Systematic review about data quality and protocol compliance in clinical trials

Bei Investigator Initiated Trials (IITs) werden alternative risikoadaptierte Monitoring-Strategien in Abhängigkeit vom individuellen Studiendesign und dem Risikoprofil diskutiert, um bei oft restriktiven Ressourcen eine den gesetzlichen Vorgaben genügende Qualität der Studiendurchführung und der Daten zu gewährleisten. Aufgrund einer Literaturanalyse sollten in der vorliegenden Arbeit Untersuchungen ausgewertet werden, in denen quantitative Aussagen zu Datenqualität und Prüfplan-Compliance in klinischen Prüfungen gemacht wurden. Bei der Interpretation der Ergebnisse sollten die implementierten Qualitätssicherungsmaßnahmen berücksichtigt werden. Aufgrund einer systematischen Recherche in MEDLINE konnten 21 Publikationen identifiziert werden, bei denen die Daten- und Prozessqualität in klinischen Prüfungen untersucht, die Qualität durch Überprüfungen mit Source Data Verification vor Ort oder Überprüfung übermittelter Quelldaten in der Studienzentrale ermittelt wurde und quantitative Informationen zu den Bereichen Datenqualität, Protokoll-Compliance oder Defizite bei Einwilligungserklärungen vorlagen. Die Mehrzahl der Untersuchungen ist drei Organisationen zuzuordnen: European Organization für Research and Treatment of Cancer (EORTC) (n=7), National Cancer Institute (NCI) (n=7) und Untersuchungen der Trans-Tasman Radiation Oncology Group (TROG) (n=4). Darüber hinaus wurden drei Untersuchungen weiterer Studiengruppen identifiziert. Die Untersuchungen wurden im Zeitraum von 1981 bis 2003 publiziert. Überwiegend wurden in der Literatur onkologische Studien betrachtet (n=19), wobei die Radiotherapie im Vordergrund stand (n=8). Für die EORTC-Studien wurde in der Regel eine gute Datenqualität berichtet (80-90% korrekte Daten). Punktuelle Probleme wurden im Hinblick auf die Protokoll-Compliance und das Berichten von Nebenwirkungen/schwerwiegenden unerwünschten Ereignissen festgestellt. Eine gute Qualität wurde ebenfalls bzgl. des korrekten Einschlusses von Patienten beobachtet. Durch das NCI wurde ein standardisiertes Audit-System eingeführt und innerhalb von kooperativen Studiengruppen implementiert. Im Rahmen dieser Audits wurden verschiedene Kriterien überprüft und eine überwiegend gute Datenqualität und Protokoll-Compliance festgestellt. Mängel wurden in ca. 5% der Fälle im Hinblick auf die Einwilligungserklärung, die korrekte Anwendung der Einschlusskriterien, Protokollverletzungen, bei der Ermittlung des Zielkriteriums, der Erfassung der Toxizität, der adäquaten Datenlieferung und bei der Datenverifikation beobachtet. In einzelnen Untersuchungen ergaben sich Probleme mit der Behandlungscompliance (10-20%), bei Protokollabweichungen im Hinblick auf die Arzneimitteldosis (10%) und bei der Drug Accountability (15%). Von der TROG wurde ein Qualitätssicherungsprozess implementiert, der auf zentralem Monitoring von kopierten Quelldaten basiert. Durch den Qualitätssicherungsansatz der TROG konnten schwerwiegende Probleme mit der Protokoll-Compliance unter 10% gesenkt werden, ebenso konnte eine gute Datenqualität mit einer Fehlerrate unter 5% erreicht werden. Die korrekte Handhabung von Ein- und Ausschlusskriterien stellte in Einzelfällen ein Problem dar. Zusammenfassend kann festgestellt werden, dass die in dem Review erfassten Studiengruppen von einer guten Datenqualität und einer guten bis moderaten Protokoll-Compliance berichten. Diese basiert nach Aussage der Autoren im wesentlichen auf etablierten Qualitätssicherungs-Prozeduren, wobei das durchgeführte Audit ebenfalls einen potentiellen Einflussfaktor darstellt. Geringe Probleme wurden in der Regel im Hinblick auf die Einwilligungserklärung, die korrekte Handhabung der Ein- und Ausschlusskriterien und die Datenqualität beobachtet. In einzelnen Studien gab es jedoch Probleme mit der Protokoll-Compliance. Insgesamt hängen Anzahl und Art der Mängel von dem Studientyp, dem Qualitätsmanagement und der Organisation der Studiengruppe ab. Wissenschaftsbetrug wurde nur in sehr wenigen Fällen durch die Audits festgestellt. Die vorgelegten Informationen beziehen sich nahezu ausschließlich auf etablierte Studiengruppen; bezüglich Datenqualität und Protokoll-Compliance außerhalb der Studiengruppen liegen kaum Informationen in der Literatur vor. Bei der Bewertung der Ergebnisse sollte berücksichtigt werden, dass es sich zum Teil um Eigenauswertungen der Studiengruppen und nicht um unabhängige externe Prüfungen (z.B. externe Audits) handelt. Inwieweit die Ergebnisse einer konsequenten Überprüfung nach derzeitigen Good Clinical Practice (GCP) – Regeln standhalten würden, kann aus der Analyse nicht beantwortet werden. Aus der vorliegenden Literaturanalyse ergeben sich Konsequenzen für die Planung einer prospektiven kontrollierten Studie zum Vergleich unterschiedlicher Monitoring-Strategien. Wesentlicher Einflussfaktor für die Datenqualität und Protokollcompliance in einer klinischen Studie ist das Qualitätsmanagement. Dieses Qualitätsmanagement umfasst neben Monitoring zahlreiche andere Maßnahmen. Um zu einer Bewertung von Monitoringstrategien kommen zu können, müssen daher alle Qualitätssicherungsmaßnahmen im Rahmen einer Studie berücksichtigt werden. Für den Vergleich unterschiedlicher Monitoringstrategien sind geeignete Zielparameter zu definieren (z.B. schwerwiegende Defizite bzgl. Ein- und Ausschlusskriterien, Sicherheit). Die vorliegende Analyse ergibt, dass bei gutem Qualitätsmanagement ohne umfassendes vor Ort Monitoring schwerwiegende Fehler nur mit relativ niedriger Häufigkeit festgestellt wurden. Unterschiede zwischen Monitoringstrategien könnten, gegeben ein funktionierendes Qualitätsmanagementssystem, sich als quantitativ gering erweisen. Testet man auf Äquivalenz von Monitoringstrategien, sind nur niedrige Differenzen zu akzeptieren, was wiederum eine Auswirkung auf die Fallzahlplanung hat. Weiterhin muss berücksichtigt werden, dass zur Feststellung der Auswirkung unterschiedlicher Monitoringstrategien auf die Sicherheit der Patienten und die Validität der Daten im Rahmen einer kontrollierten Untersuchung ein unabhängiges Audit notwendig ist. Dabei ist zu berücksichtigen, dass ein Audit bereits einen möglichen Einflussfaktor für die Datenqualität und Protokoll-Compliance darstellen kann, und damit eine Bewertung des Nutzens einer Monitoringstrategie erschwert werden könnte. Schlüsselwörter: systematisches Review, Datenqualität, Protokoll-Compliance, klinische StudieFor Investigator Initiated Trials (IITs) alternative risk-adapted monitoring strategies are discussed in order to fulfill rules and regulations, taking into consideration the restricted resources. In this systematic review investigations, presenting quantitative data about data quality and protocol compliance in clinical trials, are analyzed. The results are discussed taking into account the quality assurance procedures implemented. Based on a systematic MEDLINE retrieval, 21 studies could be identified in which data and process quality in clinical trials were investigated and assessed by site visits with source data verification or review of copied source data in the study center and quantitative information about data quality and protocol compliance was available. The majority of investigations were performed by three organizations: European Organization for Research and Treatment of Cancer (EORTC) (n=7), National Cancer Institute (NCI) (n=7) and investigations of the Trans-Tasman Radiation Oncology Group (TROG) (n=4). In addition three investigations of other study groups were identified. The investigations were published between 1981 and 2003. In the majority of cases oncological trials were investigated (n=19) with a focus on radiotherapy trials (n=8). In the EORTC-trials an overall good data quality was assessed (80–90% correct data). Singular problems were found with respect to protocol compliance and reporting of adverse reactions and serious unexpected events. Good quality was also observed with respect to the correct inclusion of patients into trials. By the NCI a standardized audit system was introduced and implemented within cooperative study groups. In the context of these audits different criteria were assessed and a good data quality and protocol compliance were measured. Deficits occurred in about 5% of the cases with respect to informed consent, correct application of inclusion criteria, protocol compliance, assessment of outcome criteria, assessment of toxicity, adequate data reporting and data verification. In some investigations problems with treatment compliance (10-20%), drug dose deviations (10%) and drug accountability (15%) were identified. By the TROG a quality assurance procedure was implemented, based on central monitoring of copied source data. By this approach major problems with protocol compliance could be reduced to less than 10% together with a good data quality with an error rate under 5%. The correct handling of in- and exclusion criteria was a problem in individual cases. In summary we found out that good data quality and good to moderate protocol compliance were reported by the study groups that are included in the systematic review. Due to the authors this is mainly due to an established quality assurance system, taking into consideration that audits itself may be an influential factor. Generally, minor problems were observed with respect to informed consent, correct handling of in- and exclusion criteria and data quality, however, in some studies there were problems with protocol compliance. Overall, number and type of deficits depend on study type, quality management and organization of the study group. Fraud was detected only in very few cases. The available evidence refers mainly to established study groups; for data quality and protocol compliance outside these groups only few information is available. However, it should be taken into consideration, that the analysis was performed, at least partly, by the study groups themselves and is not based on independent audits (e.g. external audits). The analysis cannot answer the question whether the results would have been replicable if a strict review according to criteria of Good Clinical Practice (GCP) would have been performed. From the systematic review consequences have to be taken for planning a prospective controlled trial comparing different monitoring strategies. The main influence factor for data quality and protocol compliance in a clinical trial is the quality management system. Quality management covers several other measures apart from monitoring. In order to assess monitoring strategies, all quality assurance procedures within a clinical trial have to be taken into consideration. For the comparison of different monitoring strategies adequate outcome parameter have to be defined (e.g. severe deficits with respect to inclusion and exclusion criteria, safety). The analysis indicates that with good quality management and no extensive on-site monitoring severe errors were detected only at relative low frequency. It could well be that with an efficient quality management system differences between monitoring strategies would be small. In order to demonstrate statistical equivalence of monitoring strategies, only small differences can be accepted which again leads to consequences for the sample-size calculation. In addition, it must be taken into consideration that within a controlled trial an independent audit is necessary to assess the effect of different monitoring strategies on the safety of patients and the quality of data. Audits however may be a possible influence factor for data quality and protocol compliance and may complicate the evaluation of the benefit of a monitoring strategy. Keywords: systematic review, data quality, protocol compliance, clinical tria

Market uptake of pegylated interferons for the treatment of hepatitis C in Europe : meeting abstract

Introduction and Objectives Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease with life threatening sequelae such as end-stage liver cirrhosis and liver cancer. It is estimated that the infection annually causes about 86,000 deaths, 1.2 million disability adjusted life years (DALYs), and ¼ of the liver transplants in the WHO European region. Presently, only antiviral drugs can prevent the progression to severe liver disease. Pegylated interferons combined with ribavirin are considered as current state-of-the-art treatment. Objective of this investigation was to assess the market uptake of these drugs across Europe in order to find out whether there is unequal access to optimised therapy. Material and Methods We used IMS launch and sales data (April 2000 to December 2005) for peginterferons and ribavirin for 21 countries of the WHO European region. Market uptake was investigated by comparing the development of country-specific sales rates. For market access analysis, we converted sales figures into numbers of treated patients and related those to country-specific hepatitis C prevalence. To convert sales figures into patient figures, the amount of active pharmaceutical ingredients (API) sold was divided by average total patient doses (ATPD), derived by a probability tree-based calculation algorithm accounting for genotype distribution, early stopping rules, body weight, unscheduled treatment stops and dose reductions Ntotal=APIPegIFNalpha-2a/ATPDPegIFNalpha-2a+APIPegIFN&alpha-2b/ATPDPegIFNalpha-2b For more concise result presentation the 21 included countries were aggregated into four categories: 1. EU founding members (1957): Belgium, France, Germany, Italy and Netherlands; 2. Countries joining EU before 2000: Austria (1995), Denmark (1973), Finland (1995), Greece (1981), Republic of Ireland (1973), Spain (1986), Sweden and UK (1973) 3. Countries joining EU after 2000: Czech Republic (2004), Hungary (2004), Poland (2004) and Romania (2007); 4. EU non-member states: Norway, Russia, Switzerland and Turkey. Results Market launch and market uptake of the investigated drugs differed considerably across countries. The earliest, most rapid and highest increases in sales rates were observed in the EU founding member states, followed by countries that joined the EU before 2000, countries that joined the EU after 2000, and EU non-member states. Most new EU member states showed a noticeable increase in sales after joining the EU. Market access analysis yielded that until end of 2005, about 308 000 patients were treated with peginterferon in the 21 countries. Treatment rates differed across Europe. The number of patients ever treated with peginterferon per 100 prevalent cases ranged from 16 in France to less than one in Romania, Poland, Greece and Russia. Discussion Peginterferon market uptake and prevalence adjusted treatment rates were found to vary considerably across 21 countries in the WHO European region suggesting unequal access to optimised therapy. Poor market access was especially common in low-resource countries. Besides budget restrictions, national surveillance and prevention policy should be considered as explanations for market access variation. Although our results allowed for the ranking of countries in order of market access, no final conclusions on over- or undertreatment can be drawn, because the number of patients who really require antiviral treatment is unknown. Further research based on pan-European decision models is recommended to determine the fraction of not yet successfully treated but treatable patients among those ever diagnosed with HCV. ..

Biometric authentication using brain responses to visual stimuli

This paper studies the suitability of brain activity, namely electroencephalogram signals, as raw material for conducting biometrie authentication of individuals. Brain responses were extracted with visual stimulation, leading to biological brain responses known as Visual Evoked Potentials. We evaluated a novel method, using only 8 occipital electrodes and the energy of differential EEG signals, to extract information about the subjects for further use as their biometrie features. To classify the features obtained from each individual, we used a one-class classifier per subject and we tested four types of classifiers: K-Nearest Neighbor, Support Vector Data Description and two other classifiers resulting from the combination of the two ones previously mentioned. After testing these four classifiers with features of 70 subjects, the results showed that visual evoked potentials are suitable for an accurate biometrie authentication

Evaluation of Biometric System - Eye Iris Technology

Tato práce stručně popisuje základní pojmy z oblasti biometrie, historii biometrie, biometrický systém a jeho vlastnosti. Dále pojednává o základních principech technologie rozpoznávání podle duhovky oka. Také jsou popsány testy provedené na několika různých systémech rozpoznávání podle duhovky oka a nakonec jsou shrnuty dosažené výsledky.This thesis briefly describes basic biometric terms, a brief history of biometrics, biometric system and its performance and characteristics. Basic principles of iris recognition technology are also discussed. Finally, this thesis describes tests performed on various iris recognition systems and sums up the results.

Multi-sample fusion with template protection

The widespread use of biometries and its increased popularity introduces privacy risks. In order to mitigate these risks, solutions such as the helper-data system, fuzzy vault, fuzzy extractors, and cancelable biometries were introduced, also known as the field of template proteetion. Besides these developments, fusion of multiple sources of biometrie information have shown to improve the verification performance of the biometrie system. Our work eonsists of analyzing feature-level fusion in the context of the template proteetion framework using the helper-data system. We verify the results using the FRGC v2 database and two feature extraction algorithms

Application Demonstrating Multi-Biometric Fusion

Tato práce je zaměřena na oblast biometrie, multi-biometrie, normalizace a fúze v multi-biometrických systémech a jejich hodnocení výkonnosti. Obsahuje stručný úvod do této problematiky a přehled používaných technik. Cílem práce je navrhnout a poté implementovat aplikaci demonstrující výkonnost systémů spadajících do kategorie multi-modálních biometrických systémů. Dále jsou popsány experimenty s databází šablon z multi-biometrického systému a v závěru jsou shrnuty dosažené výsledky.This work is focused on biometrics, multi-biometrics, normalization and fusion in multi-biometrics systems and their performance evaluation. It contains a brief introduction to the problem and an overview of the techniques. The aim is to design and then implement an application demonstrating the performance of systems that fall into the category of multi-modal biometric systems. Furthermore, the experiments with the database templates of multi-biometric system and the conclusion summarizes the results.

Central Venous Catheter Complications during Home Parenteral Nutrition: A Prospective Pilot Study of 481 Patients with More than 30,000 Catheter Days

Background: Home parenteral nutrition (HPN) has been shown to delay deterioration in cancer patients with malnutrition. Its risk-benefit ratio, however, is determined by the threat of central venous catheter (CVC) complications. Only few prospective studies on this subject exist, most of them based on small samples. The objective of this study was to provide reliable estimates of incidence rates of CVC complications in everyday HPN patient care in Germany. Patients and Methods: Aiming for a large prospective cohort study, we cooperated with a service provider caring for HPN patients nationwide. Between July 1 and November 30, 2006, all consecutive adult patients with more than 10 infusion days and no previous history of HPN were recruited. Follow-up ended on January 31, 2007. Data were collected in a standardised way by the provider's staff. To prevent underreporting, we used computer-assisted telephone interviews with medical caregivers as a provider-independent data source. Results: 481 patients met the inclusion criteria, contributing a total of 31,337 catheter days. 52 patients experienced a total of 63 CVC complications, resulting in an incidence rate of 2.01 CVC complications per 1,000 catheter days including 1.02 CVC infections per 1,000 catheter days. Conclusion: HPN administration can be safely performed with a relatively low rate of CVC complications

The magic of the century we live in. The supremacy of three bio factors and their impact on firms trading

Technology has come to be appreciated as key to the competitiveness of micro and macroeconomic level. Technological environment affecting business firms by increasing trade efficiency in making services and quality of services. Usually there should be no problems related to computer equipment or communications systems. Life of individuals and firms will be influenced increasingly more by biotechnology, bionic or biometrics. Today it put more emphasis on the development of biotechnology, whose future shows to be as extensive as in the case of information technology. Biotechnology also founded an alternative universe.technology, biotechnology, bionic, biometrics, firms trading