A clinical trial may have no subject (0%) or every subject (100%) developing the outcome of concern in either of the two comparison groups. This will cause a zero-cell in the four-cell (2x2) table of a trial using a binary outcome and make it impossible to estimate the odds ratio, a commonly used effect measure. A usual way to deal with this problem is to add 0.5 to each of the four cells in the 2x2 table. This is known as Haldane's approximation. In meta-analysis, Haldane's approximation can also be applied. Two approaches are possible: add 0.5 to only the trials with a zero cell or to all the trials in the meta-analysis. Little is known which approach is better when used in combination with different definitions of the odds ratio: the ordinary odds ratio, Peto's odds ratio and Mantel-Haenszel odds ratio. / A new formula is derived for converting Peto's odds ratio to the risk difference. The derived risk difference through the new method was then compared with the true risk difference and the risk difference derived by taking the Peto's odds ratio as the ordinary odds ratio. All simulations and analyses were conducted on the Statistical Analysis Software (SAS). / Conclusions. The estimated confidence interval of a meta-analysis would mostly exclude the truth if an inappropriate correction method is used to deal with zero cells. Counter-intuitively, the combined result of a meta-analysis will be worse as the number of studies included becomes larger. Mantel-Haenszel odds ratio without applying Haldane's approximation is recommended in general for dealing with sparse data in meta-analysis. The ordinary odds ratio with adding 0.5 to only the trials with a zero cell can be used when the trials are heterogeneous and the odds ratio is close to 1. Applying Haldane's approximation to all trials in a meta-analysis should always be avoided. Peto's odds ratio without Haldane's approximation can always be considered but the new formula should be used for converting Peto's odds ratio to the risk difference. / In addition, the odds ratio needs to be converted to a risk difference to aid decision making. Peto's odds ratio is preferable in some situations and the risk difference is derived by taking Peto's odds ratio as an ordinary odds ratio. It is unclear whether this is appropriate. / Methods. For studying the validity of Haldane's approximation, we defined 361 types of meta-analysis. Each type of meta-analysis is determined by a unique combination of the risk in the two compared groups and thus provides a unique true odds ratio. The number of trials in a meta-analysis is set at 5, 10 and 50 and the sample size of each trial in a meta-analysis varies at random but is made sufficiently small so that at least one trial in a meta-analysis will have a zero-cell. The number of outcome events in a comparison group of a trial is generated at random according to the pre-determined risk for that group. One thousand homogeneous meta-analyses and one thousand heterogeneous meta-analyses are simulated for each type of meta-analysis. Two Haldane's approximation approaches in addition to no approximation are evaluated for three definitions of the odds ratio. Thus, nine combined odds ratios are estimated for each type of meta-analysis and are all compared with the true odds ratio. The percentage of meta-analyses with the 95% confidence interval including the true odds ratio is estimated as the main index for validity of the correction methods. / Objectives. (1) We conducted a simulation study to examine the validity of Haldane's approximation as applied to meta-analysis, and (2) we derived and evaluated a new method to covert Peto's odds ratio to the risk difference, and compared it with the conventional conversion method. / Results. By using the true ordinary odds ratio, the percentage of meta-analyses with the confidence interval containing the truth was lowest (from 23.2% to 53.6%) when Haldane's approximation was applied to all the trials regardless the definition of the odds ratios used. The percentage was highest with Mantel-Haenszel odds ratio (95.0%) with no approximation applied. The validity of the corrections methods increases as the true odds ratio gets close to one, as the number of trials in a meta-analysis decreases, as the heterogeneity decreases and the trial size increases. / The proposed new formula performed better than the conventional method. The mean relative difference between the true risk difference and the risk difference obtained from the new formula is -0.006% while the mean relative difference between the true risk difference and the risk difference obtained from the conventional method is -10.9%. / The validity is relatively close (varying from 86.8% to 95.8%) when the true odds ratio is between 1/3 and 3 for all combinations of the correction methods and definitions of the odds ratio. However, Peto's odds ratio performed consistently best if the true Peto's odds ratio is used as the truth for comparison among the three definitions of the odds ratio regardless the correction method (varying from 88% to 98.7%). / Tam Wai-san Wilson. / "Jan 2006." / Adviser: J. L. Tang. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6488. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 151-157). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Conclusion. The missing data is a common problem in clinical trial. The methodology development is urgently needed to detect the difference of two treatments drug in patient quality of life. The modified pattern mixture model incorporating generalized estimating equation method or multiple imputation method provides a solution to tackle the non-ignorable missing data problem. Different clinical trials with various treatment schedules, missing data patterns will be formed. Further studies are needed to study the optimal choice of patterns under the methods. / Introduction. Health-related Quality of Life (HRQoL) has now been included as a major endpoint in many cancer clinical trials in addition to the traditional endpoints such as tumor response and survival. It refers to how illness or its treatment affects patients' ability to function and whether it induces symptoms. Toxicity, progression and death are common outcome affecting patient's QOL in cancer trial. Since this type of missing data are not occurred at random and are called non-ignorable missing data, conventional methods of analyses are not appropriate. It is important to develop general methods to deal with this problem so that treatment effectiveness for improving patient's QOL or those with serious side effect that is detrimental to patient's QOL can be identified. / Methods. The generalized estimating equation based on modified pattern mixture model is constructed to deal with non-ignorable missing data problem. We conducted a simulation study to examine performance of the model for different types of data. Two scenarios were examined. The first case assumes that two groups have quadratic trend but with different rates of change. The second case assumes that one group has linear trend with time while the other group has quadratic trend with time. Moreover, the second methodology is the multiple imputation based on modified pattern mixture model. The main idea is to resample the data within each pattern to create the full data set and use the standard method to analyze the data. Comparison between two methods was carried out in this study. / Recently, joint models for the QOL outcomes and the indicators of drop-outs are used in longitudinal studies to correct for non-ignorable missing. Two broad classes of joint models, selection model and pattern mixture model, were used. Most of the methodology has been developed in the selection model while the pattern mixture model has attracted less attention due to the identifiability problem. Although pattern mixture model has its own limitation, a modified version of this model incorporating Generalized Estimating Equation can be used in practice. / Result. The power of generalized estimating equation alone is higher than pattern mixture model when the missing data is missing at random. Moreover, the bias of generalized estimating equation is less than that of pattern mixture model when the missing data is missing at random. However, the pattern mixture model performs well when the missing data is missing not at random. On the other hand, the modified pattern mixture model has higher power than the standard pattern mixture model if one group has quadratic trend and other group has linear trend. However, the power of modified pattern mixture model is similar or worst than the standard when the data is both quadratic trends with different rates of change. On the other hand, the results of multiple imputation based on modified pattern mixture model were similar but the power was less than the generalized estimating equation model. / Mo Kwok Fai. / "August 2006." / Adviser: Benny Zee. / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 6051. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 91-93). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Source: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1576. Advisers: Dejian Lai; Asha S. Kapadia. Includes bibliographical references.

Platform trials evaluating multiple treatment arms against a shared control are an efficient alternative to multiple two-arm trials. Motivated by a randomized clinical trial of the effectiveness of two neuroprotection devices during aortic valve surgery against a control, this dissertation addresses two open questions in the optimal design of these trials. First, to explore whether multiplicity adjustments are necessary in a platform design, simulation studies evaluating the operating characteristics of platform designs relative to independent two-arm trials were conducted. Under the global null hypothesis, relative to a set of two-arm trials, we found that platform trials have slightly lower familywise error; however, conditional error rates for an experimental treatment being declared effective given another was declared effective are above the nominal alpha-level. Adjusting for multiplicity reduces familywise error, but has little impact on conditional error. These studies show that multiplicity adjustments are unnecessary in platform trials of unrelated treatments. Second, to determine the optimal approach for comparing delayed entry arms to the shared control, five methods for incorporating historical controls into two-arm trials were applied to the analyses of simulated open platform trials and compared to pooling all controls. We found that when response rates are constant, pooling yields the lowest error and most precise, unbiased estimates. However, if drift occurs, pooling results in type I error inflation or deflation depending on the direction of drift, as well as biased estimates. Although superior to naive pooling, none of the alternatives explored guarantee error control or unbiased estimates in the presence of drift. Thus, only concurrent controls should be used as comparators in the primary analysis of confirmatory studies. Finally, these findings were applied to assess the design and analysis of the neuroprotection 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]

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.

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.

published_or_final_version / Community Medicine / Master / Master of Public Health

published_or_final_version / Community Medicine / Master / Master of Public Health