analytical methodology describes the assay of levobupivacaine in human plasma using HPLC. Calibration graphs relating peak height ratios and concentrations were linear over the range 10-3000 ng/ml (r=0.9995). The chromatography was achieved with an XTerra MS C18 column with the ultraviolet monitor set at 210 nm. The sample preparation steps were similar to the first analytical method, but with a different internal standard used. Precision and accuracy were assessed by performing analysis on replicate control plasma samples. The within-day (intra-assay) coefficient of variation of the assay varied between 4.25% at 50 ng/ml, 3.38% at 500 ng/ml, 3.76% at 1000 ng/ml and 3.14% at 2000 ng/ml. The between-day (inter-assay) coefficient of variation of the assay varied between 4.68% at 50 ng/ml, 4.94% at 500 ng/ml, 4.25% at 1000 ng/ml and 2.94% at 2000 ng/ml. The limit of detection was 10 ng/ml. / The third analytical methodology details the development and validation of a chiral analytical technique. This is the first report describing the development of a simple, isocratic, reversed-phase, liquid-liquid extraction procedure of a direct chiral method that allows the simultaneous detection of either free or total concentrations of bupivacaine enantiomers and ropivacaine in one single injection. It is also a novel technique to assay bupivacaine enantiomers with the use of vancomycin CSP column and liquid chromatography-mass spectrometry (LC-MS/MS) analysis, which achieved the lowest published detection limit with the lowest volume of plasma used. Calibration graphs were linear over the range 0.1-2000 ng/ml. Precision and accuracy were assessed by performing analysis on replicate control plasma samples. The within-day (intrassay) coefficient of variations of the assay for the drugs ropivacaine, levobupivacaine, dextrobupivacaine varied from 2.20% to 5.78%, 1.96% to 9.64%, 1.78% to 6.34%, respectively, for concentrations between 0.5 ng/ml to 2000 ng/ml. The between-day (interassay) coefficient of variations of the assay for the drugs ropivaciane, levobupivacaine, dextrobupivacaine varied from 3.66% to 9.61%, 3.18% to 8.34%, 2.22% to 10.59%, respectively, for concentrations between 0.5 ng/ml to 2000 ng/ml. The limit of detection was 0.05 ng/ml. / Wong Sum Yee April. / "November 2005." / Advisers: Manoj Karmakar; Tony Gin. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6370. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 207-217). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.