Dissertations / Theses on the topic 'Trials'

Thesis: M. Eng., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2019
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (pages 59-64).
The objective of this thesis is to study the challenges of data sharing in healthcare (namely clinical trials), and propose the use of Open Algorithms (OPAL) as a viable solution for research collaboration that allows for access to data without compromising data ownership (data is only used once for the intended purpose, raw data is never leaked, the value generated from the data is transferred to the owner). This thesis surveys the challenges unique to clinical trials, and highlights the various methods for privacy-preserving computation prior to this work. Through the overview of OPAL's solution in the space of privacy-preserving computation, we show the implementation details of how OPAL was applied to clinical trials in a project called Open Trial Chain, a platform for clinical trial data built for analytics, security, and incentivized sharing through technologies like federated learning and blockchain. With motivated examples derived from real-world reported problems in healthcare, we also demonstrate speed, accuracy, and security metrics. In the application, Open Trial Chain can drastically reduce clinical trial costs, reduce error, and increase quality of analysis diversity. Overall, this project shows promise for further extension in other health datasets for compliance in an ever-complicated move towards regulations that reflect for conscientiousness for data security, ownership, and provenance.
by Anne Kim.
M. Eng.
M.Eng. Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science

Des données complexes sont fréquentes dans les essais cliniques récents et nécessitent des méthodes statistiques adaptées. La recherche vaccinale du VIH est un exemple d’un domaine avec des données complexes et une absence de critères de jugement validés dans les essais précoces. Cette thèse d’Université concerne des recherches méthodologiques sur la conception et les aspects statistiques des essais cliniques vaccinaux du VIH, en particulier sur les critères de jugement d’immunogénicité et les schémas d’essai de phase I-II. A l’aide des données cytokiniques multiplex, nous illustrons les aspects méthodologiques spécifiques à une technique de mesure. Nous proposons ensuite des définitions de critères de jugement et des méthodes statistiques adéquates pour l'analyse des données d'immunogénicité multidimensionnelles. En particulier, nous montrons l’intérêt des scores multivariés non-paramétriques, permettant de résumer l’information à travers différents marqueurs d’immunogénicité et de faire des comparaisons inter- et intra-groupe. Dans l’objectif de contribuer à la conception méthodologique des nouveaux essais vaccinaux, nous présentons la construction d’un schéma d’essai optimisé pour le développement clinique précoce. En imbriquant les phases I et II d’évaluation clinique, ce schéma permet d’accélerer le développement de plusieurs stratégies vaccinales en parallèle. L’intégration d’une règle d’arrêt est proposée dans des perspectives fréquentistes et Bayesiennes. Les méthodes mises en avant dans cette thèse sont transposables à d’autres domaines d’application avec des données complexes, telle que les données d’imagerie ou les essais d’autres immunothérapies
Complex data are frequently recored in recent clinical trials and require the use of appropriate statistical methods. HIV vaccine research is an example of a domaine with complex data and a lack of validated endpoints for early-stage clinical trials. This thesis concerns methodological research with regards to the design and analysis aspects of HIV vaccine trials, in particular the definition of immunogenicity endpoints and phase I-II trial designs. Using cytokine multiplex data, we illustrate the methodological aspects specific to a given assay technique. We then propose endpoint definitions and statistical methods appropriate for the analysis of multidimensional immunogenicity data. We show in particular the value of non-parametric multivariate scores, which allow for summarizing information across different immunogenicity markers and for making statistical comparisons between and within groups. In the aim of contributing to the design of new vaccine trials, we present the construction of an optimized early-stage HIV vaccine design. Combining phase I and II assessments, the proposed design allows for accelerating the clinical development of several vaccine strategies in parallel. The integration of a stopping rule is proposed from both a frequentist and a Bayesian perspective. The methods advocated in this thesis are transposable to other research domains with complex data, such as imaging data or trials of other immune therapies

TESIS PARA OPTAR AL GRADO DE MAGÍSTER EN ADMINISTRACIÓN
Ricardo Enrique Cuevas Arriagada [Parte I], Neil William Páez Bustos [Parte II]
El presente trabajo desarrolla una idea de negocio llamada B-Trials, cuyo origen surge a partir de una necesidad específica en la ejecución de Estudios Clínicos de la Industria Farmacéutica local, que corresponde al aumento en la participación de pacientes en la ejecución de los protocolos de estudios, a modo de aumentar la competitividad frente a los otros países de la región. Actualmente, son los médicos tratantes, colegas y/o contactos de los mismos quienes derivan pacientes a los Estudios Clínicos, por lo que este proyecto plantea la creación de una nueva forma de captación de pacientes e implementar una nueva forma de derivación de pacientes, con el fin de revolucionar a este mercado de USD $30 MM anuales. Gracias a la fluidez de los procesos regulatorios y obtención de resultados requeridos por las compañías farmacéuticas, es que Chile se hace atractivo, sopesando la menor cantidad de pacientes que puede ofrecer a diferencia de países como Argentina, Brasil, Colombia y México. Dado que desde los inicios de la Investigación Clínica en Chile se ha utilizado el mismo sistema de derivación de pacientes, B-Trials toma esta oportunidad y captará pacientes en el mundo de las Redes Sociales, que cada vez son más utilizadas por la sociedad, los que serán registrados en una página web y se construirá una base de datos propia. La base de datos permitirá identificar a distintos pacientes dispuestos a participar en los Estudios Clínicos, de acuerdo a parámetros clínicos específicos y zonas geográficas donde se encuentran, permitiendo la derivación de estos a Centros de Estudios ya operativos y dando la opción de tener la información necesaria para la instalación de un Centro de Estudios Clínicos propio en la ubicación con mayor demanda de pacientes y abastecerlo de pacientes. El equipo gestor está encargados del marketing, operaciones y comercial, áreas cruciales para la obtención de la ventaja competitiva. El proyecto B-Trials requiere de una Inversión Inicial de CLP $67 MM., con Payback de 3,5 años, TIR = 31% y VAN al año 5 de CLP $ 23 MM. Valor Residual = $ 403 MM. Tasa de descuento aplicada = 20,4%. B-Trials representa un negocio que satisface una necesidad de la Industria en forma innovadora, siendo pionero en el país y escalable en el territorio nacional y latinoamericano, mejorando la calidad de vida de los pacientes a través del acceso gratuito a tratamientos de última generación.

Olympic Trials is a literary thriller that explores the dark side of sporting culture, including the many sacrifices, dysfunctional relationships and extreme behaviours that are common aspects of participating in a high performance sport environment. Juxtaposed with the stories of the athletes, there is the tale of an aspiring terrorist. His relentless devotion to a coach-like cult leader, and his physical, spiritual and psychological struggles on his journey to the Olympic Games mirrors the challenges of the athletes. The research portion of the thesis examines many of the texts generally included in the canon of sport fiction. Paramount here is the emergence of the anti-hero typology, figured within the framework of a quest narrative. These fictional athletes are depicted as inhuman⎯distinct in nature to the average citizen. Though these protagonists possess heroic strength or skill, they simultaneously demonstrate an inability to harness those attributes. They are distinctly flawed characters, who operate outside of acceptable moral parameters and the social norms of a community, although their misbehavior, including misogyny, homophobia and violence, is often endorsed by society. They live life at the mercy of sporting culture and their insatiable desires.

Aim PRECIS (PRagmatic Explanatory Continuum Indicator Summaries 2009) is a tool with a simple wheel format that trialists can use when designing their trials to improve the applicability of results but users highlighted problems. The aim of the study was to produce an improved and validated version of PRECIS, called PRECIS-2 and test this tool out with trial teams designing primary care trials. Methods Brainstorming and a 2-round Delphi survey of authors who cited PRECIS plus user-testing of candidate PRECIS-2 models was followed by validity and reliability testing of the most promising PRECIS-2 candidate using a sample of 15 trials rated by 19 different trialists. The validated PRECIS-2 tool was then used to consider the risk of bias (internal validity) and estimates of treatment effect of a matched set of explanatory (ideal conditions) and pragmatic (real world) trials. The PRECIS-2 website was also created with a database of pragmatic trials and a toolkit for trial groups. This was tested out at the Pragmatic Clinical Trials Unit (PCTU) in London with trial teams designing primary care trials. Results Forty-two people responded to the Delphi and highlighted scoring, domain choice, and tool format as issues. An expert panel of 14 in Toronto provided the basis for a PRECIS-2 model that was then user tested by 19 other methodologists and trialists. After 13 iterations, a PRECIS-2 model with 9 domains (i.e. Eligibility, Recruitment, Setting, Organisation, Flexibility Delivery, Flexibility Adherence, Follow up, Primary Outcome, Primary Analysis) was tested for validity and reliability. Inter-rater reliability was generally good, with eight of nine domains having an ICC over 0.65. Discriminant validity was reasonable for all domains, though with wide confidence intervals. Matching trials taking pragmatic (‘real world’) and explanatory (‘ideal world’) approaches was challenging but we found no indication that a pragmatic approach compromises internal validity. We were unable to extract sufficient information for a planned analysis of estimates of treatment effect. At the PCTU, the tool highlighted differences in opinion with trial team members and demonstrated convergence of opinion following discussion. There was acknowledgment that scoring of PRECIS-2 domains assisted trials teams in considering the intended audience and creation of trials relevant to practice. Useful feedback was obtained to improve the PRECIS-2 tool software for users. Conclusions PRECIS was improved by the addition of scoring and additional domains after consultation with over 80 international trialists. We have a validated PRECIS-2, in the visually appealing wheel format with 9 spokes, which is being made available through an increasingly accessed website. Work at the PCTU improved the usability of the PRECIS-2 website and demonstrated that the tool increases transparency in trial design and assists trialists in considering applicability of trial results. More matching work on the impact of design approaches on effect size is needed, and further data to support the risk of bias results would be valuable.

Fifty-one overseed entries were evaluated in 1997-1998 for turfgrass performance. New experimental accessions of perennial ryegrass were darker in color than most of the commercially available germplasm included in this test. Ryegrass germplasm had better turfgrass quality after April, than did mixtures of perennial ryegrass with Poa trivialis, which performed well in December, January and March. General appearance for total plot leaf texture was best generally among the Poa trivialis containing mixtures. Hybrid (or intermediate) ryegrasses (L. which are crosses between perennial X annual ryegrass, are generally closer to annual ryegrass in performance. There was a vast improvement in L. hybridum (Pick YNC) when compared to annual ryegrass alone for turf performance. Intermediate and annual ryegrasses did show signs of decline in June (more so than ryegrass or Poa trivialis blends), which was desirable from a transition standpoint.

This thesis examines the mode of trial concerns in the U.S.A., New York State, California, England and Wales and Canada --specifically the ability of the jury to comprehend complex cases and the perception/reality that bench trials may not be as fair as jury trials. Defining complex cases as those involving serious fraud indictments, capital murder trials, and lawsuits or indictments against corporations and their managers, the thesis examines problems associated with jury trials in such cases. It evaluates the comparative law and customs and practices regarding the use of juries, emphasizing problems with jury selection, deficits in jury deliberation and post trial problems associated with jury verdicts. The thesis also evaluates the judge only trial, attempting to determine whether a state imposed non jury trial in a criminal case as is presently proposed in the England and Wales Parliament creates an unfairness to the defendant because bench trials significantly differ from jury trials in the application of the rules of evidence and in the role of the judge. The thesis reports on the results of a survey of New York State trial judges, a like survey of New York State lawyers, and the opinions of nine England and Wales judges authorized to try serious fraud cases who were interviewed regarding these issues. The surveys and interviews finds that there is a high degree of support for jury verdicts expressed by the judges, examines evidentiary and pretrial practices in both modes of trial and attempts to evaluate whether claims of procedural flaws and prejudice in bench trials by respected academics are accurate. The thesis concludes by affirming the competence of juries to try complex cases, proposing modifications to post jury verdict procedures to evaluate jury misconduct and advocating that the bench trial evidentiary rules and conduct rules become comparable to the jury trial. The thesis recommends that mode of trial choices be given to the defendant, advocates that when a bench trial is selected that peremptory challenges of the trial judge be permitted and postulates that these reforms will make the bench trial a more attractive alternative to the jury trial in complex cases.

Abstract Background The randomised-controlled trial (RCT) provides the best evidence for evaluating treatment effects and is accepted as a gold standard for clinical and regulatory decision making (1;2). One of the major challenges to the conduct of RCTs is the recruitment of adequate numbers of participants. Inadequate numbers reduce the power of a study to detect statistically significant treatment effects, and may cause delays, increased costs and failure to complete trials. The need for clinical trials in children has been increasingly recognised by the scientific community, resulting in increased demands for the inclusion of children in trials. For several reasons, recruiting children to trials is more challenging than recruiting adults, as consent issues are more difficult because parents make decisions about trial participation on behalf of their child. Despite general professional and community support for paediatric clinical trials, parents and paediatricians express reluctance when their own child or patient is asked to participate. Although researchers working with children commonly experience difficulty with recruiting children to RCTs, little is known about this very important subject. The method by which potential participants are approached for trial participation, the influence of their health care provider and the attitude of potential participants (or their parents, in the case of children), are critical to the understanding of the decision making process for trial participation. This thesis is one of the first major attempts to explore the issues surrounding the recruitment of children to RCTs, and is divided into four studies which address these issues. Methods Recruitment strategies used to encourage participation in randomised controlled trials (systematic review) Eligible experimental and observational studies comparing methods of recruiting participants for RCTs were identified after a comprehensive search of Medline, Embase, the Cochrane Library and reference lists. Independent data extractions were completed by two reviewers who assessed the studies for eligibility and methodological quality. Outcome measures were consent rates, proportion enrolled by each method and cost of recruitment per participant. Summary estimators of effects were calculated using a random effects model and expressed as relative risk with 95% confidence intervals. Heterogeneity was analysed using the Q statistic. Paediatricians� attitudes to children�s participation in randomised controlled trials (focus group research) Qualitative analysis of focus group discussions involving 16 paediatricians and 5 trainees from a paediatric teaching hospital in Sydney was undertaken. Doctors varied in occupation, experience, research activity, age, gender, ethnicity and parenthood experience. A professional facilitator conducted the semi-structured group discussions. Recruitment ceased when informational redundancy was reached, after 4 focus groups involving 21 participants. The transcribed audiotapes were analysed by theme linkage using the constant comparative method. Australian paediatricians� and adult physicians� attitudes to randomised controlled trials (survey) A 44-item questionnaire was sent to 250 paediatricians and 250 adult physicians randomly selected from the membership list of the Royal Australasian College of Physicians. Questions assessing doctors� treatment philosophies and attitudes to trials were compared with demographic and practice variables. Parents� attitudes to children�s participation in randomised controlled trials (focus group research) Qualitative analysis of focus group discussions involving 33 parents from 5 different settings (representing parents of children with a life threatening, chronic or acute illness, with experience in trials and of healthy children) was undertaken. Parents varied in age, gender, ethnicity, level of education, research experience and their child�s health status. The transcribed discussions were analysed by theme linkage using the constant comparative method. Results Recruitment strategies used to encourage participation in randomised controlled trials (systematic review) Fifty papers were included (out of 8602 titles and abstracts searched) which described 8 RCTs, 2 quasi RCTs, 13 prospective cohort studies, 30 retrospective cohort studies and 2 before-after studies. These studies assessed how over 4 million people were approached for RCT participation using 87 different recruitment strategies, with 103,406 people enrolling in RCTs. Health care provider (HCP) referrals had the highest participant consent rates at the time of exposure to trial information (HCP referral versus target mailing: relative risk (RR) 1.84 (95% confidence interval (95%CI) 1.08, 3.13)). They also had the highest consent rates when potential participants respond to the recruitment material by further enquiry about the trial (HCP referral versus community presentation: RR 1.37 (1.06; 1.78); HCP referral versus worksite approach: RR 25.20 (20.19, 31.45); HCP referral versus general community approach: RR 2.53 (0.46, 14.05); HCP referral versus mailing: RR 3.29 (1.26, 8.60); HCP referral versus media: RR 2.66 (1.31, 5.41)). However, by the time potential participants attend eligibility assessment for trial participation, no difference in consent rates could be distinguished by method of recruitment. Higher proportions of study participants were recruited by methods that exposed larger numbers of potential candidates to trial information (despite their lower consent rates). The stated recruitment cost ranged from US$0 to $1108 per participant, with mailing being the most cost-effective method and community methods (such as community presentations, pamphlets and posters displayed at community sites) the least effective. Paediatricians� attitudes to children�s participation in randomised controlled trials (focus group research) From the focus group discussions, paediatricians thought parents balanced perceived gains and risks when deciding about trial participation. They also believed the child�s condition and parents� health beliefs and personal attributes influenced parents� decisions. Other factors thought to be important by paediatricians were the doctors� beliefs and their relationship with the investigators. Paediatricians perceived gains for trial participation including professional benefits for themselves, improved patient care, convenience for the families and themselves and scientific advancement. Perceived risks included inconvenience, inadequate resources and potential harms to the patient and the doctor-patient relationship. Paediatricians with previous research experience were most knowledgeable about RCTs and perceived greatest gains from trial participation. Paediatricians� personal treatment preferences hindered trial support. Australian paediatricians� and adult physicians� attitudes to randomised controlled trials (survey) Response rate from the paediatricians� and adult physicians� survey was 60% (300/500). Australian paediatricians and adult physicians are very similar in their treatment philosophies, and are clinician-oriented rather than research-oriented in their attitudes, with primary allegiance to their patients and preference for selecting treatment rather than referring for trial participation in the face of treatment uncertainty. Professional activities are clinically focused, with limited time assigned for research. Australian doctors perceive little reward for trial participation and claim that the opinions of referring doctors regarding RCTs does not influence them. Predictors of favourable attitudes to trial participation from the survey were time allocation for research, a history of referring patients to trials in the past and younger age (all p values less than 0.0001). Parents� attitudes to children�s participation in randomised controlled trials (focus group research) When parents were interviewed, they acknowledged balancing risks and benefits when deciding about trial participation for their child. Perceived benefits include the offer of hope, better care of their child, the opportunity to access new treatments, healthcare professionals and health information, meeting others in similar circumstances and helping others. Perceived risks include potential side effects, being randomised to ineffective treatments and the inconvenience of participation. The decision for trial participation is also influenced by parental factors (parents� knowledge, beliefs and emotional response), child factors (the child�s health status and preference about participation), trial factors (the use of placebos and the uncertainties of research) and doctor factors (doctor�s recommendations and communication of trial information). Conclusions There are many challenges to the successful conduct of RCTs. Ways of addressing these include: using effective methods of recruiting potential study participants (such as mailing of recruitment material to potential participants) and abandoning ineffective strategies (such as community methods): fostering greater willingness for trial participation by addressing parents� and paediatricians� concerns including enhancing communication between researchers, paediatricians and parents, and improving the gains-hazard balance (by increasing incentives while decreasing inconveniences); and reforming in the health care system to raise the priority placed on clinical research by restructuring clinical research in a clinically predominant workplace and with a clinically predominant workforce. The findings from this study have implications for researchers planning RCTs for children in the future. Careful consideration of the above will enhance RCTs participation for children improving efficiency, lowering costs and ultimately improving the future health care of children.

A sample size estimate for a clinical trial is an important issue as incorrectly estimating it could have both ethical and financial implications for the trial. Calculating the required sample size for a trial with a continuous outcome requires an estimate of the population variance. A pilot trial can be used to get an estimate of the population variance. However, pilot trials are often small and may give imprecise estimates; adjustment methods are discussed which allow for this imprecision. Theoretical minimum values for the overall trial sample size when using an adjustment method to design the main trial after an external pilot trial are provided. Using the results recommendations for external pilot trial sample size are presented which aim to minimise the overall trial sample size. It was found that the optimal pilot trial sample size increases with the size of the main trial, therefore stepped rules of thumb are proposed. For a 90% powered main trial this method indicates that the sample size for a two-armed pilot trial to minimise the overall sample size should be 150, 50, 30 and 20 for standardised effect sizes (δ) of δ < 0.1, 0.1 ≤ δ < 0.3, 0.3 ≤ δ < 0.7 and δ ≥ 0.7 respectively. The work is extended to allow for unequal cost per patient between the two trials. The results show that when the pilot trial is less expensive per patient than the main trial the optimal pilot trial sample size increases, giving more precision for the variance estimate and a relatively small main trial. The opposite is true when the main trial is less expensive than the pilot trial. For a 90% powered main trial this method indicates that the sample size for a two-armed pilot trial to minimise the overall sample size should be between 40- 260, 20-80, 20-40 and 20-30 dependent on the relative cost of the pilot and main trial per participant for standardised effect sizes (δ) of δ < 0.1, 0.1 ≤ δ < 0.3, 0.3 ≤ δ < 0.7 and δ ≥ 0.7 respectively. For internal pilot trials it is shown that the restricted sample size recalculation procedure raises the average sample size and power of the main trial. Aiming to minimise the overall trial sample size, it was found that the optimal pilot trial sample size rises as the main trial size increases. The work presented aims to help researchers choose sample sizes for pilot trials and to assess the impact selected methods have on the power and required sample size of the subsequent main trial.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.
Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Epidemiology, School of Public Health." Discipline: Epidemiology; Department/School: Public Health.

Unplanned changes to the research plan of a randomised controlled trial (RCT) may be a necessary response to unforeseen circumstances. Such changes can help ensure the value and relevance of a trial, but also have the potential to introduce a bias if performed inappropriately. This thesis addresses three broad aims. The first was to highlight the methodological implications of approaches to making various unplanned changes through a series of simulation studies. The second was to estimate the prevalence of such changes to a contemporary sample of published RCTs registered with the Australian New Zealand Clinical Trial Registry (ANZCTR). The third was to assess, and extend as applicable, recommendations for ensuring such changes are performed appropriately and are well documented. The simulation studies were performed using data from a large RCT of statin therapy for secondary prevention. The first of these demonstrated how unplanned changes (to various aspects of the design such as the primary endpoint) risks introducing a bias if undertaken with knowledge of treatment allocation, but not if made without knowledge of treatment allocation. The second investigated strategies for reacting to an observed imbalance on baseline prognostic factors in an RCT. It demonstrated that: continuing with original plans of unadjusted analyses, provided valid p-values irrespective of the direction of the prognostic imbalance, and any decisions informed by knowledge of the direction of the prognostic covariate imbalance were prone to bias. The third simulation study investigated strategies for reacting to a lower-than-expected event rate. It showed that switching to an expanded composite endpoint in response to a low pooled event rate does not inflate the type 1 error rate (and is likely to improve the statistical power, provided the expanded composite is sound). A sample of 181 RCTs that were registered with the ANZCTR and had published a primary result paper were assessed for changes to their research plans, and whether these changes were legitimate or not (that is, made with or without knowledge of treatment allocation). A full audit was conducted on trials with accessible protocols (N=124) and a limited central review on trials without accessible protocols (N=57). The primary results publication was cross-checked with the protocol documents across six methodological aspects for the full audit, and trialists were contacted to resolve queries as necessary. The publication was checked against the registry record for the limited central review, over a subset of three methodological aspects. A key finding of this study was that it was often not possible to reliably assess whether changes had been made or whether changes were made in a blinded manner, based on review of documentation alone. After clarification was sought from the participating trialists, changes were found to be relatively common but typically made in a blinded manner. Improvements to the way unplanned changes to RCT research plans are documented are needed. A set of recommendations to supplement existing guidelines relating to the documentation of RCT research plans was developed. One key recommendation was that trialists should adopt and implement the principles of the recently developed CONSERVE 2021 Statement to appropriately perform and document substantive changes. A second was that strategies that oblige trialists to upload full protocols (and protocol amendments) to clinical trial registries warrant further investigation and further consideration should be given to including all key methodological aspects in registry records. The work undertaken provides valuable guidance for trialists (and stakeholders) on how to make and document a methodologically justifiable change to a planned RCT design/analysis and highlights the circumstances under which a change can lead to bias. This is important for ensuring that methodically unsound changes to RCTs are recognised and avoided, and that RCTs that have undergone methodically sound changes are not incorrectly dismissed as potentially biased.

This thesis investigates how researchers can take advantage of the rapid adoption of mobile technology that has brought with it transformations in social and cultural practice; the expectations of what computers are, what they can do, and the role of digital objects in everyday life. In particular this thesis presents and discuses the use of new App Store style software distribution methods to reduce the cost, in terms of researcher time and hardware, of recruiting a large group of participants for a trial ‘in the wild’ while increasing the potential diversity of users is becoming an attractive option for researchers pursuing the ubicomp vision. It examines the procedures for running large scale trials with the deployment of three applications released to a combined user base of over 135,000 in such a way as to keep the qualitative detail necessary to inform design while gain- ing the diversity of users for claims of generalisability. More generally, it discusses the results that can be expected from this ‘mass participation’ approach, and the ethical responsibilities they place upon researchers. The contributions of this thesis for mobile HCI show that in large-scale trials, relatively rich qualitative data can be collected along with substantial quantitative data, and that a hybrid trial methodology combining a large- scale deployment with a local trial can be a powerful tool in addressing shortcomings of trials that are either solely local or solely global. This thesis also contributes guidelines for researchers running large-scale user trials that give consideration to the established research norms and practices, in an attempt to strike a new balance between invasiveness and utility.

Bayesian adaptive designs are emerging as popular approach to develop adaptive clinical trials. In this dissertation, I describe the mathematical steps for computing the theoretical optimal adaptive designs in biomarker-integrated trials and in trials with survival outcomes. Section 1 discusses the optimal design in personalized medicine. The optimal design maximizes the expected trial utility given any pre-specified utility function, though the discussion here focuses on maximizing responses within a given patient horizon. This work provides absolute benchmark for the evaluation of trial designs in targeted therapy with binary treatment outcomes. While treatment efficacy can be measured by a short-term binary outcome in many phase II and phase III trials, patients' progression-free survival time is with significant importance in cancer clinical trials. However, it is often difficult to make a design adaptive to survival outcomes because of the long observation time. In Section 2, an optimal adaptive design is developed so that treatment assignment decision for later patients can be made with complete or partial survival outcomes of early patients. The design also maximizes the expected trial utility given any pre-specified utility function that is of clinical importance. In this section, the focus is on maximizing the expected progression-free survival time. Both Sections1 and 2 include examples of comparing adaptive designs, such as the bayesian adaptive randomization and the play-the-winner rule, in terms of the expected trial utility with respect to the best achievable result. In Section 3, a simulation-based p-value is proposed and can be used to conduct frequentist analysis of Bayesian adaptive clinical trials. The optimal Bayesian design is compared to the equal randomization design in terms of the Type I error and the statistical power. With a fixed trial size and Type I error, the power of the equal randomization design depends on the difference in treatment efficacy, meanwhile the power of the optimal Bayesian design also depends on the size of the patient horizon.

Overseeding trials were conducted to evaluate the turf-type fitness of cool season grasses for use in the desert when bermudagrass is dormant. Perennial ryegrass, fine fescues, rough stalk bluegrasses and creeping bentgrasses were tested for turfgrass quality, color, percent ground cover and uniformity under a close mowing (3/8 inch) regime. Entries varied significantly from each other once seasonal hard frosts did not recur after January. Certain entries had better turf performance under hot (late spring) conditions. Both commercially available and experimental germplasm were evaluated.

A field test was conducted to evaluate the turf performance of improved hybrid ryegrass (sometimes called intermediate ryegrass) Lolium hybridum versus that of perennial ryegrass germplasm (Lolium perenne) for winter overseeding purposes. "Gulf" annual ryegrass was also evaluated for comparison purposes. On all evaluation dates, the treatment effect was significant for all visual response variables measured (quality, color, texture, density, etc.). The mixture of LHRT hybrid ryegrass/Poa trivialis established quicker than other treatments during the first month (November). Perennial ryegrass entries provided the darkest color turf. Among hybrid ryegrasses, Pick A-97 was slightly darker in turf color when compared to LHRT. LHRT alone was darker in color than when mixed with Poa trivialis. In terms of overall turf quality, Pick A-97 and LHRT hybrid ryegrasses were essentially equal in performance. The spring decline was greater among hybrid ryegrasses than that of perennial ryegrass. Both hybrid ryegrasses (A-97 and LHRT) were superior to annual ryegrasses in all aspects of turf performance. By mid-June of 1999, Pick A-97 had more bermudagrass present (52%) than LHRT (28%). LHRT had more straw-colored (dead transition grass) than A-97 as well. By early July, A-97 and LHRT had 72% and 62% bermudagrass, respectively, and essentially the same amount of overseed present (20-23%). LHRT had 15% plot straw at this time, while A-97 had 8%. Among perennial ryegrasses, Sunshine had the slowest transition (42%), followed by Jiffie (50%) and Future 2500 (71%) by early July. The addition of Poa trivialis to LHRT hybrid ryegrass increased overall quality of the LHRT alone, but slowed transition slightly, most likely due to increased canopy densities achieved by the addition of Poa trivialis. This test demonstrated that the hybrid ryegrass germplasm tested here provided adequate fairway turf performance, and that transition among and between Lolium germplasm is variable, and genetically dependant.

The question we posed at the beginning of this thesis was whether, in the presence of a clinical superiority of one of two possible treatments, it was possible to find an appropriate statistical methodology that would allow us to reach this goal. We were thus led to explore many possibilities to carry out this analysis and randomly assign patients to the two treatments, as required by the particular nature of these experiments. Specifically, we made a close examination of the methods of randomization, especially appreciating the flexibility of the adaptive responses, and could see the strengths of urn models. We started with the study of the urn for excellence, Polya's urn. Next, we analyzed some extensions and generalizations, focusing especially on two kinds of urns with random reinforcement. We exposed the results obtained throughout simulations concerning the convergence of the proportion of the best treatment, which came from the comparison of the models studied. In the end, we showed how the urn model works in a real case, comparing two treatments with continuous response in one ICU trial on Melatonin. We'll see how the properties demonstrated in theory are confirmed in practice. The project ends by giving a hint of a new adaptive model that we have started to idealize in collaboration with the team of Prof. Parmigiani and Prof. Trippa of the "Biostatistics and Computational Biology" Department, Harvard T.H. Chan School of Public Health.

Abstract Chapter 1 provides an introduction to stroke including its current prevalence both nationally and globally, aetiology, global importance and social & financial burden. We also describe here current acute stroke management practices, the role of clinical trials in the development of therapies, the richness of data within clinical trials and changes in regulatory thinking regarding data access. We provide recommendations for the use of trial data for novel exploratory investigations of clinical trial design and epidemiological studies. In Chapter 2 we describe the establishment of the Virtual International Stroke Trials Archive (VISTA) to address the need for reliable data on which to plan future clinical trials. This chapter details the methodology and logistics of establishing the resource, including details of regulatory policy for data collection and use, establishment of a Steering Committee and development of a constitution to safeguard data access and use. As of June 2008, VISTA contains 28 acute stroke clinical trials and one acute stroke registry. We collated data on over 27,500 patients with either ischaemic or haemorrhagic stroke. Patient age ranges from 18 to 103 years and outcome measures include Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset to treatment times are readily available and computed tomography (CT) lesion data are available for selected trials. We discuss the establishment and potential uses of this resource in the context of existing stroke resources. Chapter 3 demonstrates how we utilised VISTA to investigate natural history patterns in acute stroke. There are prominent differences in stroke incidence and outcome across different geographical locations; these are not confined to the Eastern- Western axis. We aimed to examine whether there were any differences in index stroke severity, stroke risk factors, and stroke outcome between geographical locations, after adjusting for case-mix. We found that patients who were enrolled in the USA and Canada had the worst index strokes, whilst patients enrolled in Austria and Switzerland had the mildest index stroke, and better functional (p=0.023) and neurological outcome (p=0.034) at 90 days. 90 –day survival was greater in patients who were enrolled in Spain and Portugal (p<0.0001). Chapter 4 demonstrates the use of VISTA to inform stroke clinical trial design by examining the impact of early follow up on adverse event and functional outcome profiles. We aimed to assess the contribution of adverse complications unrelated to stroke, to 30 and 90- day functional outcome. If fewer ‘stroke-unrelated’ adverse events were seen at later time points, and if the absence of these events appeared to influence functional outcome, then further investigation into shortening the follow up period of clinical trials with a view to minimizing complications may be warranted. We identified idiopathic post-stroke complications (deemed to be ‘stroke- unrelated’) but their absence did not beneficially alter outcome at either 30 days (p<0.0001, adjusted OR for good outcome =0.47, 95% CI [0.26, 0.67]), or 90 days (p=0.002, adjusted OR for good outcome =0.38, 95% CI [0.14, 0.61]). We concluded that shortening the follow up period with the aim of minimizing ‘stroke-unrelated’ complications did not benefit functional outcome, however further investigation is required. Chapter 5 illustrates the use of VISTA to investigate the natural history of complications after intracerebral haemorrhage (ICH). Treatments available for ICH remain limited. The use of haemostatic agents to promote local coagulation has had no significant benefit on outcome. However promising results from a subgroup analysis of patients from the FAST trial has raised the possibility of treatment with recombinant factor VIIa (rFVIIa) in patients with ICH. We sought to document the natural history of complications after ICH in order to inform safety in future trials of haemostatic agents for ICH. We found that the risk of thromboembolic complications after ICH was low (4 events affecting 2% of patients). The absence of these thromboembolic complications did not significantly affect the attainment of good functional outcome (p>0.05). The occurrence of haemorrhagic expansion was common, affecting 14% of patients, and significantly influenced attainment of good functional outcome at 90 days (p= p<0.0001, adjusted odds ratio for good functional outcome=21.9, 95% confidence interval [5.5, 88.3]). Although infection occurred in 11% of patients, this did not significantly influence attainment of good functional outcome at 90 days (p=0.8). The complications encountered in this investigation and their time to onset will serve to inform prophylaxis in future ICH clinical trials. Chapter 6 describes the processes involved in drug development from phase I, first- in – man studies to phase III efficacy trials and identifies a key area in the drug development process where use of VISTA as a historical comparator resource could be of benefit: phase II studies. We detail here the types of conventional comparator groups available for use in a phase II investigation, advantages and disadvantages of using each of these comparator groups, the potential for use of historical comparators in some scenarios where use of conventional comparator groups is infeasible, and possible solutions to address the limitations associated with use of historical comparators. Chapter 7 illustrates the use of VISTA as a resource for historical comparators in the context of an acute stroke device trial conducted by a small company with limited resources. BrainsGate, the manufacturers of the NeuroPath™ Device for treatment of ischaemic stroke, sought to collaborate with the VISTA group to examine initial efficacy of their device against outcomes derived from VISTA historical comparators. We discuss the example of this device in early phase testing, where VISTA was primed for use as a resource for historical comparators. We also describe the limitations associated with the use of historical comparators, how these limitations could be overcome in practice through use of matched patients, implementation of strict eligibility criteria and use of similar follow up periods and stroke scales, as well as the measures taken to ensure the validity of results. Chapter 8 describes a collaboration with the DESTINY trial group to investigate stroke outcomes after malignant middle cerebral artery occlusion (mMCAO). The DESTINY trial examined the impact of decompressive hemicraniectomy on outcome after mMCAO, compared with randomised controls. We compared the outcomes of operated patients from the DESTINY trial with historical comparators from VISTA to determine whether the findings could be replicated and if historical comparators could be used as an alternative in a situation where a randomised controlled trial (RCT) is infeasible or unethical. We found that fewer patients in the VISTA comparator group achieved a good functional outcome by mRS at final follow up (19%), when compared with the DESTINY surgical group (47%, Chi- Square test p=0.04). This difference persisted after adjusting for baseline NIHSS (logistic regression p=0.04). Analysis of Barthel Index at final follow up revealed no significant difference between the two groups and we also found no difference in 6 month survival rates between the surgical and VISTA comparator groups (Cox Proportional Hazards model p>0.05). We concluded that for effective replication of results, the database from which historical comparators are to be drawn should cover a similar or broader spectrum of patient prognostic factors. Chapter 9 discusses the implications of the investigations described in this thesis, outlines the scope for expanding the resource and proposes areas for future research.

The dissertation aims to analyse the problem of informed consent in clinical drug trials. Understanding of the provided information is one of the basic components of a person’s sound and informed decision to participate in a clinical trial. Our research evaluated informedness about clinical trials of patients participating in clinical drug trials in Lithuania, with emphasis on the informedness about key elements of clinical trial design (placebo-control, double-blindness, and randomisation). An anonymous survey of patients participating in clinical drug trials was conducted for the purposes of this study. The results of the study reveal that the legal framework sets the basis for adequate informedness about clinical trials of clinical trial participants, however, patients participating in placebo-controlled clinical trials are insufficiently informed about clinical trials. Patients participating in placebo-controlled clinical trials are better informed about the rights of clinical trial participants than about clinical trial design, however, informedness about design is a more important condition for overall informedness. The majority of placebo-controlled clinical trial participants do not understand at least one of the three key elements of clinical trials design and they tend to interpret the scientific methods used in clinical trials therapeutically.
Disertacijoje analizuojama informuoto asmens sutikimo įgyvendinimo klinikiniuose vaistinio preparato tyrimuose problema. Pateiktos informacijos supratimas yra viena svarbiausių asmens apsisprendimo dalyvauti klinikiniame tyrime sąlygų. Moksliname darbe vertinamas pacientų, dalyvaujančių placebu kontroliuojamuose klinikiniuose vaistinio preparato tyrimuose Lietuvoje (toliau – klinikinių tyrimų dalyviai), informuotumas apie klinikinius tyrimus, akcentuojant informuotumą apie klinikiniuose tyrimuose taikomus mokslinius metodus (placebo kontrolę, dvigubą aklumą, atsitiktinį tiriamųjų grupių sudarymą). Klinikinių tyrimų dalyvių informuotumas buvo tiriamas atliekant anoniminę apklausą. Mokslinio darbo rezultatai parodė, kad teisinis reglamentavimas sudaro prielaidas klinikinių tyrimų dalyvių informuotumui, tačiau jų informuotumas yra nepakankamas. Respondentai buvo geriau informuoti apie klinikinių tyrimų dalyvių teises nei apie klinikinių tyrimų metodologiją, tačiau informuotumas apie klinikinių tyrimų metodologiją yra svarbesnė prielaida bendram informuotumui. Dauguma klinikinių tyrimų dalyvių nesuprato vieno ar daugiau iš trijų pagrindinių klinikiniuose tyrimuose taikomų mokslinių metodų (placebo kontrolės, dvigubo aklumo, atsitiktinio tiriamųjų grupių sudarymo) ir buvo linkę suteikti jiems terapinę reikšmę. Tyrimo rezultatai sudaro prielaidas kryptingam klinikinių tyrimų dalyvių informuotumo gerinimui, informacijos apie klinikinius tyrimus viešinimui.

Introduction and background Recruitment to cancer clinical trials needs to be improved, as does patient understanding about clinical trials, to enable patients to make an informed choice about whether or not to take part. The main reason that clinically eligible patients do not take part in clinical trials is because they refuse; poor understanding of the research has been associated with patient refusal. Audiovisual patient information (AVPI) has been shown to improve knowledge/understanding in various areas of practice but there is limited information about its effect in the cancer clinical trial setting, particularly in relation to recruitment rates. Understanding the research is necessary for informed consent, and it was hypothesised that if patient understanding about clinical trials was increased with AVPI, then this could result in a reduction in the number of patients refusing clinical trials, and therefore provide an ethical approach to improving recruitment. This study aimed to test the impact of an audiovisual patient information intervention on recruitment to randomised cancer clinical trials (refusal rates), patient understanding of the information given, and levels of anxiety. Reasons for patients’ decisions about trial participation were also assessed. Method An AVPI intervention was developed that aimed to address the common misconceptions associated with randomisation and clinical equipoise, as well as improve patient understanding generally of randomised cancer trials, and of other core clinical trial informational requirements, such as voluntariness. Patients were randomised to receive either AVPI in addition to the standard trial-specific written information, or the written information alone. A new questionnaire was developed to assess patient understanding (also referred to as knowledge) in the randomised trial setting and, following testing with patients and research nurses, this was shown to be reliable and valid. Patients completed self-report questionnaires to assess their understanding (new knowledge questionnaire) and anxiety (Spielberger State-Trait Anxiety Inventory), at baseline and after they had made their decision about clinical trial entry, when their perceptions of the intervention, as well as factors contributing to their decision were also determined (this tool incorporated Jenkins and Fallowfield’s (2005) questionnaire which assessed reasons for accepting and declining randomised cancer trials). Results A total of 173 patients with breast cancer (65%), colorectal cancer (32%) and lung cancer (3%) were entered into the main study. The median age was 60 (range 37-92 years). There was no difference in clinical trial recruitment rates between the two groups: 72.1% in the AVPI group and 75.9% in the standard information group. The estimated odds ratio for refusal (intervention/no intervention) was 1.19 (95% ci 0.55-2.58, p=0.661). Knowledge scores increased more in the intervention group compared to the standard group (U= 2029, p=0.0072). The change in anxiety score between the arms was also statistically significant (p=0.011) with anxiety improving in the intervention arm more than in the no-intervention arm. The estimated difference in the median anxiety change score between the groups is –4.6 (95% ci –7.0 to –2.0). Clinical trial entry was not influenced by tumour type, stage of cancer, age, educational qualifications or previous research experience, however, there was a modest association with deprivation status (p=0.046) where more affluent patients were the least likely to consent to a trial. Educational qualifications and stage of cancer were independently associated with knowledge: patients who were better educated had higher levels of knowledge about randomised trials, and patients who had limited stage of cancer had higher baseline knowledge than patients with advanced cancer. Acceptability of the intervention was high with 93% of those who watched it finding it useful, and 42% stating that it made them want to take part in the clinical trial. Personal benefit and altruism were key motivating factors for clinical trial participation, with reasons for refusal being less clear. Discussion and conclusions Although the potential for AVPI to increase clinical trial recruitment rates was highlighted in the literature, in this study, AVPI was not shown to have any effect on refusal rates to randomised cancer trials. However, by improving patient understanding prior to decision making, AVPI was shown to be a useful addition to the consent process for randomised cancer trials. AVPI addresses the fundamental ethical challenges of informed consent by improving patient understanding, and supports the ethical framework integral to Faden and Beauchamp’s (1986) theory of informed consent. The new knowledge questionnaire was shown to be a sensitive and effective instrument for measuring understanding of randomised clinical trials in the cancer setting, although it would benefit from further testing. The AVPI appears to reduce anxiety at the decision making time point and has been shown to be an acceptable medium for patients. This study confirms existing findings from studies assessing factors affecting decision making, with personal benefit and altruism being key motivating factors, and reasons for refusal being less clear. The need for further qualitative work in this area is highlighted to gain a deeper understanding of what is important to patients, in terms of why they refuse clinical trial participation. Implications for practice and further research Several implications for practice have been identified, including using AVPI as part of the standard information package for patients considering randomised cancer trials, and focussing on patient and staff education in this area. The knowledge questionnaire could be introduced to routine practice as a tool to determine patient understanding prior to decision making, allowing clinicians the opportunity to correct any misconceptions prior to consent. Further research focussing on AVPI specific to individual trials would be helpful, to determine if a more customised approach would be of benefit in terms of clinical trial recruitment. The importance of studying other aspects of the consent process such as the interaction between the clinician and the patient, in addition to more detailed exploration of the factors affecting patients’ decisions were highlighted.

Texte remanié de: Ph.D.--Southampton, 1998. Titre de soutenance : The Holocaust on trial : the war crime trials in the formartion of history and memory.
Documents en annexes (verdicts du procès de Nuremberg et d'autres procès). Bibliogr. p. 233-261. Index.

Zoonotic visceral leishmaniasis (ZVL) is a fatal disease caused by the sandfly-borne intracellular protozoan parasite Leishmania infantum, and vaccine development in the reservoir host (the domestic dog) is a current research priority. The aims of this study were (1) to conduct safety and immunogenicity trials of two candidate vaccines in dogs, and (2) to compare and demonstrate the utility of immunological and molecular tools for measurement of vaccine efficacy in naturally exposed dogs. DNA/ modified vaccinia virus Ankara (MVA) prime/boost canine vaccines expressing the Leishmania proteins TRYP and LACK were safe, and elicited a type-1 cytokine response, in vivo delayed-type hypersensitivity and IgG2 class responses, consistent with superior protective immunogenicity of TRYP over LACK. However, inconsistent associations were found between progressive disease in infected dogs and IgG class levels, prompting caution in use of the latter as a proxy for protective immunogenicity. Specific serological responses in vaccinated dogs did not cross-react with an unrelated diagnostic antigen rK39, and responses to crude parasite antigen (CLA) were minimal, enabling serological detection of infection incidence in vaccinated dogs. Particularly in early stage infection, CLA ELISA was more sensitive than rK39 ELISA and an rK39-based rapid diagnostic test, though rK39 serology was sensitive for diagnosis of symptomatic clinical cases. A commercially available PCR kit incorporating a rapid oligochromatographic detection step was tested for the first time in dogs, and proved highly sensitive for detection of ZVL infection in bone marrow, comparable to existing nested PCR methods. Molecular methods were investigated as proxy measures to replace labour-intensive xenodiagnosis for detection of the infectiousness of dogs to biting sand flies. Conventional and real-time PCR of tissues from naturally infected dogs were sensitive tests to identify infectiousness, but showed low to moderate specificity. Recommendations are made to improve the application of molecular methods as proxy measures of infectiousness and hence vaccine efficacy.

The focus of this thesis is on practice changing clinical studies which impact upon the day to day treatment of patients with pleural infection, answering specific questions on several aspects of patient management. Specific areas of assessment in this thesis include: Assessment of the current evidence for optimal drain size choice in patients with pleural infection; Analysis and statistical modelling of a previous cohort of patients with pleural infection, in order to assess optimal drain size choice in pleural infection; The design, conduct and analysis of a 2 x 2 factorial multi-centre randomised, placebo controlled trial to assess the efficacy of two novel intrapleural agents (tPA and DNase) in aiding drainage in patients with pleural infection (The 2nd Multi-centre Intrapleural Sepsis Trial, referred to from here on as MIST2); Validation work informing the primary outcome measure of MIST2, assessing the relationship between chest radiograph imaging of infected pleural effusion and CT measured volume of pleural fluid using novel digital measurement strategies.

Background: the dose and the length of rehabilitative interventions for optimal motor recovery after stroke are unknown. Dose optimization studies are required as precursors to efficacy trials, but are rarely conducted in stroke rehabilitation research. Objective: to overcome the knowledge gap on appropriate dose and length of rehabilitative interventions guiding the implementation of novel effective approaches to dose optimization in stroke rehabilitation research. Method: two systematic reviews on dose optimization in exercise-based training and pharmaceutical clinical research guided the development of a new approach to dose-finding suitable for physical interventions. The feasibility of a novel phase I 3+3 rule-based, outcome-adaptive dose-finding design was assessed with stroke survivors with moderate upper limb paresis. Moreover, the feasibility of a repetitive assessment procedure to identify the appropriate length of motor interventions was explored in stroke rehabilitation research. Results: the first literature review showed a lack of reliable approaches to dose optimization in exercise-based training. The review of pharmaceutical research highlighted dose optimization “gold” standard approaches, and helped in devising the dose-finding study for physical intervention. The dose-finding study was feasible using the applied model-task intervention. Preliminary explorations on the dose-response relationship were possible indicating a maximum tolerable dose and a potential recommended dose of 209 and 162 repetitions respectively of the applied intervention-task. The repetitive assessment procedure was found feasible in a clinical efficacy stroke rehabilitative trial. The repetitive assessment procedure provided relevant data on the therapy effect over-time showing that more than six weeks of the applied upper limb intervention may be necessary to reach maximal therapy effects. Whereas, five weeks of intervention appeared enough to exploit therapy effects for the lower limb. Conclusions: results are promising on identifying relevant dose and protocol endpoints implementing dose-finding and repetitive assessments approaches in stroke rehabilitation. Further confirmative data are needed to validate these findings.

Surgery, as a scientific discipline, should be supported by research. Surgeons depend on the availability and quality of an adequate evidence base to provide best possible care. Randomised trials are often considered the best form of evidence when assessing the efficacy of an intervention. Surgical research has been derided because of the paucity of randomised trials published. Many efforts have been made to combat this crisis of credibility, including the creation of the IDEAL Collaboration, which aims to improve “the quality of research in surgery by emphasizing appropriate methods, transparency of data and rigorous reporting of outcomes”. This has occurred within the wider context of a drive to improve research standards across the medical research community, with notable examples being the EQUATOR Network, the COMET group, the STaR child health group, the Cochrane Collaboration, the James Lind Alliance and AllTrials initiative. These groups have made strong efforts to improve the design, conduct and reporting of clinical trials. These efforts aimed at improving research standards are likely to influence the surgical literature in a positive way. This thesis is presented as a thesis by publication: containing published and submitted work on the theme of trials and outcomes in surgery. The work presented in the first chapters of this thesis has striven to identify, evaluate and quantify the need for surgical research. The next chapters evaluate research methodology and standards in the surgical literature with a focus on paediatric surgery. The thesis concludes with an evaluation of the impact of research standards within a regulatory framework, from the perspective of medical devices. The overarching purpose of these studies was to promote the underlying theme of the thesis: to inform and improve research standards and outcomes within the field of surgery.

Several crops were evaluated at Worthy farms, near Marana, AZ, Wakimoto farms, Mohave Valley, near Bullhead City, AZ, and the Tucson Plant Materials Center for use as a winter cover crop following cotton with potential to reduce wind erosion and produce one to two hay cuttings. Hairy vetch (Vicia villosa), 'Lana' woolypod vetch (Vicia villosa ssp. varia), 'Papago' pea (Pisum sativum), and 'Biomaster' pea (Pisum sativum) were sown at the Tucson Plant Materials Center. Species sown at Worthy farm were: Papago pea, Lana vetch, and Biomaster pea. Species sown at Wakimoto farm were: Biomaster pea, Lana vetch, 'Seco' barley (Hordeum vulgare), and 'Multi-cut' berseem clover (Trifolium alexandrinum). Forage yield varied between locations due to sowning date, number of irrigations, and soil textures. Biomaster pea, Papago pea, and Lana vetch performed well at all three locations. However, Biomaster yields were more consistent and due to its shorter growing season may be the better choice as a winter cover between cotton crops. Additional trials are scheduled for the fall of 1998.