A Research Report submitted to the Faculty of Science in partial fulfilment of the requirements for the degree of Master of Science. 26 October 2016. / The cost of healthcare has become generally expensive the world over, of which the greater part of the money is spent buying drugs. In order to reduce the cost of drugs, drug manufacturers came up with the idea of manufacturing generic drugs, which cost less as compared to brand name drugs. The challenge which arose was how safe, effective and efficient the generic drugs are compared to the brand name drugs, if people were to buy them. As a consequence of this challenge, bioequivalence studies evolved, being statistical procedures for comparing whether the generic and brand name drugs are similar in treating patients for various diseases. This study was undertaken to show the existence of bioequivalence in drugs. Bioavailability is considered in generic drugs to ensure that it is more or less the same as that of the original drugs by using statistical tests. The United States of America’s Food and Agricultural Department took a lead in the research on coming up with statistical methods for certifying generic drugs as bioequivalent to brand name drugs. Pharmacokinetic parameters are obtained from blood samples after dosing study subjects with generic and brand name drugs. The design for analysis in this research report will be a 2 2 crossover design. Average, population and individual bioequivalence is checked from pharmacokinetic parameters to ascertain as to whether drugs are bioequivalent or not. Statistical procedures used include confidence intervals, interval hypothesis tests using parametric as well as nonparametric statistical methods. On presenting results to conclude that drugs are bioequivalent or not, in addition to hypothesis tests and confidence intervals, which indicates whether there is a difference or not, effect sizes will also be reported. If ever there is a difference between generic and brand name drugs, effect sizes then quantify the magnitude of the difference. KEY WORDS: bioequivalence, bioavailability, generic (test) drugs, brand name (reference) drugs, average bioequivalence, population bioequivalence, individual bioequivalence, pharmacokinetic parameters, therapeutic window, pharmaceutical equivalence, confidence intervals, hypothesis tests, effect sizes. / TG2016

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Science in Medicine (Pharmaceutical Affairs) Johannesburg, 29 August 2014 / In South Africa’s current healthcare structure, about 8.3% of GDP is spent on healthcare. This is well above the WHO recommended 5% of GDP spend. Despite the heavy spending, health outcomes remain poor when compared to similar middle-income countries. Solutions need to be found to cut back on healthcare costs. Approximately half (4.1%) of the healthcare spend is consumed by the private sector which benefits a very small segment (16%) of the population. This segment is largely on medical schemes. Using generic medicines can aid in cutting back on drug costs but are generics being adequately assimilated by the consumers of healthcare in the private sector? The objective of the study was to evaluate the perceptions attitudes and knowledge of the consumers of healthcare in the Northern suburbs of Johannesburg towards generic medicines. A survey was conducted on a sample of 402 respondents across 9 randomly selected pharmacies in the Johannesburg north region between November 2012 and February 2013. A researcher administered questionnaire was the sole data collection tool. Questions asked covered the research objectives and also included demographic data and other explanatory variables. Data analysis was carried out in SAS. The 5% significance level was used throughout, unless specified otherwise. The chi-squared (Χ2 ) test was used to assess the relationships between categorical variables. Fisher’s exact test was used for 2 x 2 tables or where the requirements for the Χ2 test could not be met. The strength of the associations was measured by Cramer’s V and the phi coefficient respectively. Key results on respondent demographics included high representation of the higher income earning groups (78% >R10 000); furthermore 44% had completed tertiary education, 60% were comprehensively insured, 61% regularly visited a pharmacy, 38% were on prescription medication and 24% on chronic medicine. On knowledge, 5% of respondents were able to most accurately define generic medicines. On attitudes, 78% had used generics however the level of agreement was lower for the highest education category (p<0.0001; Cramer’s V=0.18). Trends favoured brands over generics with increasing severity of illness as generics were chosen by 10% in major illness and 5% in chronic illness. 80% perceived generics as safe while 95% perceived brands as safe. 75% of respondents felt that generic medicines were as effective as branded medicines. 15% indicated that branded medicines have fewer side effects. 64% showed positive perceptions of quality of generics compared to 93% for brands. Bowker’s test of symmetry was significant (p<0.0001) showing a shift towards slightly more negative perceptions towards generic medicines amongst those who thought highly of brand quality. Knowledge of generics was overall low. Perceptions regarding safety, quality, efficacy, and side effects of generic medicines were generally positive but responses proved more positive for brands. Attitudes towards generic medicines were mostly positive however willingness to use generics lessened with increasing severity of illness. Household income, health insurance (medical aid) status, level of education, experience with medicines and racial demographics played a key role in explaining consumer beliefs and behaviours. Pharmacists and Doctors had a positive influence on generic use patterns amongst other factors.

Thesis (Ph. D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Biostatistics. Title from title-page of electronic thesis. Includes bibliographical references (p. 126-131).

Abstract Background The South African Healthcare landscape has changed dramatically over the last two years with the implementation of mandatory substitution, single exit pricing and prescribed minimum benefits. The private market for medicines is becoming more competitive and commoditized. Between July 2004 and June 2005 there were 119 generic registrations at the Medicines Control Council. In the US and Canada research has been conducted on the change in prescribing behaviour induced through incentive based formularies and the impact of generic medicines on healthcare costs. This research protocol aims to build on this body of knowledge by analysing sales trends within a therapeutic class after the launch of a generic molecule in the same class. This research investigates how the introduction of generics may impact the growth of the innovator molecules and subsequent generics. The therapeutic class Acid Pump Inhibitors has been selected. Method Unit sales of Proton Pump Inhibitors are drawn monthly from sales in the total private market. They are then grouped by molecule and comparisons are drawn between the originator and it’s generic to determine association. This is also done at the aggregate level where the originators form one group and generics the second group. Each aggregate group’s average growth in the therapeutic class is then calculated to determine the aggregate group’s evolution index. Data Analysis Data is analysed through descriptive and interpretative statistics. The descriptive statistics establish a relationship between generisized molecules and the non generisized molecules. A t-test for two independent means is used to test the hypothesis that the non generisized molecules in the therapeutic class have a significant higher growth. Conclusion The results demonstrate that the number of units sold of the generisized molecules increase as they become more affordable, however contrary to intuition the number of iv units sold of the non generisized molecules also increase. The research shows that there is a statistically significant greater growth, albeit on a smaller base, of the non generisized molecules over generisized molecules.

O objetivo deste trabalho é analisar a influência dos veículos pesados na capacidade de rodovias de pista simples e mão dupla de direção através da determinação de fatores de equivalência veicular para diversos comprimentos e magnitudes de aclives. A presença de veículos de grande porte em rodovias de pista simples contribui para a redução dos níveis de serviço devido ao seu tamanho e desempenho. Um caminhão ocupa mais espaço na via que um automóvel, em função de seu maior comprimento, reduzindo a capacidade da via. Numa rodovia de pista simples, os automóveis devem ultrapassar os veículos pesado; caso a ultrapassagem não seja possível, ocorre a formação de pelotões, que ocasionam uma degradação no nível de serviço. O método proposto determina os fatores de equivalência a partir das velocidades médias dos veículos ao longo dos aclives e das oportunidades de ultrapassagem. Para o cálculo dos headways na corrente oposta necessários para uma ultrapassagem, este trabalho propõe um novo modelo cinemático de ultrapassagem. Os fatores de equivalência são calculados para diversas categorias veiculares; um conjunto de tabelas determinadas a partir da composição de tráfego observada é também apresentado. O efeito da sobrecarga na capacidade é estudado para a categoria de caminhões mais comum, os caminhões semi-pesados. / This study assesses the impacts of heavy vehicles on the capacity of two-lane highways through equivalency factors determined for various grade lengths and magnitudes. Heavy vehicles impact negatively the capacity of two-lane highways due to their size and performance. As a truck is longer than a car, it reduces the capacity of the road due to its length. Given that trucks have poorer performances than cars, in a two-lane road, cars generally pass trucks, and platoons are formed when passing opportunities are scarce. The formation of platoons cause a noticeable reduction on the level of service. The proposed method calculates equivalency factors from the averaqe speeds on grades and from the passing opportunities. A new cinematic model for the passing maneuver that is able to determine the required headways in the opposite flow for a safe passing maneuver is proposed. The equivalency factors are determined for a set of pre-defined vehicular classes; a set of truck equivalents is also calculated for the observed traffic mix. The effect of overloading on capacity is analized for the most common truck type.

O objetivo deste trabalho é analisar a influência dos veículos pesados na capacidade de rodovias de pista simples e mão dupla de direção através da determinação de fatores de equivalência veicular para diversos comprimentos e magnitudes de aclives. A presença de veículos de grande porte em rodovias de pista simples contribui para a redução dos níveis de serviço devido ao seu tamanho e desempenho. Um caminhão ocupa mais espaço na via que um automóvel, em função de seu maior comprimento, reduzindo a capacidade da via. Numa rodovia de pista simples, os automóveis devem ultrapassar os veículos pesado; caso a ultrapassagem não seja possível, ocorre a formação de pelotões, que ocasionam uma degradação no nível de serviço. O método proposto determina os fatores de equivalência a partir das velocidades médias dos veículos ao longo dos aclives e das oportunidades de ultrapassagem. Para o cálculo dos headways na corrente oposta necessários para uma ultrapassagem, este trabalho propõe um novo modelo cinemático de ultrapassagem. Os fatores de equivalência são calculados para diversas categorias veiculares; um conjunto de tabelas determinadas a partir da composição de tráfego observada é também apresentado. O efeito da sobrecarga na capacidade é estudado para a categoria de caminhões mais comum, os caminhões semi-pesados. / This study assesses the impacts of heavy vehicles on the capacity of two-lane highways through equivalency factors determined for various grade lengths and magnitudes. Heavy vehicles impact negatively the capacity of two-lane highways due to their size and performance. As a truck is longer than a car, it reduces the capacity of the road due to its length. Given that trucks have poorer performances than cars, in a two-lane road, cars generally pass trucks, and platoons are formed when passing opportunities are scarce. The formation of platoons cause a noticeable reduction on the level of service. The proposed method calculates equivalency factors from the averaqe speeds on grades and from the passing opportunities. A new cinematic model for the passing maneuver that is able to determine the required headways in the opposite flow for a safe passing maneuver is proposed. The equivalency factors are determined for a set of pre-defined vehicular classes; a set of truck equivalents is also calculated for the observed traffic mix. The effect of overloading on capacity is analized for the most common truck type.

This thesis describes a project to produce controlled release ketoprofen beads for capsules, both at Oregon State University and in an industrial scale-up operation, that are bioequivalent to the commercial product Oruvail. A bead formulation was produced by layering drug and binders in water onto nonpareil sugar seeds in a spray coating apparatus. Ketoprofen beads manufactured in this manner will immediately release their drug content in either an in vitro or an in vivo environment. Industrially produced beads were non-homogeneous in size. Large beads in a coating batch sweep up a disproportional amount of coating material leading to a thicker coating layer and decreased drug release rates. In order to predict the effects of coating modifications, an equation was developed to accurately predict the coating thickness of any material applied to spherical particles of any size. The equation developed is suggested as a replacement for one that has been in published and cited for over 20 years, but overestimates coating thickness. The bulk of this thesis details the process of altering the drug release characteristics of the beads through application of diffusional and enteric barrier coatings, and testing for bioequivalence with Oruvail through biostudy data gathered from human volunteers. Urinary drug excretion rates were measured as a substitute for timed blood sampling of the subjects. Validity of the substitution was shown. Fed state biostudies involved beads manufactured and coated at Oregon State University. Fasted state biostudies involved beads that were industrially manufactured in a scale-up operation and coated both industrially and at Oregon State University. Deconvolution, a mathematical tool, was used to determine in vivo dissolution rates and the need for further coating modification. Statistical testing using a Two 1-Sided T test was the final arbiter of whether or not bioequivalence was concluded. Bioequivalence was achieved in subjects under a fed state and finally under fasting conditions, as required by the Food and Drug Administration, with drug beads coated with ethylcellulose to slow drug release and overcoated with an enteric bather to retard early drug release. Deconvolved in vivo dissolutions originating from biostudy data were used to develop In Vitro / In Vivo Correlations (IVIVC's). IVIVC's were used to predict in vivo biostudy data from in vitro dissolution results following coating formulation modification. A practical guide for the development and use of an IVIVC was written for pharmaceutics practitioners who have an understanding of pharmacokinetics, but may lack sufficient expertise in pharmacokinetics to develop an IVIVC. / Graduation date: 1998

La compensación ambiental se refiere a la provisión adicional de recursos naturales, servicios ecológicos o de bienestar social a través de proyectos de reparación que son equivalentes en magnitud a las pérdidas producidas por daños ambientales. En la Unión Europea, la Directiva de Responsabilidad Medioambiental establece el marco legal para introducir responsabilidad ambiental debido a daños producidos al medio ambiente por actividades industriales. La responsabilidad ambiental establece que los recursos naturales dañados deben devolverse al estado que hubieran tenido de no producirse el daño en cuestión (restauración primaria) así como la provisión de una compensación por pérdidas acumuladas (o pérdidas provisionales) producidas desde el momento en que ha ocurrido el incidente hasta que el medio ambiente ha vuelto a su estado original (restauración compensatoria). Los Análisis de Equivalencia representan un instrumento que se utiliza para determinar la cuantía por daños al medio ambiente. Esta investigación aplica una metodología de análisis de equivalencia conocida como método valor-a-valor como una herramienta para escalar la cantidad de remediación requerida y de esta manera estimar la cantidad de reparación para compensar las pérdidas ambientales producidas tras un incendio forestal ocurrido en el noreste de España. Para efectos del Análisis de Equivalencia de Valor (AEV) se ha diseñado un ejercicio de Valoración Contingente (VC) que estima la media de la cantidad mínima de compensación física requerida para compensar los daños producidos según las preferencias sociales. A continuación, el estudio explora cuestiones que tienen que ver con la localización del proyecto de remediación cuando éste se sitúa a cierta distancia del sitio dañado. Intuitivamente, la idea de que la ubicación de un proyecto de restauración se encuentre alejado de la ubicación inicial (la zona dañada) podría implicar una mayor cantidad de compensación en comparación a un proyecto de reparación localizado más próximo al sitio del daño. Para este fin se ha diseñado un ejercicio adicional que utiliza modelos de elección que permite estimar la cantidad de compensación requerida cuando el proyecto de reparación se localiza en un sitio distinto al de la zona afectada. Finalmente, la última parte de esta investigación explora los efectos en la disposición a pagar de la información proporcionada en el cuestionario relacionada con los pagos de un programa de reparación; específicamente, cómo pagarán por el programa y si los pagos corresponden a valores nominales o reales. Con el fin de analizar este tema la pregunta de valoración toma una forma dicotómica simple en la cual los pagos deben hacerse anualmente, durante diez años, y con incrementos anuales de acuerdo a la inflación. / Environmental compensation implies the provision of additional natural resources, services or social welfare through restoration projects that are scaled to equal the losses due to environmental damage. The Environmental Liability Directive provides legal framework in the European Union for introducing environmental liability due to damages to the environment caused by industrial operators. Environmental liability requires that harmed natural resources be restored to baseline conditions (primary restoration) and compensated for the accumulated losses (interim losses) produced from the time of the incident until the environment reaches baseline conditions (compensatory restoration). Equivalency Analysis is a methodology used to determine compensation for environmental damage. This study uses an Equivalency Analysis (EA) approach namely the value-to-value approach as a tool to scale remediation and to estimate the amount of compensatory restoration to off-set an environmental damage following a wild forest fire in the northeast of Spain. Value Equivalency Analysis (VEA) is undertaken by a Contingent Valuation (CV) exercise to determine the welfare loss from the initial damage and interim loss and then a remediation project that can be established based on that information. The study elicits the minimum amount of compensation required to make individuals as well off as they would be in the baseline situation. After this the study explores remediation located at a geographical distance from the site of damage. In some cases displacement between damaged resources and restored resources is allowed, this study explores whether longer distance from the damaged site could imply a larger amount of compensation to offset the change in natural resource location. For this, an additional exercise was designed to estimate the trade-off rate for compensating in a farther away site using choice experiment techniques. Finally, the last section focuses on the information provided to respondents regarding payments in the survey instrument. This includes informing respondents how they would pay for the restoration program and whether payments correspond to nominal or real values. The survey instrument takes the form of a single bounded dichotomous choice where the payments are to be made every year over a ten year period and they would go up every year according to inflation.

The high-volume air sampling (PS-1) and micro-orifice uniform deposit impactor (MOUDI) were used to measure the concentrations of polycyclic aromatic hydrocarbons (PAHs) in the atmosphere for four seasons at Zuoying and Siaogang in Kaohsiung city, together with the size distributions. Also, the CMB (Chemical Mass Balance) receptor model was employed to determine the potential sources of PAHs. The results show that the highest concentrations of PAHs occurred in winter, being 143.9 ng/m3 and 182.9 ng/m3 at Zuoying and Siaogang, respectively; while the lowest concentrations of PAHs occurred in summer, being 81.4 ng/m3 and 95.2 ng/m3. The low-weight PAHs in the two sites were abundant in gaseous phase, being 55.89 - 95.89 % and 67.07 - 96.61 % at Zuoying and Siaogang, respectively. Meanwhile, the high-weight PAHs were almost present in particulate phase, being 55.24 - 83.50 % and 46.87 - 77.26 % at Zuoying and Siaogang, respectively. The sizes of 50th percentile of cumulative size distribution, d50 of Zuoying and Siaogang were 0.89 £gm and 0.35 £gm, respectively. Hence, most atmospheric PAHs existed in fine-particle ranges (¡Õ1.0£gm). The results of by CMB receptor modeling indicated that the major sources of pollution was exhaust emission (49 - 62 %) in Zuoying, and was burning source (49 - 64 %) in Siaogang.

Thesis (Ph. D.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 199-211). Also available on the World Wide Web.