This thesis assesses the current status of Canadian prescription drug regulation and the policy drivers that guide this process. This analysis is accomplished by first providing a general survey of the steps, law, and institutional players involved in the full life-cycle of a drug. Next the evolution of current clinical trials and the gaps that the present legal regime creates in the scientific standards employed in clinical research is reviewed. This is followed by a discussion of how commercialization (innovation) and speed of approval (market access) are slowly becoming the dominant policy drivers for the Canadian regime. Finally a discussion of the proposed Progressive Licensing model, and Bill C-51-An Act to Amend the Food and Drug Act, raises the concerns with a shift to a system largely based on risk assessment and post-market monitoring (pharmacovigilence).

Orientador: Rosângela Gonçalves Peccinini / Resumo: A doença de Chagas é uma enfermidade que afeta milhões de pessoas no mundo, principalmente em países em desenvolvimento. No Brasil, o único fármaco disponível para tratamento desta doença é o benzonidazol (BNZ). Atualmente o regime posológico para adultos consiste na administração deste fármaco na forma de comprimidos de liberação imediata de 100 mg em duas ou três tomadas diárias, durante 60 dias. Apesar da elevada eficácia desse fármaco na fase aguda da doença (aproximadamente 70%), os eventos adversos são frequentes e muitas vezes causam a interrupção do tratamento. Diante desse cenário, o Laboratório de Tecnologia de Medicamentos (LTM) da Universidade Federal de Pernambuco (UFPE) desenvolveu comprimidos de liberação prolongada, visando a redução da frequência de administrações do fármaco e a melhoria do tratamento com doses mais precisas. Em estudos pré-clínicos foram observadas vantagens da administração do comprimido de liberação prolongada na cinética do fármaco benzonidazol quando comparada a administração do comprimido de liberação imediata (formulação convencional). Entretanto, a continuidade do desenvolvimento do produto farmacêutico para aplicação terapêutica exige a avaliação em humanos. Logo, o objetivo deste trabalho foi reunir todas as informações e documentos necessários para a elaboração do protocolo de estudo clínico da nova formulação de liberação prolongada para futura submissão ao CEP e à ANVISA. Estabeleceu-se o protocolo para estudo Clínico de fase I –... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Chagas disease affects millions of people worldwide, especially in developing countries. In Brazil, the only drug available for treatment of this disease is benzonidazole (BNZ). Currently, the dosage regimen for adults consists of administration of this drug in the form of 100 mg immediaterelease tablets in twice or three times a day for 60 days. Despite the high efficacy of this drug in the acute phase of the disease (approximately 70%), adverse effects are common and often cause discontinuation of treatment. In this scenario, the Laboratory of Drug Technology (LTM) of the Federal University of Pernambuco (UFPE) has developed extended-release tablets aimed at reducing the frequency of drug administration and improving treatment at more precise doses. In preclinical studies, advantages of extended-release tablet administration have been observed in the kinetics of the drug benzonidazole when compared to the administration of the immediate release tablet (conventional formulation). However, the continued development of the pharmaceutical product for therapeutic application requires evaluation in humans. Therefore, the objective of this study was to gather all the information and documents necessary for the elaboration of the clinical study protocol of the new extended release formulation for future submission to the IRB (Institutional Review Board) and Brazillian Health Regulatory Agency (ANVISA). The protocol for Phase I clinical study - comparative, open, randomized, cross-o... (Complete abstract click electronic access below) / Mestre

Submitted by Carolina Peres null (carol_peres88@hotmail.com) on 2017-10-20T13:48:07Z No. of bitstreams: 1 Dissertação completa mestrado.pdf: 3043086 bytes, checksum: 409a3054d7b6e44ea30ba5eca7aac1bf (MD5) / Approved for entry into archive by Luiz Galeffi (luizgaleffi@gmail.com) on 2017-10-23T19:13:46Z (GMT) No. of bitstreams: 1 peres_c_me_bot.pdf: 3043086 bytes, checksum: 409a3054d7b6e44ea30ba5eca7aac1bf (MD5) / Made available in DSpace on 2017-10-23T19:13:46Z (GMT). No. of bitstreams: 1 peres_c_me_bot.pdf: 3043086 bytes, checksum: 409a3054d7b6e44ea30ba5eca7aac1bf (MD5) Previous issue date: 2017-08-31 / A doença de Chagas é uma enfermidade que afeta milhões de pessoas no mundo, principalmente em países em desenvolvimento. No Brasil, o único fármaco disponível para tratamento desta doença é o benzonidazol (BNZ). Atualmente o regime posológico para adultos consiste na administração deste fármaco na forma de comprimidos de liberação imediata de 100 mg em duas ou três tomadas diárias, durante 60 dias. Apesar da elevada eficácia desse fármaco na fase aguda da doença (aproximadamente 70%), os eventos adversos são frequentes e muitas vezes causam a interrupção do tratamento. Diante desse cenário, o Laboratório de Tecnologia de Medicamentos (LTM) da Universidade Federal de Pernambuco (UFPE) desenvolveu comprimidos de liberação prolongada, visando a redução da frequência de administrações do fármaco e a melhoria do tratamento com doses mais precisas. Em estudos pré-clínicos foram observadas vantagens da administração do comprimido de liberação prolongada na cinética do fármaco benzonidazol quando comparada a administração do comprimido de liberação imediata (formulação convencional). Entretanto, a continuidade do desenvolvimento do produto farmacêutico para aplicação terapêutica exige a avaliação em humanos. Logo, o objetivo deste trabalho foi reunir todas as informações e documentos necessários para a elaboração do protocolo de estudo clínico da nova formulação de liberação prolongada para futura submissão ao CEP e à ANVISA. Estabeleceu-se o protocolo para estudo Clínico de fase I – biodisponibilidade comparativa, aberto, aleatorizado, cruzado e monocêntrico. A administração foi estabelecida em dois tratamentos, duas sequências, dois períodos, nos quais os participantes recebem, em cada período, a formulação teste ou a formulação referência. Serão realizados dois estudos independentes, no qual o primeiro estudo, os participantes estarão em jejum (Estudo I) e no segundo estudo, estarão alimentados (Estudo II). Serão 24 participantes para cada estudo, sendo 12 participantes de cada sexo. Os resultados deste estudo proporcionarão informações para avaliar se a administração da formulação Teste, benzonidazol 200mg, determina níveis plasmáticos semelhantes aos da formulação Referência, benzonidazol 100mg e se os mantém por período suficiente para a assunção de uma administração diária. Esta avaliação culminará com a decisão sobre a substituição da apresentação atualmente utilizada no tratamento da tripanossomíase pela nova formulação de liberação prolongada. / Chagas disease affects millions of people worldwide, especially in developing countries. In Brazil, the only drug available for treatment of this disease is benzonidazole (BNZ). Currently, the dosage regimen for adults consists of administration of this drug in the form of 100 mg immediaterelease tablets in twice or three times a day for 60 days. Despite the high efficacy of this drug in the acute phase of the disease (approximately 70%), adverse effects are common and often cause discontinuation of treatment. In this scenario, the Laboratory of Drug Technology (LTM) of the Federal University of Pernambuco (UFPE) has developed extended-release tablets aimed at reducing the frequency of drug administration and improving treatment at more precise doses. In preclinical studies, advantages of extended-release tablet administration have been observed in the kinetics of the drug benzonidazole when compared to the administration of the immediate release tablet (conventional formulation). However, the continued development of the pharmaceutical product for therapeutic application requires evaluation in humans. Therefore, the objective of this study was to gather all the information and documents necessary for the elaboration of the clinical study protocol of the new extended release formulation for future submission to the IRB (Institutional Review Board) and Brazillian Health Regulatory Agency (ANVISA). The protocol for Phase I clinical study - comparative, open, randomized, cross-over and monocentric was established. The administration was established in two treatments, two sequences, two periods, in which the participants receive, in each period, the test formulation or the reference formulation. Two independent studies will be performed, in which the first study, participants will be fasted (study I) and in the second study, they will be fed (study II). There will be 24 participants for each study, 12 participants of each sex. The results of this study will provide information to assess whether administration of the Test formulation, benzonidazole 200mg, determines plasma levels similar to those of the Reference formulation, benzonidazole 100mg, and if these levels are maintained for a sufficient time for daily administration. This evaluation will culminate with the decision on the replacement of the present presentation used in the treatment of trypanosomiasis by the new extendedrelease formulation.

My diploma thesis deals with the Clinical trial in the Czech Republic in the period from 1989 to present and on its impact on management in organizations dealing with clinical trials. The aim of this thesis is to identify key changes that occurred in the clinical trial and to identify how these changes infuenced the management of clinital trial organizations. This will be done based on the qualitative research. The theoretical part provides information about the history of the clinical trial, about internation and the Czech legislation, including ethical principles, the submission process including description of institution that are reviewing the clinical research. The theory also explains the issue of management, its organizational developments and its expected development in the future. In the research part I described the chosen research method, which extend from the semi- structured interview after the pilot part to the use of the focus group method - in the combination with semi-structured interview. Based on these interviews and focus group have been evaluated 7 parts to describe the evolution of the clinical trial and its impact on the management of clinical trials, including one topic that addresses the expected development of this field in the future. Key words: clinical trial, clinical...

In this paper, a rheumatoid arthritis (RA) medicine clinical dataset with an ordinal response is selected to study this new medicine. In the dataset, there are four features, sex, age,treatment, and preliminary. Sex is a binary categorical variable with 1 indicates male, and 0 indicates female. Age is the numerical age of the patients. And treatment is a binary categorical variable with 1 indicates has RA, and 0 indicates does not have RA. And preliminary is a five class categorical variable indicates the patient’s RA severity status before taking the medication. The response Y is 5 class ordinal variable shows the severity of patient’s RA severity after taking the medication. The primary aim of this study is to determine what factors play a significant role in determine the response after taking the medicine. First, cumulative logistic regression is applied to the dataset to examine the effect of various factors on ordinal response. Secondly, the ordinal response is categorized into two classes. Then logistic regression is conducted to the RA dataset to see if the variable selection would be different. Moreover, the shrinkage methods, elastic net and lasso are used to make a variable selection on the RA dataset of two-class response for the purpose of adding penalization to increase the model’s robustness.The four model results were compared at the end of the paper. From the comparison result, logistic regression has a better performance on variable selection than the other three approaches based on P-value.

In recent times, there has been an increasing interest in adaptive designs for clinical trials. As opposed to conventional designs, adaptive designs allow flexible design adaptation in the middle of a trial based on accumulated data. Although various models have been developed using both frequentist and Bayesian perspectives, relative statistical performances of adaptive designs are somewhat controversial and little is known about those of Bayesian adaptive designs. Most comparison studies also focused on single experimental treatment rather than multiple experimental treatments. In this report, both frequentist and Baysian adaptive designs were compared in terms of statistical power by a simulation study, assuming the situation when multiple experimental treatments are tested in multiple stages. The designs included in the current study are group sequential design (frequentist), adaptive design based on combination tests (frequentist), and Bayesian adaptive design (Bayesian). Based upon the results under multiple scenarios, the Bayesian adaptive design showed the highest power, and the design based on combination tests performed better than group sequential designs when proper interim adaptation could be conducted to increase power. / text

First-in-man (FIM) Phase I clinical trials are part of the critical path in the development of a new compound entity (NCE). Since FIM clinical trials are the first time that an NCE is dosed in human subjects, the designs used in these trials are unique and geared toward patient safety. We develop a method for obtaining the desired response using an adaptive non-linear approach. This method is applicable for studies in which MTD, NOEL,NOAEL, PK, PD effects or other such endpoints are evaluated to determine the desired dose. The method has application whenever a measurable PD marker is an indicator of potential efficacy and could be particularly useful for dose finding studies. The advantages in the adaptive non-linear methodology is that the actual range of dose response and lowest non-effective dose levels are more quickly and accurately determined using fewer subjects than typically needed for a conventional early phase clinical trial. Using the nonlinear logistic model, we demonstrate, with simulations, that the DOSEFIND approach has better asymptotic relative efficiency than a fixed-dose approach. Further, we demonstrate that, on average, this method is consistent in reproducing .the target dose, that it has very little bias. This is an indicator of reproducibility of the method, showing that the long-run average error is quite small. Additionally, DOSEFIND is more cost effective because the sample size needed to obtain the desired target dose is much smaller than that needed in the fixed dose approach.

Classical phase II trial designs assume a patient population with a homogeneous tumor type and yield an estimate of a stochastic probability of tumor response. Clinically, however, oncology is moving towards identifying patients who are likely to respond to therapy using tumor subtyping based upon predictive markers. Such designs are called targeted designs (Simon, 2004). For a given phase I1 trial predictive markers may be defined prospectively (on the basis of previous results) or identified retrospectively on the basis of analysis of responding and non-responding tumors. For the prospective case we propose two Phase I1 targeted designs in which a) the trial is powered to detect the presence of responding subtype(s) as identified either prospectively or retrospectively by predictive markers or b) the trial is powered to achieve a desired precision in the smallest subtype. Relevant parameters in such a design include the prevalence of the smallest subtype of interest, the hypothesized response rate within that subtype, the expected total response rate, and the targeted probabilities of type I and II errors (α and β). (The expected total response rate is needed for design a) but not for b)). Extensions of this design to simultaneous or sequential multiple subtyping and imperfect assays for predictive markers will also be considered. The Phase II targeted design could be formulated as a single stage or Simon two-stage design. For multiple subtyping corrections to the significance level will be considered. Sample size calculations for different scenarios will be presented. An implication of this approach is that Phase II trials based upon classical designs are too small. On the other hand, trials involving "reasonable" numbers of patients must target relatively high threshold response rates within tumor subtypes. For the retrospective case we will provide the power to detect desired rates in the subtypes and provide the sample sizes required to achieve desired power. Retrospective analysis has the advantages that the analysis can be "supervised" by grouping responding and non-responding tumors; and multiple hypotheses, including hypotheses not formulated at the time of trial design, can be tested.

The goal of this escalating single-dose phase I research study was to determine the safety, tolerability, pharmacokinetics, pharmacodynamics as well as in vitro metabolism and plasma protein binding of MS-275, a novel histone deacetylase inhibitor, in patients with solid tumors and lymphomas. A validated LC/MS assay was developed to quantitate MS-275 in plasma, human liver microsomes and urine. The pharmacokinetic (PK) evaluation was done using a non-compartmental approach. In-vitro plasma protein binding profile of MS-275 was characterized by a validated micro-equilibrium dialysis method. In vitro phase I and phase II hepatic metabolism of MS-275 were evaluated using human liver microsomes. A correlative covariate analysis was performed in an effort to explain the wide inter-individual variability among patients.Results from the study demonstrate that the validated LC-MS assay is specific, accurate, precise and sensitive. MS-275 demonstrates a substantial inter-individual PK variability in systemic exposure and clearance; exposures increase in near-proportion, while peak concentrations increase more than-proportionally with an increase in dose. Mean apparent oral clearance (CL/F) is independent of dose and exhibits apparent dose-independent PK behavior over the studied dose range. Oral absorption is highly variable. MS-275 has a 50-fold longer half-life in humans compared to pre-clinical species. PK/PD analysis showed significant correlation between occurrence of DLT and higher systemic exposures. Although there was an increase in the acetylation of histone H3 and H4 over time, preliminary analysis showed no significant correlation between PK parameters and change in % histone acetylation after 24 hours. MS-275 is moderately bound to plasma proteins. Hepatic phase I and II metabolic pathways are only minor routes of elimination, and MS-275 is neither a substrate for liver-specific organic anion transporting proteins, OATP1B1 and OATP1B3, nor a substrate for gastrointestinal efflux transporters ABCB1 (P-gp) or ABCG2. No significant correlation was found between CL/F and demographic, body measures and other clinical covariates, and inter-patient variability in CL/F remained similar in magnitude even after correcting dose for body surface area (BSA) or other body measures. BSA is not a significant predictor of MS-275 PK, and flat-fixed dosing can be used in the future.

Clinical trials of medicinal products is increasingly important area of pharmaceutical law. Number of clinical trials and amount of financial resources is constantly rising and therefore the rules and principles of the clinical trials itself are being clarified overtime. This diploma thesis aims to provide an overview of the basic aspects of clinical trials of medicinal products for human use from a legal point of view. The author focuses in particular on the national legislation of clinical trials, which is complemented by the legislation of the European Union and important sources of the international law. Author is more closely analysing the particular procedures performed within the clinical trials, especially from the point of view of the administrative law. Particular attention is paid to the ethical review of the clinical trials, their particular aspects and the overall concept. The thesis is divided into twelve chapters. In the introduction, the author focuses on the development of the clinical trials and mentions the crucial moments that contributed to the formulation of the basic rules of the clinical trials. The following chapter focuses on the sources of law. Firstly, sources of international law are described, where more general sources and specific sources of law of medicinal products...