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PhD thesis assessing the role of non-randomized studies with randomized in evidence syntheses of health interventions. / Randomized studies (RS) are considered the best source of evidence for knowledge syntheses (e.g., systematic reviews, health technology assessments, health guidelines, among others) about healthcare interventions. Historically, non-randomized studies (NRS) have been usually discarded from knowledge syntheses of interventions due to their intrinsic risk of bias and confounding, and they are used only when RS are considered unfeasible or unethical to conduct. With better research methods in observational studies and new tools for the evaluation of risk of bias, NRS are more likely to be a helpful source of information when used as replacement, sequential, or complementary evidence. This, together with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, provide an opportunity for guiding decisions about using RS and NRS in knowledge synthesis and increasing our certainty in a body of evidence. This work aims to improve research synthesis methods by assessing the role and use of RS and NRS in knowledge syntheses using GRADE. This can help health professionals, researchers, guideline developers, and policy-makers build better and more complete healthcare recommendations. / Thesis / Doctor of Philosophy (PhD) / All recommendations about healthcare interventions (from common medicines to strategies to prevent diseases) should ideally come from an adequate synthesis (e.g., systematic reviews) of the least biased studies. Many researchers and authors of health syntheses consider randomized studies (RS), the ‘gold standard’ to demonstrate if an intervention is truly effective. Unfortunately, they are not always available, feasible, or ethical to conduct. Non-randomized studies (NRS), also called observational studies, can potentially provide complementary evidence for a research question. Unfortunately, they are usually considered of poorer quality because of their intrinsic nature of being prone to bias and confounding. In most circumstances, authors of syntheses discard these types of studies from the outset, without considering their potential for providing evidence that could complement or even replace that from randomized studies. This work aims to improve this situation by offering methods for evaluating the appropriateness of integrating both RS and NRS, guiding authors and researchers in cases where this is possible, hence increasing the certainty in a body of evidence and help all stakeholders reach decisions.

The notion that pretrial media coverage impacts the judicial process of highly publicized trials is not limited to contemporary times. This study sheds light on the modem day issues that pretrial media surrounding celebrity criminal cases imposes on the United States judicial system and juries. A literature review examines the conflict between the First, Sixth and Fourteenth Amendment rights to free press and fair trials, the impact of prejudicial pretrial media, precedents established in case law, and remedies that the courts use to limit the effects of prejudicial media. Expanding upon the literature review, the study next analyzes the public's view on crime, the media's manipulation of celebrity criminal trials, social and psychological theories on pretrial publicity, problems with current remedial measures, and specific celebrity case examples. The study provides a comprehensive analysis examining each individual aspect in determining the overall effect pretrial media has on celebrity criminal cases. The media is an essential part of society, but its reporting of the pretrial stages of celebrity criminal court cases impacts the jury's ability to give a celebrity defendant a fair trial.

Darbo tikslas. Įvertinti N ligoninės gydytojų nuomonę apie klinikinius vaistinių preparatų tyrimus. Darbo uždaviniai. Įvertinti veiksnius veikiančius, gydytojų motyvaciją vykdyti klinikinius vaistinių preparatų tyrimus bei veiksnius, kurie kliudo gydytojams įsitraukti į juos Įvertinti gydytojų požiūrį į klinikinius vaistinių preparatų tyrimus. Palyginti dalyvavusių ir nedalyvavusių klinikiniuose vaistinių preparatų tyrimuose gydytojų požiūrį į juos. Tyrimo metodika. Buvo atlikta vienos iš Lietuvos ligoninės gydytojų anoniminė anketinė apklausa (n=133, atsako dažnis - 78 proc.). Duomenys buvo analizuojami naudojant SPSS statistinį duomenų analizės paketą bei Excel duomenų analizės paketą. Atskirų kokybinių rodiklių tarpusavio ryšys buvo vertinamas naudojant duomenų Chi kvadrato (χ2) testą. Ryšys buvo laikomas statistiškai reikšmingu, jei paklaidos tikimybė buvo p<0,05. Rezultatai. Pagal atliktą apklausą, klinikinius tyrimus vykdė 61, nevykdė 72 gydytojai. Beveik 46 proc. gydytojų, tiek vykdžiusių tiek nevykdžiusių klinikinius tyrimus, užteko turimų žinių apie juos, tačiau norėtų žinoti daugiau. Vidutiniškai su įstatymine klinikinių tyrimų baze buvo susipažinę 45,9 proc gydytojų kurie vykdė klinikinius tyrimus ir šiek tiek susipažinę 47,2 proc. gydytojų, kurie jų nevykdė. Reikalingumą mokyti studentus atskiros disciplinos apie klinikinius tyrimus jautė 59 proc. vykdžiusių ir 63,9 proc. nevykdžiusių klinikinių tyrimų gydytojų. Kad klinikiniai tyrimai duoda profesinės naudos manė... [toliau žr. visą tekstą] / Aim of the research. To evaluate the physicians‘ of N Hospital opinion on clinical trials of medicinal products. Objectives. To evaluate the factors affecting physicians' motivation to perform clinical trials of medicinal products as well as those that prevent the physicians getting involved in the trials. To assess physicians' attitude towards clinical trials of medicinal products. To compare the opinions of physicians who have and have’nt participated in clinical trials. Methods of research. An anonymous questionnaire survey of the physicians of one Lithuanian Hospital has been carried out (n = 133, response rate - 78%). The data were analyzed using SPSS statistical package and Excel data analysis package. Relations between qualitative indicators were assessed using the chi-squared (χ2) test. The association was considered to be statistically significant if p <0.05. Results. According to the survey, 61 physicians have conducted clinical trials and 72 physicians haven’t. Almost 46% of all physicians had sufficient knowledge about them, but would have liked to know more. On the average, 45.9% of those, who have conducted clinical trials, were familiar with their statutory basis and 47.2% of physicians, who haven’t conducted them, were somewhat familiar. The need to teach students about clinical trials as an individual discipline was implied by 59% of physicians who have conducted clinical trials and 63.9% of those who haven’t. Professional benefit from clinical trials... [to full text]

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 274-292).

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.

Bakgrund: Förordningen (EU) nr 536/2014 artikel 35 reglerar kliniska prövningar i akuta situationer. Lagen gäller inom EU/EES sedan januari 2022 och tillåter inkludering av kritiskt sjuka patienter med uppskjutet informerat samtycke, vilket innebär att den första prövningsspecifika interventionen görs innan försökspersonen eller deras juridiska ombud samtycker till deltagande i prövningen.  Syfte: Syftet med projektet är att beskriva de kliniska prövningar som sökts i akuta situationer sedan starten av den nya EU-förordningen om kliniska prövningar fram till den 15 september 2023. Metoder: Informationssystem för kliniska prövningar (CTIS) och konfidentiella databaser vid Läkemedelsverket användes för att samla in information om de sökta kliniska prövningarna enligt den nya förordningen. Resultat: Alla prövningar som definierats av sponsorn som involverade akuta situationer identifierades, omfattande 32 unika kliniska prövningar. Efter att ha analyserat ansökningsunderlagen och granskningar av medlemsstaterna, visade sig endast två tredjedelar av de inlämnade försöken involvera verkliga medicinska nödsituationer. En av dessa försöksansökningar avslogs, tre drogs tillbaka eller besvarades inte inom den maximala tiden för sponsorns feedback på frågor. Slutsatser: Den nya förordningen om kliniska prövningar tillåter forskning om akuta medicinska tillstånd som tidigare har varit uteslutna i de flesta EU/EES-medlemsstater. Det är viktigt för sponsorer att bekräfta att alla krav i artikel 35 är uppfyllda innan en klinisk prövning definieras som en klinisk prövning i en akut situation. Medlemsstaterna bör lära av varandra om hur rättsliga ombud för försökspersoner utses.

<p>Correlated data with complex association structures arise from longitudinal studies and cluster randomized trials. However, some methodological challenges in the design and analysis of such studies or trials have not been overcome. In this thesis, we address three of the challenges: 1) <em>Power analysis for population based longitudinal study investigating gene-environment interaction effects on chronic disease:</em> For longitudinal studies with interest in investigating the gene-environment interaction in disease susceptibility and progression, rigorous statistical power estimation is crucial to ensure that such studies are scientifically useful and cost-effective since human genome epidemiology is expensive. However conventional sample size calculations for longitudinal study can seriously overestimate the statistical power due to overlooking the measurement error, unmeasured etiological determinants, and competing events that can impede the occurrence of the event of interest. 2) <em>Comparing the performance of different multiple imputation strategies for missing binary outcomes in cluster randomized trials</em>: Though researchers have proposed various strategies to handle missing binary outcome in cluster randomized trials (CRTs), comprehensive guidelines on the selection of the most appropriate or optimal strategy are not available in the literature. 3) <em>Comparison of population-averaged and cluster-specific models for the analysis of cluster randomized trials with missing binary outcome</em>: Both population-averaged and cluster-specific models are commonly used for analyzing binary outcomes in CRTs. However, little attention has been paid to their accuracy and efficiency when analyzing data with missing outcomes. The objective of this thesis is to provide researchers recommendations and guidance for future research in handling the above issues.</p> / Doctor of Philosophy (PhD)

This thesis explores the effectiveness of the Food and Drug Administration’s implementation of Breakthrough Therapy Designation (BTD), focusing on the low number of approval rates and repercussions of BTD for the development of new drugs for patients suffering serious life threatening illnesses. BTD, as an expedited review process, shows potential for improvement in its guidelines for necessary qualifications for BTD. Cutting costs, through a shortening in development time, and raising profits, through first mover status of new to market drugs, BTD is regarded by pharmaceutical executives as a tool to insure not only return on investment but also the rewards that accompanies a profitable blockbuster drug. Lessons learned from activism from 1980’s HIV/AIDS crisis show how advocates and “activist-experts” can rebalance and refocus more attention on the necessary beneficence for patients. A policy stipulation that insures all members: corporate, regulatory, and patient advocate, sit together at the decision making table will insure a more balanced discussion in regards to drug development.