Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (p. 158-160).

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.

Sephton, Carmen Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 127-144). / Abstracts in English and Chinese. / Chapter A. --- Acknowledgement --- p.ii / Chapter B. --- Abstract in English --- p.iii / Chapter C. --- Abstract in Chinese --- p.v / Chapter D. --- Table of Contents --- p.vii / Chapter E. --- List of Abbreviations --- p.xii / Chapter D. --- Table of Contents / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Basic background of TCM --- p.3 / Chapter 1.2 --- Choosing TCM Over Western Medication --- p.6 / Chapter 1.3 --- TCM Clinical Trials --- p.7 / Chapter 1.4 --- Evidence Based Medicine and Good Clinical Practice --- p.11 / Chapter 1.5 --- Outline of ICH GCP guidelines used for evaluation --- p.15 / Chapter 2. --- Aim and Objectives --- p.18 / Chapter 3. --- Method --- p.19 / Chapter 3.1 --- Rational for choosing the two studies for comparison --- p.21 / Chapter 3.2 --- Literature Search --- p.25 / Chapter 4. --- Method - Traditional Chinese Medicine clinical trial --- p.27 / Chapter 4.1 --- Protocol Development --- p.27 / Chapter 4.2 --- Consent Form Development --- p.28 / Chapter 4.3 --- Ethics Committee Submission and Approval --- p.29 / Chapter 4.4 --- Case Report Form Development --- p.29 / Chapter 4.5 --- Investigator Folder Development --- p.32 / Chapter 4.6 --- GCP Documentation Collection and Development --- p.33 / Chapter 4.6.1 --- Curriculum Vitae Collection --- p.33 / Chapter 4.6.2 --- Site Personnel Log --- p.34 / Chapter 4.6.3 --- Subject Screening Log --- p.34 / Chapter 4.6.4 --- Subject Identification Code List --- p.35 / Chapter 4.6.5 --- Subject Enrolment Log --- p.35 / Chapter 4.7 --- Medication --- p.36 / Chapter 4.7.1 --- Capsules --- p.36 / Chapter 4.7.2 --- Randomisation Code --- p.39 / Chapter 4.7.3 --- Labelling of Study Medication --- p.40 / Chapter 4.7.4 --- Storage --- p.40 / Chapter 4.7.5 --- Drug Accountability --- p.40 / Chapter 4.8 --- Investigator Brochure --- p.41 / Chapter 4.9 --- Monitoring --- p.41 / Chapter 5. --- Method - Western medication clinical trial --- p.42 / Chapter 5.1 --- Protocol Development --- p.42 / Chapter 5.2 --- Consent Form Development --- p.43 / Chapter 5.3 --- Ethics Committee Submission and Approval --- p.43 / Chapter 5.4 --- Case Report Form Development --- p.43 / Chapter 5.5 --- Investigator Folder Development --- p.44 / Chapter 5.6 --- GCP Documentation Collection and Development --- p.44 / Chapter 5.6.1 --- Curriculum Vitae Collection --- p.44 / Chapter 5.6.2 --- Site Personnel Log --- p.45 / Chapter 5.6.3 --- Subject Screening Log --- p.45 / Chapter 5.6.4 --- Subject Identification Code List --- p.45 / Chapter 5.6.5 --- Subject Enrolment Log --- p.45 / Chapter 5.7 --- Medication --- p.46 / Chapter 5.7.1 --- Tablets --- p.46 / Chapter 5.7.2 --- Randomisation Code --- p.46 / Chapter 5.7.3 --- Labelling of Study Medication --- p.47 / Chapter 5.7.4 --- Storage --- p.47 / Chapter 5.7.5 --- Drug Accountability --- p.48 / Chapter 5.8 --- Investigator Brochure --- p.48 / Chapter 5.9 --- Monitoring --- p.48 / Chapter 6. --- Results & Discussion --- p.49 / Chapter 6.1 --- Protocol Development --- p.49 / Chapter 6.2 --- Consent Form Development --- p.59 / Chapter 6.3 --- Case Report Form Development --- p.65 / Chapter 6.4 --- Ethics Committee --- p.67 / Chapter 6.5 --- Investigator Folder Development --- p.68 / Chapter 6.6 --- GCP Documentation --- p.68 / Chapter 6.7 --- Medication --- p.69 / Chapter 6.7.1 --- Study Medication --- p.69 / Chapter 6.7.2 --- Randomisation Code and Code Break Envelops --- p.71 / Chapter 6.7.3 --- Labelling --- p.71 / Chapter 6.7.4 --- Storage --- p.73 / Chapter 6.8 --- Investigator Brochure (IB) --- p.73 / Chapter 6.9 --- Monitoring Visits --- p.75 / Chapter 6.9.1 --- Source document verification --- p.76 / Chapter 6.10 --- Results of Literature Search --- p.80 / Chapter 7. --- Discussion --- p.95 / Chapter 7.1 --- Discussion on the implementation of GCP in the two clinical trials evaluated --- p.95 / Chapter 7.2 --- Role and Importance of the Study Monitor & Results of Source Document Verification --- p.99 / Chapter 7.3 --- Blinding & randomisation procedures --- p.103 / Chapter 7.4 --- Good clinical Practice & TCM clinical trials --- p.103 / Chapter 7.5 --- Performing Literature Search in Preparation for TCM Clinical Trials --- p.110 / Chapter 7.6 --- Standardisation of Herbs and GMP Issues --- p.112 / Chapter 7.7 --- TCM Medical Practitioner (Investigator) Selection --- p.116 / Chapter 7.8 --- Method of Diagnosis --- p.117 / Chapter 7.9 --- Randomisation & Blind Assessment (placebo or control treatment) --- p.118 / Chapter 7.10 --- Adverse Events in TCM Clinical Trials --- p.122 / Chapter 7.11 --- Other Issues or Considerations & Future Work to be Performed at the CPSU --- p.122 / Chapter 8. --- Conclusion --- p.125 / Chapter 9. --- Reference List --- p.127 / Chapter 10. --- Appendices --- p.145

Complete randomized experimental design has been a popular standard in clinical trials due to its abilities to yield a smaller bias and to provide a strong foundation for statistical inferences. However, because of ethical issues, there is a growing demand for response adaptive designs which shift the allocation probabilities such that more patients receive the better treatment. The principal idea of response adaptive designs to allocate fewer patients to treatments which appears to be inferior based on the accruing response data and information collected up to the current stage. Although they are more complex than complete randomized experiments in theory and method, adaptive designs are practically more useful. The objective of this dissertation is to develop an adaptive design, the generalized drop-the-loser rule, for comparing multiple treatments in clinical trials, including the situation where the responses of patients are delayed moderately. Asymptotic properties including strong consistency and asymptotic normality of the new design are investigated through the martingale technique. Monte Carlo simulation studies are conducted to reveal the empirical performance of this design. The new design will be potentially useful in the practical context of clinical trials. / Sun Ruibo. / "July 2006." / Adviser: Siu Hung Cheung. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6488. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 62-66). / 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.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (p. 148-153).

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 107-111).

Thesis (Ph.D. in Biostatistics) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 104-106). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

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.

A clinical trial may have no subject (0%) or every subject (100%) developing the outcome of concern in either of the two comparison groups. This will cause a zero-cell in the four-cell (2x2) table of a trial using a binary outcome and make it impossible to estimate the odds ratio, a commonly used effect measure. A usual way to deal with this problem is to add 0.5 to each of the four cells in the 2x2 table. This is known as Haldane's approximation. In meta-analysis, Haldane's approximation can also be applied. Two approaches are possible: add 0.5 to only the trials with a zero cell or to all the trials in the meta-analysis. Little is known which approach is better when used in combination with different definitions of the odds ratio: the ordinary odds ratio, Peto's odds ratio and Mantel-Haenszel odds ratio. / A new formula is derived for converting Peto's odds ratio to the risk difference. The derived risk difference through the new method was then compared with the true risk difference and the risk difference derived by taking the Peto's odds ratio as the ordinary odds ratio. All simulations and analyses were conducted on the Statistical Analysis Software (SAS). / Conclusions. The estimated confidence interval of a meta-analysis would mostly exclude the truth if an inappropriate correction method is used to deal with zero cells. Counter-intuitively, the combined result of a meta-analysis will be worse as the number of studies included becomes larger. Mantel-Haenszel odds ratio without applying Haldane's approximation is recommended in general for dealing with sparse data in meta-analysis. The ordinary odds ratio with adding 0.5 to only the trials with a zero cell can be used when the trials are heterogeneous and the odds ratio is close to 1. Applying Haldane's approximation to all trials in a meta-analysis should always be avoided. Peto's odds ratio without Haldane's approximation can always be considered but the new formula should be used for converting Peto's odds ratio to the risk difference. / In addition, the odds ratio needs to be converted to a risk difference to aid decision making. Peto's odds ratio is preferable in some situations and the risk difference is derived by taking Peto's odds ratio as an ordinary odds ratio. It is unclear whether this is appropriate. / Methods. For studying the validity of Haldane's approximation, we defined 361 types of meta-analysis. Each type of meta-analysis is determined by a unique combination of the risk in the two compared groups and thus provides a unique true odds ratio. The number of trials in a meta-analysis is set at 5, 10 and 50 and the sample size of each trial in a meta-analysis varies at random but is made sufficiently small so that at least one trial in a meta-analysis will have a zero-cell. The number of outcome events in a comparison group of a trial is generated at random according to the pre-determined risk for that group. One thousand homogeneous meta-analyses and one thousand heterogeneous meta-analyses are simulated for each type of meta-analysis. Two Haldane's approximation approaches in addition to no approximation are evaluated for three definitions of the odds ratio. Thus, nine combined odds ratios are estimated for each type of meta-analysis and are all compared with the true odds ratio. The percentage of meta-analyses with the 95% confidence interval including the true odds ratio is estimated as the main index for validity of the correction methods. / Objectives. (1) We conducted a simulation study to examine the validity of Haldane's approximation as applied to meta-analysis, and (2) we derived and evaluated a new method to covert Peto's odds ratio to the risk difference, and compared it with the conventional conversion method. / Results. By using the true ordinary odds ratio, the percentage of meta-analyses with the confidence interval containing the truth was lowest (from 23.2% to 53.6%) when Haldane's approximation was applied to all the trials regardless the definition of the odds ratios used. The percentage was highest with Mantel-Haenszel odds ratio (95.0%) with no approximation applied. The validity of the corrections methods increases as the true odds ratio gets close to one, as the number of trials in a meta-analysis decreases, as the heterogeneity decreases and the trial size increases. / The proposed new formula performed better than the conventional method. The mean relative difference between the true risk difference and the risk difference obtained from the new formula is -0.006% while the mean relative difference between the true risk difference and the risk difference obtained from the conventional method is -10.9%. / The validity is relatively close (varying from 86.8% to 95.8%) when the true odds ratio is between 1/3 and 3 for all combinations of the correction methods and definitions of the odds ratio. However, Peto's odds ratio performed consistently best if the true Peto's odds ratio is used as the truth for comparison among the three definitions of the odds ratio regardless the correction method (varying from 88% to 98.7%). / Tam Wai-san Wilson. / "Jan 2006." / Adviser: J. L. Tang. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6488. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 151-157). / 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.