Class of 2010 Abstract / OBJECTIVES: The objective was to compare differences in weight loss data presented in published orlistat studies on orlistat to their corresponding studies submitted to the FDA. METHODS: This meta-­‐analysis compared one-­‐year weight loss data reported in six published orlistat 120 mg studies to data reviewed by the FDA in the New Drug Application (NDA). The primary dependent variables were the percentage of subjects achieving 5% and 10% weight loss. Prior to analysis, weight loss data was stratified into placebo and orlistat groups. Potential for bias was assessed with a funnel plot and by calculating Kendall’s tau. The a priori alpha level was 0.05. RESULTS: Corresponding FDA reviews were located for 6 published orlistat trials. The pooled odds ratio of published vs. FDA 5%weight loss data for the placebo arm was 2.18 (95% CI: 1.83 to 2.60; p < 0.001) and 1.95 (95% CI: 1.70 to 2.24; p < 0.001) for the orlistat arm. The pooled odds ratio of published vs. FDA for 10% weight loss data for the placebo arm was 2.25 (95% CI: 1.74 to 2.91; p < 0.001) and 2.20 (95% CI: 1.88 to 2.57; p < 0.001) for the orlistat arm. The p-­‐values for Kendall’s tau for the 5% and 10% weight loss data were 0.054 and 0.34, respectively. CONCLUSIONS: Published orlistat trials presented 5% and 10% weight loss data that were twice of that reported in the FDA-­‐reviewed trials, and there was potential for bias in the 5% weight loss data.

Drug development in the United States has undergone many changes in the past 25 years, but relatively few fully realize the complexities involved in developing a new drug. Once a promising compound is identified, it must undergo preclinical testing, have an Investigational New Drug Application filed with the U.S. Food and Drug Administration (FDA), and proceed through clinical testing. When sufficient information is gained, a marketing application is filed with the FDA, who identifies it as a New Drug Application for drugs or a Biologics License Application for biologics. After FDA review and approval, postmarketing studies are frequently performed. The FDA and Congress have undertaken several initiatives to expand access and to accelerate drug development and review of investigational drugs for life-threatening and/or serious illnesses. Although the ultimate goal is to bring safer and more effective medical products to patients in a timely manner, multiple challenges face those who participate in drug development.

En tredjedel av alla bypass-operationer leder till att kärlimplantaten slutar fungerar inom ettårs tid. En anledning till detta är bildandet av ogynnsam vävnad som sker i form av ärrbildning efter implantationen. Ärrvävnaden orsakar nya förträngningar vilket leder till ett försämrat blodflöde. Kärlimplantatet Y-graft har genom sin design som följer Murray´s lag, en naturlig blodflödesfördelning. Designen i form av ett Y har kunnat bekräftas vara fördelaktig då geometrin vid utflödet minskar risken för ärrbildning. Vad som saknas för att Y-graft ska kunna komma ut på marknaden är ett lämpligt material. Med detta som bakgrund uppkom syftet med litteraturstudien att undersöka vilka material meddokumenterad klinisk historik som är möjliga att använda vid textil tillverkning av Y-graft. Genom en gedigen litteratursökning med hjälp av sökverktyg som U.S. Food and Drug Administration (FDA) tillsammans med andra databaser inom de medicinska och materialtekniska områdena, har en förståelse skapats kring vilka material som används i medicintekniska produkter och som är möjliga kandidater till Y-graft. Litteraturstudien resulterade i att materialen polyetentereftalat, polybutentereftalat, polybutester polytetrafluoreten, polyester-, polyeter- och polykarbonatbaserade polyuretaner samt polypropen, polyeten, alfatisk polyamid och silke finns i godkända medicintekniska produkter på den amerikanska marknaden. De presenterade materialen har på så visdokumenterad klinisk historik och är lämpliga kandidater att använda vid textil tillverkning av Y-graft. De godkända materialkandidaterna som presenteras kan även beläggas medbiologiska polymerer för förbättrad biokompatibilitet. Materialkandidaterna har godkänts i medicintekniska produkter av U.S. Food and Drug Administration (FDA). Genom godkännandet har alla de presenterade materialen dokumenterad klinisk historik och är där med lämpliga kandidater att använda vid textiltillverkning av Y-graft. / One third of all bypass surgeries causes vascular implants to stop working within a year. A reason for this is the formation of unfavorable tissue that occurs in the form of scarring after implantation. The scar tissue causes new constrictions, which leads to impaired blood flow. The vascular implant Y-graft, by design follows Murray's law and therefore has a natural blood flow distribution. The design in the form of a Y has been confirmed to be advantageous. The Y geometry at the outflow reduces the risk of scarring. What is missing for Y-graft to be able to enter the market is a suitable material. With this as a background, the purpose of the literature study was to investigate which materials with documented clinical history can be used in textile production of Y-graft. Through a thorough literature search, using search tools like the U.S. Food and Drug Administration (FDA) together with other databases in the medical and material engineering fields, an understanding has been created about which materials are used in medical technology products and which are potential candidates for Y-graft. The literature study concluded that the materials polyethylene terephthalate, polybutheneterephthalate, polybutester polytetrafluoroethylene are found in approved medical technology products in the United States. Polyester, polyether and polycarbonate based polyurethanes and polypropylene, polyethylene, alphatic polyamide and silk are also found in the United States medical market. These presented materials thus have documented clinical history and are suitable candidates for use in textile manufacturing of Y-graft. The approved material candidates presented can also be coated with biological polymers for improved biocompatibility. The material candidates have been approved in medical technology products by the U.S. Food and Drug Administration (FDA). With this approval, all the presented materials have documented clinical history and are therefore suitable candidates to use when manufacturing Y-graft.

Ce mémoire s'intéresse à l'influence de la règlementation américaine sur la qualité des produits médicaux commercialisés au Canada et aux États-Unis. Au départ, notre recherche s'intéressait uniquement aux entreprises canadiennes mais étant donné la taille restreinte et la récence de ce marché, et qu'il nous fallait des entreprises qui avaient connu les changements règlementaires des trente dernières années, nous l'avons étendu aux entreprises américaines. L'objectif de recherche consiste à établir si la réglementation influence, à elle seule, la qualité des produits ou si c'est l'effet de plusieurs variables citées dans la littérature, notamment la technologie, les institutions de santé et les besoins d'utilisateurs. L'analyse contextuelle a permis de tracer, sur une période de trente années, les événements historiques importants qui auraient contribué à l'évolution de la qualité. Citons, sans ordre particulier, la modernisation de l'appareil règlementaire américain, la croissance des décès issus de mauvaises manipulations des appareils médicaux, l'arrivée des innovations technologiques dans le secteur de la santé, un mouvement consumériste naissant, la montée des programmes règlementaires orientés vers l'utilisateur. En optant pour une méthodologie d'entretien individuel, nous avons pu vérifier l'influence de ces facteurs, auprès des participants, tous des cadres exécutifs ayant plus de dix ans d'ancienneté dans l'entreprise, et contrôler la qualité des verbatims. L'analyse des entretiens a démontré que, selon les répondants, la réglementation influence la qualité, voire contribue à son amélioration notamment depuis 1990 lorsque la FDA a modernisé l'acte des dispositifs médicaux pour inclure les facteurs humains, communément appelés « l'expérience utilisateur ». D'ailleurs ce dernier est désormais un critère de qualité d'importance égale aux propriétés techniques des produits grâce au lobby des entreprises innovantes pour la plupart américaines. Incombe aux entreprises "en mode réaction" d'investir dans ce domaine pourtant très répandu dans d'autres industries au lieu de se contenter de corriger les défauts techniques des produits. Par ailleurs, il ressort de notre analyse que les entreprises médicales d'origine canadienne et de moindre taille auront plus de difficulté à se mesurer aux leaders américains non pas par manque de vision ou de stratégie orientée client, mais par manque de ressources et en l'absence de partenariat. Enfin, le défi qui cette-fois concerne toutes les entreprises est celui d'innover et de promouvoir les avancées technologiques dans un système réglementé qui, historiquement, ne les facilite pas. ______________________________________________________________________________

The Cytochrome P450 family of enzymes is responsible for the majority of Phase I metabolism, and has been identified as an important source of pharmacokinetic variation in therapeutic responses. CYP2C19 and CYP2D6, metabolising >35% of commonly prescribed medications, are two of the most important pharmacogenetic markers that have been studied with the aim of improving treatment response and reducing adverse drug reactions. The Food and Drug Administration (FDA) approved AmpliChip CYP450 Test (AmpliChip) was compared to a previously developed PCR-RFLP platform and a newly developed XLPCR+ Sequencing platform for the ability to identifying genotype and predicting phenotype for CYP2C19 and CYP2D6 respectively. The AmpliChip was found not to be genotypically comprehensive enough for evaluating CYP2C19 genotype, not robust enough for determining CYP2D6 genotype and inaccurate in predicting phenotype for both. The XLPCR+ Sequencing method identified three novel alleles and one sub-variant. Advances in online column-switching solid phase extraction generated a rapid and robust LCMS/ MS method for simultaneously quantifying the probe drugs omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate) and their metabolites. Antimodes were identified for phenotypic cut-offs which offered measured phenotype for comparison to predicted phenotype. Omeprazole metabolism by CYP2C19 correlated well with predicted phenotype in a demographically representative South African cohort. There are concerns regarding the use of omeprazole as a probe drug as participants predicted to be ultrarapid metabolisers for CYP2C19 had similar rates to extensive metabolisers. Regardless of this concern, decreased metabolism was assigned to the CYP2C19*15 for the first time. CYP2D6 predicted phenotype correlated very well with measured phenotype, validating the suitability of dextromethorphan use for measuring CYP2D6 metabolism. Substrate modified activity score using 0.5 to predict intermediate metabolisers fine-tuned the XLPCR+ Sequencing platform for phenotype prediction. This finding, along with observations in CYP2C19 metabolism of omeprazole, highlights the importance of substrate specific phenotype prediction strategies. Controversially, attempts to associate CYP2D6 phenotype prediction with risperidone-related adverse drug reactions has yielded conflicting results. The XL-PCR+Sequencing platform was able to discount this association by predicting a variety of metabolisers in a pilot cohort selected to be experiencing risperidone-related adverse drug reactions. The comprehensive capability of the XL-PCR+Sequencing allowed for the identification of an additional novel allele in this cohort. The data presented in thisthesis has provided insight into the relationship between predicted and measured phenotype for CYP2C19 and CYP2D6 in the South African population. The XL-PCR+Sequencing platform can be used for future research or can be applied to improve treatment outcome. The LC-MS/MS method developed could be used for future evaluations of predicted and measured phenotype with the ability to be adjusted for therapeutic drug monitoring. This thesis advances pharmacogenetics of CYP2C19 and CYP2D6 for use in the South African population. / Thesis (PhD)--University of Pretoria, 2013. / gm2014 / Pharmacology / unrestricted

Innovation fuels American business. Commonly, innovation is judged as good. Yet, many of the new medical devices that come on the U.S. market every year are later deemed unsafe. Regulation is distorted in that 98% of medical devices are never evaluated in human trials before being introduced to the marketplace. Instead, the U.S. Food and Drug Administration (FDA) approves a new medical device through a designated 501(k) process, based upon the identification of a predicate or substantially equivalent (SE) device. This is an investigation of the tension between product innovation, government regulation, and public safety in the American healthcare industry. It is a research project in two parts. The first draws upon established methodologies and utilizes the FDA’s 501(k) database to provide an illustrated example of the sequence and dependency between generations of implanted surgical mesh devices. The analysis reveals that the 501(k) approval process reliance on predicate devices facilitates medical device innovation that is problematic in several aspects, including patient safety. To further examine medical device innovation and patient safety, the second study develops a proof-of-concept exercise to evaluate data on recorded adverse events (AEs) found in the FDA’s Total Product Lifecyle (TPLC) database for surgical mesh products. The adverse events were mapped to the Association for the Advancement of Automotive Medicine’s (AAAM’s) Abbreviate Injury Scale (AIS), following precedents found in the medico-legal literature and military injury biomechanics standards. This approach forges a path forward to determine the relative frequency and severity of adverse events of a specific medical device, compared to that of the overall FDA product category. These two research projects combine to contribute to the understanding of safety of the FDA’s approval process and by extension the medical device industry’s innovation practices. / Business Administration/Accounting

It is the purpose of this thesis to develop a course of study for pharmacy schools on drug regulation by the Food and Drug Administration (FDA). A summarization of the history of the development of the Food and Drug Administration (FDA) and of pharmacy education reveals a lack of interface between the two. The necessity for the interface of pharmacy education and the agency which has significant control over the products forming the basis of the pharmacy profession will be made apparent. A period of residency through which the course of study on drug regulation by the FDA was to be developed, will be described. This description details the responsibilities and functions of the various segments of the FDA involved in the regulation of drugs as acquired through discussion with agency officials during the residency. It is intended to be used as the textual material for the didactic portion of the course of study to be offered at schools of pharmacy. Based upon the experience, recommendations will be made regarding the applicability of the course of study to include possible residencies for pharmacy students at the agency.

Bladder Cancer is the tenth most common malignancy globally, and is the thirteenth most common cause of tumor associate morbidity. Bladder cancer is largely stratified into two categories: Non-Muscle Invasive Bladder Cancer (NMIBC) and Muscle Invasive Bladder Cancer (MIBC). NMIBC represents disease localized to the urinary bladder, and can be stratified into low and high-grade disease. MIBC represents an aggressive class of bladder cancer, with invasion into the underlying muscle layers of the bladder. MIBC can be classified as either non-metastatic MIBC, with disease localized to the bladder corpus, or metastatic MIBC, with disease spreading to sites beyond the bladder corpus. High grade NMIBC presents significant risk for progression to MIBC, and collectively both high grade NMIBC and MIBC bladder cancers demonstrate poor prognostic outcomes in clinical settings in terms of responses to therapy, recurrence risks, and overall survival. Hexaminolevulinate is a precursor of Protoporphyrin IX (PpIX) in the heme biosynthetic pathway. Hexaminolevulinate has been FDA approved under the trade name Cysview for diagnostic usage in blue light cystoscopies for fluorescence mediated visualization of disease along the bladder wall. I demonstrate that in addition to its diagnostic utility, Cysview and blue light irradiation can be utilized clinical as a potential therapeutic modality. I demonstrate the significant selective cytotoxicity of Cysview in combination with blue light against patient derived organoids (PDOs) from primary bladder cancers. My results determine that Cysview and blue light induce a rapid cell death program mediated by an influx in Reactive Oxygen Species (ROS) production, resulting in less than 5% viability within 24 hrs of treatment. This massive loss in viability is observed in low and high grade NMIBC, as well as MIBC derived PDOs with diverse mutational profiles. The results of this work demonstrate that PDOs are a significant platform for assessing therapy responses for correlation with the large patient population. Furthermore, the work identifies photodynamic therapy with Cysview and blue light irradiation as a putative therapeutic modality for localized bladder cancers, with the potential for significant improvement in patient outcomes. The identification and characterization of the therapeutic effects of Cysview come at a critical time during a global shortage of conventional therapeutics for localized bladder cancer, and presents a pathway for patients affected by these shortages. Progression in bladder cancer has been understood to be driven by processes governing subpopulation and cell state and lineage transformation. Previous studies identify phenotypic plasticity within a subset of bladder cancers and have correlated this phenomenon with an increased risk for disease progression from NMIBC to MIBC. In previous work, a subset of PDOs derived from luminal primary tumors demonstrated significant degrees of luminal to basal plasticity in vitro. In my analysis of these PDOs using transcriptomic and chromatin accessibility data, I identified a transcriptomic and epigenetic signature unique to plastic PDOs. Furthermore, I identified HNF1B, GRHL2, GATA6, and SNAI2 as putative regulators of luminal to basal plasticity in bladder cancer. Using these molecular profiles, I correlated the plasticity phenotype with reduction in overall survival using data from published bladder cancer patient cohorts. Finally, I developed a novel transcriptomic subtypes classification scheme and an accompanying R package to classify epithelial heterogeneity in bladder cancer, based on the transcriptomic subtypes I identified in bladder cancer PDOs.

FDA decisions and late-stage clinical trial results regarding new pharmaceutical approvals can cause extreme moves in the share price of small biopharmaceutical companies. Throughout the clinical trial process, many potential investors are exposed to market-moving information before such information is made available to the investing public. An investor who wished to profit from advance knowledge about clinical trial results may use the publicly traded options markets in order to increase leverage and maximize profits. This research examined options data surrounding the public release of information pertaining to the efficacy of clinical trials and approval decisions made by the FDA. Events were identified for small pharmaceutical companies with fewer than three currently approved drugs in an attempt to isolate the effect of individual clinical trial and FDA-related events on the share price of the underlying company. Option data were analyzed using logistic regression models in an attempt to predict phase II and III clinical trial outcome results and FDA new drug approval decisions. Implied volatility, open interest, and option contract delta values were the primary independent variables used to predict positive or negative event outcomes. The dichotomized version of a predictor variable designed to estimate total investment exposure incorporating open interest, option contract delta values, and the underlying stock price was a significant predictor of negative pharmaceutical related events. However, none of ii the variables examined in this research were significant predictors of positive drug research related events. The estimated total investment exposure variable used in this research can be applied to the prediction of future clinical trial and FDA decision related events when this predictor variable shows a negative signal. Additional research would help confirm this finding by increasing the sample size of events that potentially follow the same pattern as those examined in this research. / text

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