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Wheeler, Graham Mark. "Adaptive designs for phase I dose-escalation studies." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708029.
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Dube, Admire. "The design, preparation and evaluation of Artemisia Afra and placebos in tea bag dosage form suitable for use in clinical trials." Thesis, University of the Western Cape, 2006. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_2915_1188480959.
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Artemisia Afra, a popular South African traditional herbal medicine is commonly administered as a tea infusion of the leaves. However, clinical trials proving it safety and efficacy are lacking mainly due to the absence of good quality dosage forms and credible placebos for the plant. The objectives of this study were to prepare a standardized preparation of the plant leaves and freeze-dried aqueous extract powder of the leaves, in a tea bag dosage form and to design and prepare credible placebos for these plant materials.
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Onthank, David C. "Prediction of "First Dose in Human" for Radiopharmaceuticals/Imaging Agents Based on Allometric Scaling of Pharmacokinetics in Pre-Clinical Animal Models." Digital WPI, 2006. https://digitalcommons.wpi.edu/etd-dissertations/443.
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It is an FDA requirement that the“first in human" dose be based on pre-clinical animal model efficacy and safety testing to ensure a safe entry into Phase I clinical trials. Pre-clinical safety and efficacy models range from mouse to non-human primates. Interspecies scaling of pharmacokinetic parameters is therefore important for predicting drug doses in human clinical trials, although it continues to be less than optimal. Understanding the disposition of the compound in different species through in vitro and in vivo experiments is necessary to ensure appropriate species are selected for human estimates. Data for three imaging agents and a pharmacological stress agent (Oncology tumor agent (DPC-A80351), Thrombus agent (DMP-444), Infection agent (RP-517) Pharmacological stress agent (DPC-A78445-00)) that entered clinical trials and an imaging agent being developed (RP845), were assessed for scaling accuracy. Initially, pharmacokinetic data from animal models were used to extrapolate to human though body weight allometric scaling. Subsequently, the impact of adjusting for plasma protein binding and the impact of metabolic stability in the different models were examined. Allometric scaling of animal pharmacokinetic parameters (clearance (CL), half-life (t½) and volume of distribution (Vdss)) achieved a prediction of the human pharmacokinetic parameter within 13 to 109% of the observed values. This prediction was further improved by adjusting for plasma protein binding of the drug, and achieved an estimate within 5 to 57% of the clinically observed values. Since the parent compound was the dominant species (>95%) in the circulation, metabolic stability was not used as a correction factor. Weight based allometric scaling was further examined for an atherosclerotic plaque targeted radiopharmaceutical imaging agent, RP845-Tc-99m, currently in development. Pharmacokinetic parameters were determined in mouse, rat and rabbit followed by allometric scaling to predict the non-human primate values. Differences between predicted versus observed non-human primate Cl, t½ and Vdss were 40%, 52% and 8%, respectively. Correcting for plasma protein binding improved the prediction for Cl and t½ to within 12 and 3 %, respectively. The Vdss prediction, however became less accurate (38% difference). Since blood clearance is the major parameter in predicting human dose, the improvement from 40% to 12% was important. The plasma protein binding adjusted animal data was then used with allometric scaling to predict human CL, t½ and Vdss. The predicted values were 7.6 mL/min/kg, 70.6 minutes and 0.87 L/kg respectively. Based on the predicted human blood clearance and the dose required to image atherosclerosis in a rabbit model, the estimated human dose would be unacceptably high. This demonstrates how allometric scaling can be used in research projects to assess clinical feasibility. The impact of metabolism differences influencing the reliability of various species to predict for man was highlighted by DPC-A78445-00. DPC-A78445-00 is being developed as an alternative to exercise in myocardial perfusion imaging for the evaluation of coronary artery disease. DPC-A78445-00 was rapidly metabolized to the carboxylic acid by mouse and rat blood in vitro and in vivo, however longer stability was observed in the dog. In vitro human blood data was consistent with the dog, suggesting that mouse and rat would not be representative species. DPC-A78445-00 plasma protein binding was at a similar, moderate level in rat, dog and human plasma and metabolism by hepatocytes was similar in dog and human. Phase I human clinical trial testing determined the area under the blood concentration-time curve (AUC) and clearance predicted by the dog were within 32% of the human values. Overall, body weight based allometric scaling of pharmacokinetic parameters from animal models, when corrected for plasma protein binding, yielded reliable predictions of the human pharmacokinetics (within 50%) for radiopharmaceutical imaging agent. However, although predictive scaling from animal data can give insight into feasibility of compounds working in human, it is important to identify species differences with respect to metabolic stability. This allometric scaling method provides an additional tool to better predict doses in human for novel Medical Imaging agents.
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Alam, Muhammad Iftakhar. "Optimal adaptive designs for dose finding in early phase clinical trials." Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8921.
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A method of designing early clinical trials is developed for finding an optimum dose level of a new drug to be recommended for use in later phases. During the trial, the efficacious doses are allocated to the patients more often and those with a high probability of toxicity are less likely to be chosen. The method proposed is adaptive in the sense that the statistical models are updated after the data from each cohort of patients are collected and the dose level is adjusted at each stage based on the current data. Two classes of designs are presented. Although both are for efficacy and toxicity responses, one of them also considers pharmacokinetic information. The dose optimisation criteria are based on the probability of success and on the determinant of the Fisher information matrix for estimation of the dose-response parameters. They can be constrained by both acceptable levels of the probability of toxicity and desirable levels of the area under the concentration curve or the maximum concentration. The method presented is general and can be applied to various dose-response and pharmacokinetic models. To illustrate the methodology, it is applied to two different classes of models. In both cases, the pharmacokinetic model incorporates the population variability by making appropriate assumptions about the model parameters, while the dose responses are assumed to be either trinomial or bivariate binomial. Various design properties of the method are examined by simulation studies. Efficiency measures and the sensitivity of the designs to the assumed prior parameter values are presented. All of the computations are conducted in R, where the D- v optimal sampling time points are obtained by using the package PFIM. The results show that the proposed adaptive method works well and could be appropriate as a seamless phase IB/IIA trial design.
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Onthank, David C. "Prediction of "First Dose in Human" for radiopharmaceuticals/imaging agents based on allometric scaling of pharmacokinetics in pre-clinical animal models." Link to electronic dissertation, 2005. http://www.wpi.edu/Pubs/ETD/Available/etd-011006-132234/.
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Davenport, James Michael. "An Adaptive Dose Finding Design (DOSEFIND) Using A Nonlinear Dose Response Model." VCU Scholars Compass, 2007. http://hdl.handle.net/10156/13.
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Hoff, Paulo Marcelo Gehm. "Estudo de fase II avaliando eficácia e toxicidade de UFT (uracil e tegafur) e leucovorin, administrados duas vezes ao dia, no tratamento de pacientes com câncer metastático de cólon e reto." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5154/tde-31052007-162509/.
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Infusões prolongadas de 5-fluorouracil são mais seguras e potencialmente mais efetivas no tratamento do câncer de cólon metastático do que infusões rápidas da mesma medicação. No entanto, infusões prolongadas requerem a disponibilidade de um acesso venoso central, bem como de bombas de infusão dispendiosas. O desenvolvimento de fluoropirimidinas orais permitiu que pacientes fossem expostos ao 5-fluorouracil por longo tempo, com maior conveniência. UFT e leucovorin administrados três vezes ao dia demonstraram previamente uma eficácia equivalente, com menor toxicidade, quando comparados a um regime convencional de infusão rápida de 5- fluorouracil e leucovorin. Este estudo com 98 pacientes foi desenhado e conduzido com objetivo de demonstrar equivalência no tempo de progressão com o uso de UFT e leucovorin administrados duas vezes ao dia, com o uso da mesma combinação administrada três vezes ao dia. Objetivos secundários incluíram análise de toxicidade, resposta objetiva e sobrevida global. O tempo mediano de progressão foi de 3,8 meses, comparado com 3,5 meses observados com o uso da medicação três vezes ao dia e a taxa de resposta foi de 11%, com uma sobrevida mediana de 12,8 meses, sendo comparável aos resultados de 12% e 12,4 meses obtidas com o uso da combinação três vezes ao dia. A incidência de diarréia com graus 3 e 4 foi de 30% no regime de administração duas vezes ao dia, e 21% no de três vezes ao dia. Esses resultados sugerem que o uso de UFT e leucovorin duas vezes ao dia tem eficácia e toxicidade similares àquelas obtidas com o uso da mesma medicação três vezes ao dia.Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5- fluorouracil as treatment for advanced colorectal cancer. However, infusional 5- fluorouracil requires central venous access and costly infusion pumps. Development of oral fluoropyrimidines has allowed longer exposures to 5-fluorouracil with increased convenience. UFT and leucovorin given thrice daily showed improved safety and no significant difference in survival or response rate compared with bolus 5- fluorouracil and leucovorin. This study with 98 patients was conducted to evaluate whether UFT and leucovorin given twice daily provided comparable time to progression (TTP) to the same combination administered three times a day. Secondary objectives included evaluation of toxicity, overall tumor response rate, and survival. Median time to progression was 3.8 months, compared with 3.5 months observed with the thrice-daily regimen. The twice-daily regimen had a response rate of 11% and median survival of 12.8 months, comparable to the 12% and 12.4 months seen with the thrice-daily regimen. The incidence of grade 3-4 drug-related diarrhea was 30% on the twice-daily and 21% on the thrice-daily schedule. Results suggest that the twice-daily schedule has similar safety and efficacy to the thrice-daily schedule.
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McCallum, Emma Clare. "Adaptive phase II clinical trial design using nonlinear dose-response models." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709013.
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Reis, Margareta. "Pharmacokinetics of antidepressant drugs : naturalistic and clinical trials /." Linköping : Univ, 2003. http://www.bibl.liu.se/liupubl/disp/disp2003/med783s.pdf.
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Shilbayeh, Sirin. "Systematic overview of clinical trials of antiarrhythmic drugs." Thesis, University of Nottingham, 1998. http://eprints.nottingham.ac.uk/30616/.
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BACKGROUND Arrhythmia is a cardiovascular disorder which can lead to several complications. Over the past decade the introduction of many new drugs has raised concerns about their questionable benefits and cost-effectiveness. Classification of antiarrhythmic drugs has not been fully resolved. Although numerous clinical trials have been conducted, the value of antiarrhythmic drugs in many indications remains controversial. Two meta-analyses of clinical trials addressing the indication of quinidine (Class I) for maintenance of sinus rhythm after cardioversion have suggested high efficacy rates but increased mortality relative to placebo. Several overviews which were conducted to evaluate the impact of antiarrhythmic therapy on improving survival post acute myocardial infarction, have defined a turning point in the management strategy from Class I to Class III drugs, particularly amiodarone and sotalol, due to the unfavourable mortality outcome with the former Class. MAJOR AIMS This thesis was conducted with three major aims: 1) To assess both qualitatively and quantitatively the benefits and risks associated with flecainide (Class Ic), amiodarone (Class III), and sotalol (Class III & II) in treatment of chronic atrial fibrillation, acute medical or surgical supraventricular arrhythmias, and life-threatening ventricular arrhythmias developing post acute myocardial infarction; 2) To produce an overall summary estimate of effectiveness and probabilities of incidence of adverse effects, which can be useful for subsequent incorporation in cost-effectiveness analysis; 3) To validate the usefulness of various therapeutic outcomes implemented by general treatment guidelines. OVERVIEW OF THESIS A meta-analysis was carried out to compare the efficacy and safety of three antiarrhythmic agents (flecainide, sotalol, and amiodarone) in maintaining sinus rhythm after cardioversion of chronic atrial fibrillation. 42 of 119 clinical trials retrieved satisfied the predefined inclusion criteria. Data from 17 amiodarone trials (5 randomised, and 12 uncontrolled), 8 sotalol trials (6 randomised, and 2 nonrandomised), and 19 flecainide trials (8 randomised, 4 nonrandomised controlled, and 6 uncontrolled) were pooled separately after testing for homogeneity of treatment effect across the trials. Although the pooled rate difference in proportion of patients remaining in sinus rhythm between amiodarone and placebo (2 trials) was statistically nonsignificant (RD3mon = 16.1 %, 95% CI = -29.7 to 61.7, P>0.05), the pooled effect compared to Class IA drugs (3 trials) demonstrated significant differences at all time intervals (RDs were 20.5%, 31 %, and 28.8% at 3, 6, and 12 months respectively). Aggregating sotalol efficacy data in randomised or nonrandomised controlled trials has yielded highly significant effect in favour of sotalol as compared to placebo and equal effect as compared to Class IA and Class IC at all time points. Furthermore, comparison of flecainide to placebo or Class IA has revealed a highly superior effect in favour of flecainide. The calculated summary statistics (ORpeto, ORMH, RD, and RR) for the incidence of mortality and pro arrhythmia in the full-exposure group in amiodarone and sotalol trials were not significant, affirming the safety of those two drugs. In flecainide placebo-controlled trials, the ORMH for mortality and proarrhythmia were 1.8 (95% CI, 1.2-2.7, P=0.002), and (95% CI, 4.23-10.6, P<0.00l) respectively, thus indicating low benefit-risk ratio for flecainide as compared to amiodarone. The validity of this meta-analysis was examined by assessment of publication bias using funnel-plots. A funnel-plot of the amiodarone clinical trials displayed the shape of an 'inverted funnel', thus suggesting an evidence of low retrieval bias. However, due to the small sample size identified (18 trials only), a firm conclusion with regard to absence of publication bias could not be drawn. Evolving strategies for management of newly occurring supraventricular arrhythmias were reviewed. A meta-analysis was undertaken to determine the most effective agent for prompt cardioversion to sinus rhythm. Flecainide efficacy relative to placebo was confirmed by pooling data from 5 placebo-controlled trials (OR3hrs, 7.2; 95% CI, 4.7 to 11.1; Z=8.9; and OR8hrs, 5.5; 95% CI, 3.6 to 8.4; Z=7.85). However, pooling the data from three amiodarone, placebo-controlled trials at 3 and 8 hour-intervals demonstrated a nonsignificant effect (OR3hrs, 1.3; 95% CI, 0.7-2.4; Z=0.85; and OR8hrs, 1.03; 95% CI, 0.6-1.8, Z=0.12). All individual odds ratios for intravenous sotalol compared to placebo were highly significant with pooled OR at 1 hour of 8.8 (95% CI, 4.7-16.5; Z=6.8). The effect sizes of the three agents on mean ventricular response rate was estimated for both converted and unconverted patients. Whilst the effect size of flecainide versus placebo was not statistically significant at any time point, those of sotalol and amiodarone were statistically and clinically meaningful for both converted and unconverted patients. It is suggested that for acute cardioversion, intravenous flecainide or sotalol should be initially implemented. Intravenous amiodarone can be subsequently introduced for controlling the ventricular rate in persistent unconverted patients. Recent meta-analyses of randomised controlled trials of secondary prevention of myocardial infarction by antiarrhythmic agents have questioned the validity of using arrhythmia suppression as a substitutive end point for mortality. A meta-analysis examining the effect of sotalol and amiodarone for prevention of death post acute myocardial infarction was undertaken. In addition to single point estimates of pooled odds ratios of total mortality and sudden death, a meta-analysis of survival data which included censored end points was employed. An attempt was made to reconstruct the life tables in individual trials of amiodarone. The Kaplan-Meier percentages were recalculated and pooled at specific time points to reproduce the final meta-analytic survival curves of total mortality and sudden death. The meta-analysis confirmed the clinical efficacy of amiodarone for prolonging the survival in patients with congestive heart failure or myocardial infarction. The nonparametric log-rank odds ratio method was applied to raw actuarial data deduced from published Kaplan-Meier graphs as well as data generated by curve fitting. Pooling each set of data separately has yielded highly significant log-rank ORs for total mortality in the first set of four trials with censoring (log-rank OR at 102 months, 0.598; 95% CI, 0.43 to 0.83; Z = -3). However, log-rank ORs from data generated by curve fitting of data from a further three trials, were nonsignificant up to 48 months (log-rank OR, 0.87; 95% CI, 0.72 to 1.06, Z = -1.4). Merging of the two data sets has suggested strong evidence of efficacy for improving survival in terms of both total mortality and sudden death.
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Chan, Hung-kin Clive. "A multi-dimensional survey and critical analysis of clinical trial regulations in Hong Kong and a comparison of the status of clinical trial regulations in some Asian countries/Regions." Click to view the E-thesis via HKUTO, 2004. http://sunzi.lib.hku.hk/hkuto/record/B31971465.
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Soeny, Kabir. "Pharmacometrically driven optimisation of dose regimens in clinical trials." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/25822.
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The dose regimen of a drug gives important information about the dose sizes, dose frequency and the duration of treatment. Optimisation of dose regimens is critical to ensure therapeutic success of the drug and to minimise its possible adverse effects. The central theme of this thesis is the Efficient Dosing (ED) algorithm - a computation algorithm developed by us for optimisation of dose regimens. In this thesis, we have attempted to develop a quantitative framework for measuring the efficiency of a dose regimen for specified criteria and computing the most efficient dose regimen using the ED algorithm. The criteria considered by us seek to prevent over- and under-exposure to the drug. For example, one of the criteria is to maintain the drug's concentration around a desired target level. Another criterion is to maintain the concentration within a therapeutic range or window. The ED algorithm and its various extensions are programmed in MATLAB R . Some distinguishing features of our methods are: mathematical explicitness in the optimisation process for a general objective function, creation of a theoretical base to draw comparisons among competing dose regimens, adaptability to any drug for which the PK model is known, and other computational features. We develop the algorithm further to compute the optimal ratio of two partner drugs in a fixed dose combination unit and the efficient dose regimens. In clinical trials, the parameters of the PK model followed by the drug are often unknown. We develop a methodology to apply our algorithm in an adaptive setting which enables estimation of the parameters while optimising the dose regimens for the typical subject in each cohort. A potential application of the ED algorithm for individualisation of dose regimens is discussed. We also discuss an application for computation of efficient dose regimens for obliteration of a pre-specified viral load.
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Raphesu, Nomusa Joyce. "The development of a good clinical practice training model for use in South African clinical trials." Thesis, University of the Western Cape, 2005. http://etd.uwc.ac.za/index.php?module=etd&.
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Medicines for human use worldwide are generated in part through the conduct of clinical trials. This is done to ensure safety and efficacy. The involvement of human subjects in drug trials has raised concerns for the protection of human rights. As a consequence of the medical misadventures, the Declaration of Helsinki was formulated in 1964 and revised up to 2002. Today, the International Conference of Harmonization of Good Clinical Practice of 1996 guidelines are used worldwide (including South Africa) in the conduct of clinical trials. This study took place in South Africa. The objectives of the study were to first develop an instrument to be used in identifying the current good clinical practice knowledge and training needs of clinical researcherssecondly identify the knowledge level and training needs using the designed instrument and thirdly, based on the findings, develop a Good Clinical Practice training model so as to facilitate the achievement of quality standards for the conduct of clinical trials in South Africa.
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Van, Wyk Anthea. "Evaluation of guidelines for clinical trials of traditional plant medicines." Thesis, University of the Western Cape, 2005. http://etd.uwc.ac.za/index.php?module=etd&.
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The World Health Organization estimates that 4 billion people use herbal medicine for some aspect of primary health care. These herbal products are however mostly used without the necessary clinical trial done to prove their pharmacological activities and, therefore, their quality, efficacy and safety. It was the objective of this study to review the current international guidelines for the evaluation of herbal medicineto gain a perspective on the number, type and quality of clinical trials that have been done on herbal medicine and to adopt a set of guidelines that could be used to conduct trial on a traditional herbal medicine used in South Africa. To verify these guidelines, a protocol for a clinical trial was drafted and submitted for approval to the regulatory and ethical authorities in South Africa.
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Yiu, Kar-lok. "Clinical research and drug prescription patterns among private practitioners in Hong Kong /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31494857.
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Mason, Tracey. "Application of survival methods for the analysis of adverse event data." Thesis, Keele University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267646.
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The concept of collecting Adverse Events (AEs) arose with the advent of the Thalidomide incident. Prior to this the development and marketing of drugs was not regulated in any way. It was the teterogenic effects which raised people's awareness of the damage prescription drugs could cause. This thesis will begin by describing the background to the foundation of the Committee for the Safety of Medicines (CSM) and how AEs are collected today. This thesis will investigate survival analysis, discriminant analysis and logistic regression to identify prognostic indicators. These indicators will be developed to build, assess and compare predictor models produced to see if the factors identified are similar amongst the methodologies used and if so are the background assumptions valid in this case. ROC analysis will be used to classify the prognostic indices produced by a valid cut-off point, in many medical applications the emphasis is on creating the index - the cut-off points are chosen by clinical judgement. Here ROC analysis is used to give a statistical background to the decision. In addition neural networks will be investigated and compared to the other models. Two sets of data are explored within the thesis, firstly data from a Phase III clinical trial used to assess the efficacy and safety of a new drug used to repress the advance of Alzheimer's disease where AEs are collected routinely and secondly data from a drug monitoring system used by the Department of Rheumatology at the Haywood Hospital to identify patients likely to require a change in their medication based on their blood results.
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Yip, Wai Jessie. "Current trends in early human drug trials." View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36887158.
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Yip, Wai Jessie, and 葉慧. "Current trends in early human drug trials." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B39725005.
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Ma, Wing-yan. "Contract research organizations : performance and evaluation of services /." View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38030561.
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Shi, Yun, and 施昀. "Escalation with overdose control for phase I drug-combination trials." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hub.hku.hk/bib/B49799733.
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The escalation with overdose control (EWOC) method is a popular modelbased dose finding design for phase I clinical trials. Dose finding for combined drugs has grown rapidly in oncology drug development. A two-dimensional EWOC design is proposed for dose finding with two agents in combination based on a four-parameter logistic regression model. During trial conduct, the posterior distribution of the maximum tolerated dose (MTD) combination is updated continuously in order to find the appropriate dose combination for each cohort of patients. The probability that the next dose combination exceeds the MTD combination can be controlled by a feasibility bound, which is based on a prespecified quantile for the MTD distribution such as to reduce the possibility of over-dosing. Dose escalation, de-escalation or staying at the same doses is determined by searching the MTD combination along rows and columns in a two-drug combination matrix. Simulation studies are conducted to examine the performance of the design under various practical scenarios, and illustrate it with a trial example.published_or_final_version
Statistics and Actuarial Science
Master
Master of Philosophy
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McBride, Ali. "Evaluating Fast Track Time Analysis of Clinical Drug Trial Phases Utilizing a Quasi-Experimental Observational Study." The University of Arizona, 2007. http://hdl.handle.net/10150/624440.
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Class of 2007 AbstractObjectives: In this paper we analyzed the time frame for oncology drugs that were designated as a fast track drug and the time transition from a phase II to phase III clinical trial completion. Methods In our study we utilized oncology drugs that were approved between the years of 2000-2006 (FDA.gov). We then analyzed the CDER data base that provided information to Fast Track drugs that have been approved within the time period as determined by the FDA selection criteria (21 CFR 312.81(a)). Under certain circumstances, the FCA may consider reviewing portions of a marketing application in advance of the complete New Drug Application (NDA) or Biologic License Application (BLA). We will evaluate fast track designated products which may also be eligible to participate in FDA’s Continuous Marketing Applications Pilot 1 or Pilot 2 programs. For our analysis, we specifically selected oncology drugs. In particular, we analyzed 32 drugs from the stated time period. Each fast track drug was then selected and analyzed for its clinical phase development time period based on news announcements during clinical trails. For each announcement we conducted an event study analysis through lexis Nexus with respect to the announcement of a clinical trial enrollment, clinical trials news (Phase I, II, III). Results: The results of our preliminary study show that there was a shorter time to development transition for the fast track oncology drugs. The oncology clinical phase transition from II to three on average lasted 12 months with a range of 2 - 29 months The average length of the phase development had to excludes 4 drugs due to the lack of information provided from the LexisNexis database. The current timeline for fats track drugs has shown a decrease in transition from clinical trials to the market. In the example of Spyrcel, the data from our study had to be excluded, there was a definitive difference in the time to approval process for the drug as compared to other standard review entities. The approvals for dasatinib, or Sprycel, for refractory CML was shown to move through the development to approval in one of the fastest timeframes in modern development. Since its first clinical study on in Gleevec-resistant patients, the medication was decided on entering an accelerated timeline. It took us just 25 months to bring Sprycel from first-in-human dosing to a regulatory submission. In contrast, the industry average for this cycle time is 6.4 years which is three times greater than the cycle time for Sprycel. Conclusions: The new Subpart H regulations state that post-marketing studies to confirm clinical benefit that would consist usually by "studies underway” at the time of accelerated approval, this has not always been the case and is not a requirement (Dagher R, Johnson J, Williams G et al). In conclusion, the accelerated approval program in oncology has been successful in making 18 different products available to patients for 22 different cancer treatment indications since the inception of the fast track program. From the current data and transition information, there is a comparative difference between the clinical phase transitions from phase II to Phase III clinical trials. However, this preliminary data needs to be further evaluated against the standard FDA review process from oncology drugs. Moreover, further studies will be needed to interpret whether the average length of oncology studies biases the value of our study.
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Leininger, Thomas J. "An Adaptive Bayesian Approach to Dose-Response Modeling." Diss., CLICK HERE for online access, 2009. http://contentdm.lib.byu.edu/ETD/image/etd3325.pdf.
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Ma, Wing-yan, and 馬詠恩. "Contract research organizations: performance and evaluation of services." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B39724888.
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Mollel, Happiness. "Development and assessment of azithromycin paediatric suppository formulations." Thesis, Rhodes University, 2006. http://eprints.ru.ac.za/1345/.
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Chan, Hung-kin Clive, and 陳鴻健. "A multi-dimensional survey and critical analysis of clinical trial regulations in Hong Kong and a comparison of the status of clinicaltrial regulations in some Asian countries/Regions." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31971465.
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Yiu, Kar-lok, and 姚嘉諾. "Clinical research and drug prescription patterns among private practitioners in Hong Kong." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B45010547.
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Voskoglou, Theodora. "Clinical predictive value of pre-clinical cancer models, a study of the predictive value of the in vitro cell line, human xenograft and murine allograft pre-clinical cancer models for Phase II clinical trials of cytotoxic cancer drugs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ63385.pdf.
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Althanyan, Mohammed Saad. "Use of nanoemulsion liquid chromatography (NELC) for the analysis of inhaled drugs : investigation into the application of oil-in-water nanoemulsion as mobile phase for determination of inhaled drugs in dosage forms and in clinical samples." Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5184.
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There has been very little research into the bioanalytical application of Microemulsion High Performance Liquid Chromatography (MELC), a recently established technique for separating an active pharmaceutical ingredient from its related substances and for determining the quantity of active drug in a dose. Also, the technique is not good at separating hydrophilic drugs of very similar chemical structures. Different phase diagrams of oil (octane or ethyl acetate), co-surfactant (butanol), surfactant (sodium dodecyl sulphate (SDS) or Brij-35) and buffer (Phosphate pH 3) were developed and several nanoemulsion mobile phases identified. Nanoemulsion mobile phase that is, prepared with SDS, octane, butanol and a phosphate buffer, failed to separate hydrophilic compounds with a very close chemical structure, such as terbutaline and salbutamol. A nanoemulsion mobile phase containing a non-ionic surfactant (Brij-35) with ethyl acetate, butanol and a phosphate buffer, was, however, successful in achieving a base line separation, and the method was validated for simultaneous determination of terbutaline and salbutamol in aqueous and urine samples. An oil-in-water (O/W) NELC method was developed and validated for the determination of formoterol in an Oxis® Turbuhaler® using pre-column fluorescence derivatisation. Although the same mobile phase was extended for separation of formoterol in urine, the formoterol peak's overlap with endogenous peaks meant that fluorescence detection could not determine formoterol in urine samples. Solid phase extraction, concentrating the final analyte 40 times, enabled determination of a low concentration of formoterol in urine samples by UV detection. The method was validated and an acceptable assay precision %CV <4.89 inter-day and %CV <2.33 intra-day was achieved. Then after the application of O/W nanoemulsion mobile phase for HPLC was extended for the separation of lipophilic drugs. The nanoemulsion liquid chromatography (NELC) method was optimised for the determination of salmeterol and fluticasone propionate in good validation data was achieved. This thesis shows that, in general, the performance of O/W NELC is superior to that of conventional High Performance Liquid Chromatography (HPLC) for the analysis of both hydrophilic and lipophilic drugs in inhaled dosage formulations and urine samples. It has been shown that NELC uses cheaper solvents and that analysis time is faster for aqueous and urine samples. This considerable saving in both cost and time will potentially improve efficiency within quality control.
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Althanyan, Mohammed S. "Use of nanoemulsion liquid chromatography (NELC) for the analysis of inhaled drugs. Investigation into the application of oil-in-water nanoemulsion as mobile phase for determination of inhaled drugs in dosage forms and in clinical samples." Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5184.
Full textAbstract:
There has been very little research into the bioanalytical application of Microemulsion High Performance Liquid Chromatography (MELC), a recently established technique for separating an active pharmaceutical ingredient from its related substances and for determining the quantity of active drug in a dose. Also, the technique is not good at separating hydrophilic drugs of very similar chemical structures.
Different phase diagrams of oil (octane or ethyl acetate), co-surfactant (butanol), surfactant (sodium dodecyl sulphate (SDS) or Brij-35) and buffer (Phosphate pH 3) were developed and several nanoemulsion mobile phases identified. Nanoemulsion mobile phase that is, prepared with SDS, octane, butanol and a phosphate buffer, failed to separate hydrophilic compounds with a very close chemical structure, such as terbutaline and salbutamol. A nanoemulsion mobile phase containing a non-ionic surfactant (Brij-35) with ethyl acetate, butanol and a phosphate buffer, was, however, successful in achieving a base line separation, and the method was validated for simultaneous determination of terbutaline and salbutamol in aqueous and urine samples.
An oil-in-water (O/W) NELC method was developed and validated for the determination of formoterol in an Oxis® Turbuhaler® using pre-column fluorescence derivatisation. Although the same mobile phase was extended for separation of formoterol in urine, the formoterol peak¿s overlap with endogenous peaks meant that fluorescence detection could not determine formoterol in urine samples. Solid phase extraction, concentrating the final analyte 40 times, enabled determination of a low concentration of formoterol in urine samples by UV detection. The method was validated and an acceptable assay precision %CV <4.89 inter-day and %CV <2.33 intra-day was achieved. Then after the application of O/W nanoemulsion mobile phase for HPLC was extended for the separation of lipophilic drugs. The nanoemulsion liquid chromatography (NELC) method was optimised for the determination of salmeterol and fluticasone propionate in good validation data was achieved.
This thesis shows that, in general, the performance of O/W NELC is superior to that of conventional High Performance Liquid Chromatography (HPLC) for the analysis of both hydrophilic and lipophilic drugs in inhaled dosage formulations and urine samples. It has been shown that NELC uses cheaper solvents and that analysis time is faster for aqueous and urine samples. This considerable saving in both cost and time will potentially improve efficiency within quality control.
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Dyck, Erika Wright David. "Psychedelic psychiatry: LSD and post-World War II medical experimentation in Canada /." *McMaster only, 2005.
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Tavares, Janaina Pinho. "Estudo de toxicologia clÃnica de trÃs fitoterÃpicos à base de associaÃÃes de plantas, mel e prÃpolis em voluntÃrios sadios." Universidade Federal do CearÃ, 2005. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=289.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorMelparatosseÂ, Calmatoss e Saratosse sÃo produtos fitoterÃpicos, compostos de associaÃÃes de plantas, incorporados a prÃpolis e mel, em forma de xarope, utilizados no tratamento de vÃrias patologias que acometem o trato respiratÃrio. O estudo teve como objetivo avaliar a seguranÃa dessas formulaÃÃes em seres humanos. Esse estudo consistiu de trÃs ensaios clÃnicos abertos, com 26 voluntÃrios saudÃveis de ambos os sexos, com idade variando entre 18 e 49 anos, que receberam, por via oral, quatro doses de 15mL de um dos trÃs fitoterÃpicos, durante 21 dias ininterruptos; 28 dias, no caso do SaratosseÂ. Os voluntÃrios foram incluÃdos no estudo somente quando considerados saudÃveis, apÃs avaliaÃÃo clÃnica, exame fÃsico e exames laboratoriais que antecederam o estudo. A avaliaÃÃo laboratorial incluÃa: anÃlises hematolÃgicas, bioquÃmicas e sorolÃgicas. Essa mesma avaliaÃÃo foi repetida ao tÃrmino de cada semana de tratamento e no pÃs-estudo, sete dias apÃs a Ãltima administraÃÃo. Os exames clÃnicos, eletrocardiogrÃfico e laboratoriais nÃo evidenciaram sinais de toxicidade nos diversos ÃrgÃos e sistemas avaliados. Os eventos adversos relatados nos trÃs estudos foram: palpitaÃÃo, dispnÃia, astenia, tosse, tontura, aumento de transaminases, disÃria, mialgia, constipaÃÃo (n=1); pirose, flatulÃncia, dismenorrÃia, odontalgia, mal-estar (n=2); nÃusea, enxaqueca, sonolÃncia (n=3); diarrÃia, epigastralgia, dor abdominal (n=4); cefalÃia (n=9); gripe (n=9); faringite (n=11). Esses eventos foram classificados como possivelmente ou nÃo atribuÃdos aos fitoterÃpicos. Os xaropes MelparatosseÂ, Calmatoss e Saratosse foram bem tolerados pelos voluntÃrios.
MelparatosseÂ, Calmatoss e Saratosse are phytomedicine products used for the treatment of several pulmonary diseases. Their compositions include medicinal plants, as well as honey and propolis, as syrups. The study aimed to assay these formulations for their safe use in humans. It consisted of three open clinical trials with 26 healthy volunteers of both sexes each one. The vontunteers age ranged from 18 to 49 years old and they received an oral dose of 15 mL of one of these three products for uninterrupted 21 days- except SaratosseÂ, 28 days -, four times a day. To get in to the trials, the volunteers had to be considered as healthy after clinical evaluation, physical examination and laboratory tests. The laboratory tests included hematological, biochemical and serological analysis. This evaluation was repeated at the end of every week of treatment, and seven days after the last administration. Clinical, electrocardiographic and laboratory tests did not show any evidence of toxic signs in the various organs and systems studied. Adverse events related at the studies were: tachycardia, dyspnea, asthenia, cough, dizziness, increase of transaminase, dysuria, muscle pain, constipation (n=1); pyrosis, flatulence, dysmenorrhea, dental pain, malaise (n=2); nausea, migraine, drowsiness (n=3); diarrhea, epigastralgy, abdominal pain (n=4); headache (n=9); flu (n=9); pharyngitis (n=11). All the events were classified as possible or not related to the phytomedicines assayed. Those events were well tolerated by all volunteers.
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Jadhav, Pravin R. "COMPARISON OF LONGITUDINAL AND CONVENTIONAL DATA ANALYSIS METHODS FOR ASSESSING EFFECTIVENESS." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd_retro/139.
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Pharmaceutical drug development is a costly and time consuming process. Reportedly, it takes about 10-15 years and ~900 million dollars of investment to launch a new drug in the world market. Any measure that increases the power and also decreases uncertainty about that power also increases drug net present value. For some time now, it has been argued that judicious utilization of available data might lead to more efficient use of resources during drug development. Conventionally, assessment of effectiveness has been based on comparing change from baseline at some pre-specified time for the control and test treatment (SPA). The last observation carry forward (LOCF) is a widely used technique if the data are missing due to any reason. Although, LOCF is known to introduce bias, the direction and magnitude is debatable.The primary aim of the proposed simulation experiments was to assess the properties of the random effects model (REM) and mixed model repeated measures (MMRM) methods that utilize all the data collected during pivotal trials. A total of 43 scenarios based on disease progression, magnitude of drug effect, between and within subject variability and patient drop-outs were analyzed. Three analysis methods, viz. SPA, REM and MMRM, were investigated. For the SPA method, the missing data were imputed with four different methods, such as LOCF, mean imputation, population and individual regression. The false-positive, false-negative inferences and bias in estimating the effect size for each method was assessed.The most important finding of this report is that the REM and MMRM methods are efficient alternatives to the SPA methods with ~50% savings on sample size. These methods are based on sound scientific principles and provide stronger evidence against the null hypothesis. The choice of the REM versus MMRM method is dependent on the purpose of the analysis and data gathered from the experimental design. The results support the use of likelihood-based MMRM methods for regulatory decision making. The REM methods are useful in understanding the time course of the disease and drug effect, making predictions based on the data and gaining insights into time to steady state effect for rational decision making. The SPA methods are less powerful across all the scenarios. The SPA-LOCF yielded anticonservative results in some cases with type-1 error rate exceeding 15% if data were missing due to toxicity. On the other hand, the drug effect was consistently underestimated (~40%), if data were missing due to lack of effectiveness. The results demonstrate that the SPA-LOCF methods make it practically impossible to establish effectiveness in these areas with a reasonable sample size.
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Bhala, Neeraj. "Coxibs and traditional NSAIDs : systematic overviews of the randomised evidence for the effects of traditional non-steroidal anti-inflammatory drugs and selective inhibitors of cyclo-oxygenase-2 on vascular and upper gastrointestinal outcomes." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:2b6d8279-bce1-44bd-84c5-7658723786b2.
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Background: Comparative assessments of the vascular and upper gastrointestinal risks of different regimens of non-steroidal anti-inflammatory drugs (NSAIDs) are required. Methods: Meta-analyses were conducted, using individual participant data where possible, of placebo-controlled trials of a selective cyclo-oxygenase [COX]-2 inhibitor ('coxib') or traditional NSAID, or randomised trials of a coxib versus traditional NSAIDs. A prespecified subdivision of traditional NSAID regimens of those with antiplatelet activity (mainly naproxen) and those without (mainly diclofenac) was made. Primary outcomes were major vascular events (MVEs; nonfatal myocardial infarction, nonfatal stroke or vascular death) and upper gastrointestinal complications (UGICs; perforation, obstruction or bleed). Findings: Searches identified 788 trials: 200 comparisons of a coxib vs placebo (88,604 participants, mean follow-up 0.60 years), 206 comparisons of a traditional NSAID vs placebo (43,482 participants, 0.46 years) and 149 comparisons of a coxib vs traditional NSAID (137,466 participants, mean follow-up 0.95 years). Compared to placebo, allocation to a coxib increased the risk of MVEs (rate ratio 1.38, 95% CI 1.14-1.66), vascular mortality (1.58, 1.11-2.24) and UGICs (1.81, 1.17-2.81). Overall, in the population studied, coxibs were associated with three additional major vascular events (one fatal) and two (rarely fatal) upper gastrointestinal complications per 1000 person-years exposure. There was no evidence of heterogeneity by duration of follow-up, coxib type, dose (other than for celecoxib), or patient characteristics, for the primary outcomes. The risk of MVEs for traditional NSAIDs without antiplatelet activity (mostly diclofenac 75mg bd or ibuprofen 800mg tds) were comparable to coxibs (1.40, 1.15-1.72); but the risk of UGICs (1.98, 1.39-2.84) was significantly greater. For traditional NSAIDs with antiplatelet activity (mostly naproxen 500mg bd) there were no significant excess of MVEs (0.84, 0.66-1.08), but UGICs were substantially increased (4.06, 2.85-5.78). Both coxibs and traditional NSAIDs increased risk of hospitalisation for heart failure by about two-fold. Interpretation: The vascular and upper gastrointestinal risks of coxibs and high-dose tNSAID regimens can be predicted, allowing the choice of analgesia to be tailored for particular patients.
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Butlen, Florence. "Analyse des facteurs associés au résultat des demandes d’Autorisation Européenne de Mise sur le Marché pour de nouveaux traitements médicamenteux en psychiatrie." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS507.
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Malgré de nombreuses avancées faites dans le domaine des neurosciences et dans la compréhension des maladies du système nerveux central, il y a peu de nouveaux traitements en psychiatrie et de plus très peu de médicaments avec un mécanisme d’action innovant. Ce travail a permis d’analyser les facteurs associés à l’issue d’une demande d’autorisation de mise sur le marché à l’échelle européenne pour des médicaments en psychiatrie et de les comparer avec ce qui se passe en neurologie et d’autres aires thérapeutiques. Il en ressort que les problèmes ne viendraient pas de la phase d’évaluation centralisée des dossiers car les médicaments en psychiatrie ont le même taux de succès et la même durée d’évaluation que les autres. Il apparait en revanche que peu de dossiers sont déposés en psychiatrie, ce qui tend à suggérer que les problèmes arrivent davantage en amont lors des phases de développement du médicament. D’ailleurs le facteur de succès le plus important d’une demande semble être l’utilisation ou non de conseil scientifique en phase de pré-évaluation. L’étude suivante des problèmes majeurs soulevés lors de l’évaluation des programmes de développement clinique soumis dans le cadre des demandes d’autorisation de mise sur le marché centralisées a permis de mettre en évidence des difficultés particulièrement critiques pour les médicaments en psychiatrie lesquelles seraient intéressantes à prendre en considération lors de l’élaboration des essais cliniques dans ce domaine (sélection de la population, caractérisation du produit en phase précoce de développement et problèmes liés à la sécurité)Despite many advances in the field of neuroscience and in the understanding of the pathophysiology of the central nervous system diseases, there are few new treatments in psychiatry and notably very few drugs with an innovative mechanism of action. The aim of this work was to analyse the factors associated with the outcome of European marketing authorization applications for psychiatry drugs and to compare them with what is happening in neurology as well as in other therapeutic areas. It appears that the problems do not come from the centralised evaluation phase of the files since the drugs in psychiatry have the same success rate and the same evaluation length as the others. Interestingly as well, it appears that few applications are submitted in psychiatry, which tends to suggest that the problems occur further upstream during the development phases of the drug. Moreover, the most important success factor of an application seems to be the use or not of scientific advice in the pre-evaluation phase.The follow-up analysis of the major issues raised during the evaluation of the clinical development programs submitted in the context of a centralised marketing authorisation application highlighted some critical difficulties for psychiatry drugs that would be important to consider when designing clinical trials in this field (selection population, product caracterisation in the early stages of development and safety issues)
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Spence, James Michael. "A Comparison of Major Factors that Affect Hospital Formulary Decision-Making by Three Groups of Prescribers." Thesis, University of North Texas, 2018. https://digital.library.unt.edu/ark:/67531/metadc1157518/.
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The exponential growth in medical pharmaceuticals and related clinical trials have created a need to better understand the decision-making factors in the processes for developing hospital medication formularies. The purpose of the study was to identify, rank, and compare major factors impacting hospital formulary decision-making among three prescriber groups serving on a hospital's pharmacy and therapeutics (P&T) committee. Prescribers were selected from the University of Texas, MD Anderson Cancer Center which is a large, multi-facility, academic oncology hospital. Specifically, the prescriber groups studied were comprised of physicians, midlevel providers, and pharmacists. A self-administered online survey was disseminated to participants. Seven major hospital formulary decision-making factors were identified in the scientific literature. Study participants were asked to respond to questions about each of the hospital formulary decision-making factors and to rank the various formulary decision-making factors from the factor deemed most important to the factor deemed least important. There are five major conclusions drawn from the study including three similarities and two significant differences among the prescriber groups and factors. Similarities include: (1) the factor "pharmacy staff's evaluation of medical evidence including formulary recommendations" was ranked highest for all three prescriber groups; (2) "evaluation of medications by expert physicians" was ranked second for physicians and midlevel providers while pharmacists ranked it third; and (3) the factor, "financial impact of the treatment to the patient" was fifth in terms of hospital formulary decision-making statement and ranking by all three prescriber groups. Two significant differences include: (1) for the hospital-formulary decision making statement, "I consider the number of patients affected by adding, removing, or modifying a drug on the formulary when making hospital medication formulary decisions," midlevel providers considered this factor of significantly greater importance than did physicians; and (2) for the ranked hospital formulary decision-making factor, "financial impact of treatment to the institution," pharmacists ranked this factor significantly higher than did physicians. This study contributes to a greater understanding of the three prescriber groups serving on a P&T committee. Also, the study contributes to the body of literature regarding decision-making processes in medicine and specifically factors impacting hospital formulary decision-making. Furthermore, this study has the potential to impact the operational guidelines for the P&T committee at the University of Texas, MD Anderson Cancer Center as well as other hospitals.
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Mao, Xuezhou. "Sequential Designs for Individualized Dosing in Phase I Cancer Clinical Trials." Thesis, 2014. https://doi.org/10.7916/D857196S.
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This dissertation presents novel sequential dose-finding designs that adjust for inter-individual pharmacokinetic variability in phase I cancer clinical trials. Unlike most traditional dose-finding designs whose primary goals are the determination of a maximum safe dose, the goal of our proposed designs is to estimate a patient-specific dosing function such that the responses of patients can achieve a target safety level.
Extending from a single compartment model in the pharmacokinetic theory, we first postulate a linear model to describe the relationship between the area under concentration-time curve, dose and predicted clearance. We propose a repeated least squares procedure that aims to sequentially determine dose according to individual ability of metabolizing the drug. To guarantee consistent estimation of the individualized dosing function at the end of a trial, we apply repeated least squares subject to a consistency constraint based on an eigenvalue theory for stochastic linear regression. We empirically determine the convergence rate of the eigenvalue constraint using a real data set from an irinotecan study in colorectal carcinoma patients, and calibrate the procedure to minimize a loss function that accounts for the dosing costs of study subjects and future patients. When compared to the traditional body surface area and an equation based dosing methods, the simulation results demonstrate that the repeated least squares procedure control the dosing cost and allow for precise estimation of the dosing function.
Furthermore, in order to enhance the generality and robustness of the dose-finding designs, we generalize the linear association to a nonlinear relationship between the response and a linear combination of dose and predicted clearance. We propose a two-stage sequential design, the semiparametric link-adapted recursion, which targets at individualizing dose assignments meanwhile adapting for an unknown nonlinear link function connecting the response and dose along with predicted clearance. The repeat least squares with eigenvalue constraint design is utilized as the first stage, and the second stage recursively applies an iterative semiparametric least squares approach to estimate the dosing function and determine dosage for next patient. The simulation results demonstrate that: at first, the performance of repeated least squares with eigenvalue constraint design is acceptably robust to model misspecifications; at second, as its performance is close to that of repeated least squares procedure under parametric models, the semiparametric link-adapted recursion does not sacrifice much estimation accuracy to gain robustness against model misspecifications; at last, compared to the repeated least squares procedure, the semiparametric link-adapted recursion can significantly improve the dosing costs and estimation precision under the semiparametric models.
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Malani, Anup. "Placebo effects, self-selection and the external validity of clinical trials /." 2003. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3097180.
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Bruçó, Ana Leonor Pereira. "Orphan Drugs: Development Process and Clinical Use." Master's thesis, 2018. http://hdl.handle.net/10316/84645.
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Dissertação de Mestrado em Biotecnologia Farmacêutica apresentada à Faculdade de FarmáciaRare diseases have become a topic of substantial interest in recent years. These disorders are usually severe, have a genetic origin and their symptoms are generally expressed at a young age. In most cases, there is no effective treatment for patients with these conditions. Therefore, the search for new therapeutic solutions for these patients has been increasing. Medicinal products used to prevent, diagnostic or treat rare diseases are called orphan drugs. Regulatory authorities, pharmaceutical companies, academic researchers and international organizations have contributed with several efforts to facilitate the development process for these drugs.Despite those accomplishments, clinical research is particularly difficult in rare diseases, as researchers are faced with evident obstacles, such as low disease prevalence, small and heterogeneous patient populations, clinical trials recruitment difficulties and lack of scientific data on this kind of diseases.These demands require the development of novel and rigorous clinical study designs and analyses to assess treatment efficacy properly in small populations. Progresses in genetics and biotechnology can provide important tools to improve clinical trial evaluation methods. The preclinical and clinical development process, regulatory framework and market for orphan drugs will be discussed in this dissertation, as well as some therapeutic approaches for rare diseases. Relevant considerations about some rare diseases and possible future scenarios will be also given.
As doenças raras tornaram-se um tópico de grande interesse nos últimos anos. Estas doenças são geralmente graves, têm origem genética e os seus sintomas manifestam-se habitualmente numa idade jovem. Na maioria dos casos, não existe um tratamento eficaz para os doentes com estas condições. Por isso, a procura por novas soluções terapêuticas para estes doentes tem vindo a aumentar. Os medicamentos utilizados para prevenir, diagnosticar ou tratar doenças raras designam-se medicamentos órfãos. As autoridades regulamentares, as empresas farmacêuticas, os investigadores académicos e as organizações internacionais têm feito vários esforços no sentido de agilizar o processo de desenvolvimento destes medicamentos. Apesar destes progressos, a investigação clínica em doenças raras continua a ser particularmente difícil, uma vez que os investigadores se deparam com obstáculos evidentes como a baixa prevalência da doença, uma população de doentes pequena e heterogénea, dificuldades no recrutamento dos ensaios clínicos e a falta de conhecimento cientifico neste tipo de doenças. Estas exigências requerem o desenvolvimento de ensaios clínicos com desenhos novos e rigorosos e métodos de análise que avaliem adequadamente a eficácia do tratamento em populações pequenas. Os avanços na área da genética e da biotecnologia podem oferecer ferramentas importantes para melhorar os métodos de avaliação dos ensaios clínicos. O processo de desenvolvimento pré-clínico e clínico, o enquadramento regulamentar e o mercado dos medicamentos órfãos será discutido nesta dissertação, assim como algumas abordagens terapêuticas para doenças raras. Considerações relevantes sobre algumas doenças raras e possíveis cenários futuros também serão abordados.
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Günhan, Burak Kürsad. "Bayesian methods for borrowing information in clinical drug development." Doctoral thesis, 2020. http://hdl.handle.net/21.11130/00-1735-0000-0005-151F-2.
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"An investigation on the determinants of the effectiveness of anti-hypertensive drugs for primary prevention of cardiovascular disease: a systemic review of randomized controlled trials." Thesis, 2007. http://library.cuhk.edu.hk/record=b6074465.
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After adjusted for the effect of baseline MCE risk and reduction in SBP, the multivariate meta-regression showed baseline SBP was not significantly related to the RD for all the relevant outcomes examined (p>0.22) except MCE (p=0.0226). However, the baseline MCE risk remained significantly related to the RD for all the outcomes (p<0.01) except CHD (p=0.1011). The reduction in SBP remained significantly related to the RD for deaths due to CVD, MCE, CHF and stroke (p<0.01) but not to the RD for all-cause death (p=0.3788) and CHD (p=0.8755).Conclusions. This study showed that baseline CVD risk and reduction in blood pressure were strongly and consistently related to the absolute effect of treatment and surprisingly the baseline blood pressure was not. The findings lend direct support to the overall risk approach to primary prevention and suggest that contrary to conventional wisdom and current practice, the overall CVD risk rather than blood pressure alone should be used to identify and treat people to prevent major CVD events through anti-hypertensive drugs. These findings suggest that anti-hypertensive drugs should be given to those who have a high future CVD risk rather than high blood pressure alone so as to achieve better cost-effectiveness of anti-hypertensive drugs for primary prevention.
Data extraction and analyses: Two reviewers independently abstracted data on baseline variables, variables that determine methodological quality, and outcomes. The following main outcomes were assessed: all-cause deaths, deaths due to cardiovascular disease, death due to causes other than CVD, major cardiovascular events (MCE), congestive heart failure (CHF), stroke, and coronary heart disease (CHD).
Key words. hypertension, antihypertensive drugs, cardiovascular disease, meta-analysis, systematic review, randomized controlled trial, primary prevention, baseline risk, evidence based medicine
Meta-analysis was used to obtain the overall odds ratio (OR) and risk difference (RD). Forest plots, bubble plots and funnel plots were used to show the results visually or to check biases. Meta-regression was used to identify factors that may independently determine the effect of antihypertensive drugs. The control CVD risk, initial mean blood pressure and reduction in blood pressure were examined.
Method. Identification of studies: The databases searched included ACP Journal Club, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Cumulative Index to Nursing & Allied Health Literature, Chinese Medical Current Contents to identify relevant studies between 1966 and 2005. We also examined references from relevant trials, reviews and meta-analyses. For trials to be included in this review, they have to have the following characteristics: (1) essential hypertension in patients of any age, sex and race; (2) treatment intervention is antihypertensive drugs; (3) control intervention is a placebo or no treatment; (4) endpoint outcomes are all-cause death and major cardiovascular events; and (5) randomized controlled trials.
Objective. Although the overall risk approach to cardiovascular disease (CVD) primary prevention has been widely adopted, direct evidence that supports this policy is however weak and in some aspects lacking. Importantly, there is no direct evidence to show, between blood pressure and CVD risk, which is a better predictor of the absolute benefit from anti-hypertensive drugs. The evidence that the absolute benefit increases as the future CVD risk increases does not necessarily mean that treating high risk people will be more cost-effective than treating hypertensive people as blood pressure may also be positively related to treatment benefit. The high risk approach would be preferable only when we can show with strong evidence that blood pressure is not related to the absolute benefit of treatment or the CVD risk is much more strongly related to the benefit than blood pressure. We thus conducted this systematic review to examine the evidence from randomized controlled trials to directly show how blood pressure and CVD risk are related to the absolute benefit from anti-hypertensive drugs and compare the capability of the two factors in predicting the benefit. The stronger predictor should be a better indicator for identifying those who should be treated with anti-hypertensive drugs.
Results. Twenty-two eligible randomized controlled trials with a total of 55,448 participants were identified from 1967 to 2004. The average follow-up was 45.6 months ranging from 13 to 84 months. The combined RD and OR for all-cause deaths, deaths due to CVD, MCE, CHF, Stroke and CHD were all statistically significant, showing a consistent and considerable reduction in the risk of these outcomes due to the treatment of anti-hypertensive drugs (p<0.01).
Jiang, Yu.
"September 2007."
Adviser: Jin Ling Tang.
Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4657.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2007.
Includes bibliographical references (p. 107-115).
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.
Abstract in English and Chinese.
School code: 1307.
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Li, Claire. "Modeling and simulation applications with potential impact in drug development and patient care." Thesis, 2014. http://hdl.handle.net/1805/5969.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)Model-based drug development has become an essential element to potentially make drug development more productive by assessing the data using mathematical and statistical approaches to construct and utilize models to increase the understanding of the drug and disease. The modeling and simulation approach not only quantifies the exposure-response relationship, and the level of variability, but also identifies the potential contributors to the variability. I hypothesized that the modeling and simulation approach can: 1) leverage our understanding of pharmacokinetic-pharmacodynamic (PK-PD) relationship from pre-clinical system to human; 2) quantitatively capture the drug impact on patients; 3) evaluate clinical trial designs; and 4) identify potential contributors to drug toxicity and efficacy. The major findings for these studies included: 1) a translational PK modeling approach that predicted clozapine and norclozapine central nervous system exposures in humans relating these exposures to receptor binding kinetics at multiple receptors; 2) a population pharmacokinetic analysis of a study of sertraline in depressed elderly patients with Alzheimer’s disease that identified site specific differences in drug exposure contributing to the overall variability in sertraline exposure; 3) the utility of a longitudinal tumor dynamic model developed by the Food and Drug Administration for predicting survival in non-small cell lung cancer patients, including an exploration of the limitations of this approach; 4) a Monte Carlo clinical trial simulation approach that was used to evaluate a pre-defined oncology trial with a sparse drug concentration sampling schedule with the aim to quantify how well individual drug exposures, random variability, and the food effects of abiraterone and nilotinib were determined under these conditions; 5) a time to event analysis that facilitated the identification of candidate genes including polymorphisms associated with vincristine-induced neuropathy from several association analyses in childhood acute lymphoblastic leukemia (ALL) patients; and 6) a LASSO penalized regression model that predicted vincristine-induced neuropathy and relapse in ALL patients and provided the basis for a risk assessment of the population. Overall, results from this dissertation provide an improved understanding of treatment effect in patients with an assessment of PK/PD combined and with a risk evaluation of drug toxicity and efficacy.
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Rodrigues, José Miguel Gomes. "O desenvolvimento de novos fármacos antidepressivos - revisão dos fármacos recentemente aprovados desvenlafaxina, levomilnaciprano, vilazodona e esquetamina." Master's thesis, 2020. http://hdl.handle.net/10284/9599.
Full textAbstract:
A depressão é um distúrbio mental de origem multifatorial associado a altas taxas de
morbidade e mortalidade, falta de produtividade no trabalho, e aumento dos gastos com
saúde e que afeta significativamente a sociedade.
O objetivo deste trabalho foi analisar os ensaios clínicos dos fármacos: desvenlafaxina,
levomilnaciprano, vilazodona e esquetamina que em alguns países já se encontram
comercializados, mas não em Portugal, este trabalho teve, ainda, como objetivo, dar a
conhecer estes novos antidepressivos em fase avançada de ensaios clínicos.
Para a pesquisa bibliográfica deste trabalho foram usados os motores de busca “B-on”,
“Pubmed”, “Google scholar” e foram usadas as palavras chave: depressão,
desvenlafaxina, levomilnaciprano, vilazodona, esquetamina, farmacocinética, ensaios
clínicos, com diversas combinações entre elas. Desta pesquisa foram selecionados artigos
publicados nos últimos 15 anos.
Todos os antidepressivos estudados apresentaram segurança, tolerância e eficácia,
embora nem todos os estudos conseguiram comprovar a sua eficácia em relação ao
placebo. Existe uma grande procura por novos medicamentos para o tratamento da
depressão, os estudos mais recentes centram-se num novo mecanismo de ação que atua
nos recetores MNDA, sendo que a esquetamina é um dos mais recentes, mas a arketamina
e a brexanolona encontram-se em ensaios clínicos. Contudo ainda são necessários
avanços nesta área e serão necessários mais estudos e descoberta de novos fármacos para
tratar aqueles pacientes que, embora já tenham experimentado uma basta variedade de
fármacos, ainda não conseguiram atingir a remissão da depressão. A vilazodona apresenta
menos efeitos adversos comparativamente á desvenlafaxina e levomilnaciprano. A
desvenlafaxina apresenta menos interações medicamentosas que os restantes fármacos.
Avaliando e comparando os fármacos em análise conclui-se que a Vilazodona e a
Esquetamina são os fármacos mais promissores no tratamento da depressão. Sendo que o
mecanismo de ação da esquetamina pode revolucionar o modo com tratamos a depressão.Depression is a multifactorial mental disorder associated with high rates of morbidity and mortality, lack of productivity at work, and increased spending on health that significantly affects the society. The objective of this work was to analyze the clinical trials of the drugs: desvenlafaxine, levomilnacipran, vilazodone and esketamine that in some countries are already marketed, but not in Portugal, this work had, still, as objective, to discuss new antidepressants in advanced phase clinical trials. For the bibliographic search of this work, the search engines “B-on”, “Pubmed”, “Google scholar” were used and the keywords were used: depression, desvenlafaxine, levomilnacipran, vilazodone, esketamine, pharmacokinetics, clinical trials, with several combinations between them. From this research, articles published in the last 15 years were selected. All antidepressants studied showed safety, tolerance and efficacy, although not all studies were able to prove their effectiveness in relation to placebo. There is a great demand for new drugs for the treatment of depression, the most recent studies focus on a new mechanism of action that acts on MNDA receptors, being esketamine one of the most recent drugs, but arketamine and brexanolone are in clinical trials. Progress is still needed in this area and further studies for the discovery of new drugs will be needed to treat those patients who, although have already tried a sufficient variety of drugs, have not yet managed to achieve remission of depression. Vilazodone has fewer adverse effects compared to desvenlafaxine and levomilnacipran. Desvenlafaxine has fewer drug interactions than other drugs. Evaluating and comparing the drugs under analysis, Vilazodone and esketamine are the most promising drugs in the treatment of depression. Being that the mechanism of action of esketamine can revolutionize the way we treat depression.