Clinical research projects at a German medical faculty: follow-up from ethical approval to publication and citation by others

BACKGROUND: Only data of published study results are available to the scientific community for further use such as informing future research and synthesis of available evidence. If study results are reported selectively, reporting bias and distortion of summarised estimates of effect or harm of treatments can occur. The publication and citation of results of clinical research conducted in Germany was studied. METHODS: The protocols of clinical research projects submitted to the research ethics committee of the University of Freiburg (Germany) in 2000 were analysed. Published full articles in several databases were searched and investigators contacted. Data on study and publication characteristics were extracted from protocols and corresponding publications. RESULTS: 299 study protocols were included. The most frequent study design was randomised controlled trial (141; 47%), followed by uncontrolled studies (61; 20%), laboratory studies (30; 10%) and non-randomised studies (29; 10%). 182 (61%) were multicentre studies including 97 (53%) international collaborations. 152 of 299 (51%) had commercial (co-)funding and 46 (15%) non-commercial funding. 109 of the 225 completed protocols corresponded to at least one full publication (total 210 articles); the publication rate was 48%. 168 of 210 identified publications (80%) were cited in articles indexed in the ISI Web of Science. The median was 11 citations per publication (range 0-1151). CONCLUSIONS: Results of German clinical research projects conducted are largely underreported. Barriers to successful publication need to be identified and appropriate measures taken. Close monitoring of projects until publication and adequate support provided to investigators may help remedy the prevailing underreporting of research.

Anticoagulation Management Practices and Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Clinical Research Study.

Whether anticoagulation management practices are associated with improved outcomes in elderly patients with acute venous thromboembolism (VTE) is uncertain. Thus, we aimed to examine whether practices recommended by the American College of Chest Physicians guidelines are associated with outcomes in elderly patients with VTE. We studied 991 patients aged ≥65 years with acute VTE in a Swiss prospective multicenter cohort study and assessed the adherence to four management practices: parenteral anticoagulation ≥5 days, INR ≥2.0 for ≥24 hours before stopping parenteral anticoagulation, early start with vitamin K antagonists (VKA) ≤24 hours of VTE diagnosis, and the use of low-molecular-weight heparin (LMWH) or fondaparinux. The outcomes were all-cause mortality, VTE recurrence, and major bleeding at 6 months, and the length of hospital stay (LOS). We used Cox regression and lognormal survival models, adjusting for patient characteristics. Overall, 9% of patients died, 3% had VTE recurrence, and 7% major bleeding. Early start with VKA was associated with a lower risk of major bleeding (adjusted hazard ratio 0.37, 95% CI 0.20-0.71). Early start with VKA (adjusted time ratio [TR] 0.77, 95% CI 0.69-0.86) and use of LMWH/fondaparinux (adjusted TR 0.87, 95% CI 0.78-0.97) were associated with a shorter LOS. An INR ≥2.0 for ≥24 hours before stopping parenteral anticoagulants was associated with a longer LOS (adjusted TR 1.2, 95% CI 1.08-1.33). In elderly patients with VTE, the adherence to recommended anticoagulation management practices showed mixed results. In conclusion, only early start with VKA and use of parenteral LMWH/fondaparinux were associated with better outcomes.

Randomization in clinical trials in orthodontics: its significance in research design and methods to achieve it

Randomization is a key step in reducing selection bias during the treatment allocation phase in randomized clinical trials. The process of randomization follows specific steps, which include generation of the randomization list, allocation concealment, and implementation of randomization. The phenomenon in the dental and orthodontic literature of characterizing treatment allocation as random is frequent; however, often the randomization procedures followed are not appropriate. Randomization methods assign, at random, treatment to the trial arms without foreknowledge of allocation by either the participants or the investigators thus reducing selection bias. Randomization entails generation of random allocation, allocation concealment, and the actual methodology of implementing treatment allocation randomly and unpredictably. Most popular randomization methods include some form of restricted and/or stratified randomization. This article introduces the reasons, which make randomization an integral part of solid clinical trial methodology, and presents the main randomization schemes applicable to clinical trials in orthodontics.

Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium

To propose standardized consensus definitions for important clinical endpoints in transcatheter aortic valve implantation (TAVI), investigations in an effort to improve the quality of clinical research and to enable meaningful comparisons between clinical trials. To make these consensus definitions accessible to all stakeholders in TAVI clinical research through a peer reviewed publication, on behalf of the public health.

Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the valve academic research consortium

To propose standardized consensus definitions for important clinical endpoints in transcatheter aortic valve implantation (TAVI), investigations in an effort to improve the quality of clinical research and to enable meaningful comparisons between clinical trials. To make these consensus definitions accessible to all stakeholders in TAVI clinical research through a peer reviewed publication, on behalf of the public health.

IFPA Meeting 2011 workshop report I: Placenta: Predicting future health; roles of lipids in the growth and development of feto-placental unit; placental nutrient sensing; placental research to solve clinical problems--a translational approach

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2011 there were twelve themed workshops, four of which are summarized in this report. These workshops related to both basic science and clinical research into placental growth and nutrient sensing and were divided into 1) placenta: predicting future health; 2) roles of lipids in the growth and development of feto-placental unit; 3) placental nutrient sensing; 4) placental research to solve clinical problems: a translational approach.

A Research Roadmap for Complementary and Alternative Medicine – What We Need to Know by 2020

Background: The CAMbrella coordination action was funded within the Framework Programme 7. Its aim is to provide a research roadmap for clinical and epidemiological research for complementary and alternative medicine (CAM) that is appropriate for the health needs of European citizens and acceptable to their national research institutes and healthcare providers in both public and private sectors. One major issue in the European research agenda is the demographic change and its impact on health care. Our vision for 2020 is that there is an evidence base that enables European citizens to make informed decisions about CAM, both positive and negative. This roadmap proposes a strategic research agenda for the field of CAM designed to address future European health care challenges. This roadmap is based on the results of CAMbrella’s several work packages, literature reviews and expert discussions including a consensus meeting. Methods: We first conducted a systematic literature review on key issues in clinical and epidemiological research in CAM to identify the general concepts, methods and the strengths and weaknesses of current CAM research. These findings were discussed in a workshop (Castellaro, Italy, September 7–9th 2011) with international CAM experts and strategic and methodological recommendations were defined in order to improve the rigor and relevance of CAM research. These recommendations provide the basis for the research roadmap, which was subsequently discussed in a consensus conference (Järna, Sweden, May 9–11th 2012) with all CAMbrella members and the CAMbrella advisory board. The roadmap was revised after this discussion in CAMbrella Work Package (WP) 7 and finally approved by CAMbrella’s scientific steering committee on September 26th 2012. Results: Our main findings show that CAM is very heterogenous in terms of definitions and legal regulations between the European countries. In addition, citizens’ needs and attitudes towards CAM as well as the use and provision of CAM differ significantly between countries. In terms of research methodology, there was consensus that CAM researchers should make use of all the commonly accepted scientific research methods and employ those with utmost diligence combined in a mixed methods framework. Conclusions: We propose 6 core areas of research that should be investigated to achieve a robust knowledge base and to allow stakeholders to make informed decisions. These are: Research into the prevalence of CAM in Europe: Reviews show that we do not know enough about the circumstances in which CAM is used by Europeans. To enable a common European strategic approach, a clear picture of current use is of the utmost importance. Research into differences regarding citizens’ attitudes and needs towards CAM: Citizens are the driver for CAM utilization. Their needs and views on CAM are a key priority, and their interests must be investigated and addressed in future CAM research. Research into safety of CAM: Safety is a key issue for European citizens. CAM is considered safe, but reliable data is scarce although urgently needed in order to assess the risk and cost-benefit ratio of CAM. Research into the comparative effectiveness of CAM: Everybody needs to know in what situation CAM is a reasonable choice. Therefore, we recommend a clear emphasis on concurrent evaluation of the overall effectiveness of CAM as an additional or alternative treatment strategy in real-world settings. Research into effects of context and meaning: The impact of effects of context and meaning on the outcome of CAM treatments must be investigated; it is likely that they are significant. Research into different models of CAM health care integration: There are different models of CAM being integrated into conventional medicine throughout Europe, each with their respective strengths and limitations. These models should be described and concurrently evaluated; innovative models of CAM provision in health care systems should be one focus for CAM research. We also propose a methodological framework for CAM research. We consider that a framework of mixed methodological approaches is likely to yield the most useful information. In this model, all available research strategies including comparative effectiveness research utilising quantitative and qualitative methods should be considered to enable us to secure the greatest density of knowledge possible. Stakeholders, such as citizens, patients and providers, should be involved in every stage of developing the specific and relevant research questions, study design and the assurance of real-world relevance for the research. Furthermore, structural and sufficient financial support for research into CAM is needed to strengthen CAM research capacity if we wish to understand why it remains so popular within the EU. In order to consider employing CAM as part of the solution to the health care, health creation and self-care challenges we face by 2020, it is vital to obtain a robust picture of CAM use and reliable information about its cost, safety and effectiveness in real-world settings. We need to consider the availability, accessibility and affordability of CAM. We need to engage in research excellence and utilise comparative effectiveness approaches and mixed methods to obtain this data. Our recommendations are both strategic and methodological. They are presented for the consideration of researchers and funders while being designed to answer the important and implicit questions posed by EU citizens currently using CAM in apparently increasing numbers. We propose that the EU actively supports an EUwide strategic approach that facilitates the development of CAM research. This could be achieved in the first instance through funding a European CAM coordinating research office dedicated to foster systematic communication between EU governments, public, charitable and industry funders as well as researchers, citizens and other stakeholders. The aim of this office would be to coordinate research strategy developments and research funding opportunities, as well as to document and disseminate international research activities in this field. With the aim to develop sustainability as second step, a European Centre for CAM should be established that takes over the monitoring and further development of a coordinated research strategy for CAM, as well as it should have funds that can be awarded to foster high quality and robust independent research with a focus on citizens health needs and pan-European collaboration. We wish to establish a solid funding for CAM research to adequately inform health care and health creation decision-making throughout the EU. This centre would ensure that our vision of a common, strategic and scientifically rigorous approach to CAM research becomes our legacy and Europe’s reality. We are confident that our recommendations will serve these essential goals for EU citizens.

Sample size estimation: an overview with applications to orthodontic clinical trial designs

Proper sample size estimation is an important part of clinical trial methodology and closely related to the precision and power of the trial's results. Trials with sufficient sample sizes are scientifically and ethically justified and more credible compared with trials with insufficient sizes. Planning clinical trials with inadequate sample sizes might be considered as a waste of time and resources, as well as unethical, since patients might be enrolled in a study in which the expected results will not be trusted and are unlikely to have an impact on clinical practice. Because of the low emphasis of sample size calculation in clinical trials in orthodontics, it is the objective of this article to introduce the orthodontic clinician to the importance and the general principles of sample size calculations for randomized controlled trials to serve as guidance for study designs and as a tool for quality assessment when reviewing published clinical trials in our specialty. Examples of calculations are shown for 2-arm parallel trials applicable to orthodontics. The working examples are analyzed, and the implications of design or inherent complexities in each category are discussed.

Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study)

Background Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Trauma registry record linkage: methodological approach to benefit from complementary data using the example of the German Pelvic Injury Register and the TraumaRegister DGU(®)

In Germany, hospitals can deliver data from patients with pelvic fractures selectively or twofold to two different trauma registries, i.e. the German Pelvic Injury Register (PIR) and the TraumaRegister DGU(®) (TR). Both registers are anonymous and differ in composition and content. We describe the methodological approach of linking these registries and reidentifying twofold documented patients. The aim of the approach is to create an intersection set that benefit from complementary data of each registry, respectively. Furthermore, the concordance of data entry of some clinical variables entered in both registries was evaluated.

Graphical presentation of diagnostic information

BACKGROUND: Graphical displays of results allow researchers to summarise and communicate the key findings of their study. Diagnostic information should be presented in an easily interpretable way, which conveys both test characteristics (diagnostic accuracy) and the potential for use in clinical practice (predictive value). METHODS: We discuss the types of graphical display commonly encountered in primary diagnostic accuracy studies and systematic reviews of such studies, and systematically review the use of graphical displays in recent diagnostic primary studies and systematic reviews. RESULTS: We identified 57 primary studies and 49 systematic reviews. Fifty-six percent of primary studies and 53% of systematic reviews used graphical displays to present results. Dot-plot or box-and- whisker plots were the most commonly used graph in primary studies and were included in 22 (39%) studies. ROC plots were the most common type of plot included in systematic reviews and were included in 22 (45%) reviews. One primary study and five systematic reviews included a probability-modifying plot. CONCLUSION: Graphical displays are currently underused in primary diagnostic accuracy studies and systematic reviews of such studies. Diagnostic accuracy studies need to include multiple types of graphic in order to provide both a detailed overview of the results (diagnostic accuracy) and to communicate information that can be used to inform clinical practice (predictive value). Work is required to improve graphical displays, to better communicate the utility of a test in clinical practice and the implications of test results for individual patients.