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ZusammenfassungDie positive Seite der Covid-19-Pandemie ist die Stimulation von Innovationen. Als Beispiel diskutieren wir das Pragmatic Controlled Trial (PCT), eine Twinstudie, mit der die Real-World Effectiveness (RWE) von Gesundheitsleistungen unter den nicht standardisierten Bedingungen des Versorgungsalltags bestätigt werden kann. Der Nachweis der RWE kann generell für Gesundheitsleistungen mit bedingter Zulassung bedeutend werden. Das PCT verwendet das Bayes-Prinzip anstelle einer Randomisierung. Es ermöglicht die Versorgung unter nicht standardisierten Alltagsbedingungen und die unverzerrte Evaluation unter standardisierten Bedingungen. Letztere wird durch die Beschreibung der endpunkt-spezifischen Risiken jedes individuellen Patienten und durch die Klassifikation der Interventionen in einer nicht-experimentellen, aber risiko-stratifizierten und kontrollierten Studie gewährleistet. Patienten erwarten eine zeitnahe Lösung ihrer Gesundheitsprobleme. Bisher verlangt die Wissenschaft vor der Zulassung einer Innovation hinreichend fundierte Versuchsergebnisse. Die Covid-19-Pandemie hat gezeigt, dass die Forderung nach sofortiger und bestmöglicher Versorgung durch die bedingte Zulassung eines neuen Versorgungsprinzips erfüllt werden kann. Mit dem PCT beschreiben wir ein Verfahren, mit dem nach einer bedingten Zulassung die noch ausstehenden Daten erhoben werden können, um den Zulassungsprozess erfolgreich abzuschließen.

Felicitas Wiedemann,1,2 Franz Porzsolt2 1Department of General and Visceral Surgery, Stuttgart, 70176, Germany; 2Institute of Clinical Economics (ICE) e.V., Ulm, 89081, GermanyCorrespondence: Felicitas Wiedemann, Department of General and Visceral Surgery, Diakonie-Klinikum Stuttgart, Markelstraße 44, Stuttgart, Baden-Württemberg, Germany, Tel +491781731296, Email felicitas.wiedemann@gmail.comPurpose: The assessment of health-related quality of life (hrQoL) may need to be reconsidered due to important differences between efficacy (the effect of a treatment under experimental study conditions) and effectiveness (the effect of a treatment under real-world conditions). We presume that most researchers intend to describe effects under real-world conditions when investigating hrQoL as an endpoint. Unfortunately, most studies are designed to confirm two theories: the efficacy of a new intervention under experimental study conditions and the real-world effectiveness of this intervention on hrQoL under non-experimental study conditions. Conflicting information emerges when the outcomes are supposed to describe effects under real-world conditions, but the assessment generates results obtained under experimental conditions. This paper examines the existing conflict between efficacy and effectiveness in a sample of 100 studies investigating hrQoL.Methods: We analysed a sample of freely available publications of clinical studies listed in PubMed between April 2015 and August 2016 which assessed quality of life as an outcome. We assessed the following four characteristics that should differ in studies measuring either efficacy or effectiveness: 1) specification of the study as a randomised controlled trial or not, 2) description of the study design as pragmatic or not, 3) classification of the study as an efficacy or an effectiveness study and 4) number of selected inclusion and exclusion criteria.Results: 91% of the studies assessed hrQoL under experimental conditions (in a randomised controlled trial), but not under real-world conditions. The important difference between efficacy and effectiveness was not described in 60% of the studies. Only 6% of studies classified the study as a pragmatic trial. The difference between inclusion and exclusion criteria was not addressed in any of the investigated studies.Conclusion: The results of the four criteria confirmed our hypothesis that hrQoL studies are conducted mainly as experimental, but not pragmatic, trials indicating that the meaningfulness of the important difference between efficacy and effectiveness requires further discussion.Keywords: pragmatic trial, experimental study conditions, real-world conditions, efficacy, effectiveness, pragmatic.

The positive side of the Covid-19 pandemic is that it has provided a stimulation for innovations. As an example, we discuss the Pragmatic Controlled Trial (PCT), a twin study that can be used to confirm the real-world effectiveness (RWE) of health services under the non-standardized conditions of everyday care. Proof of the RWE could generally be important for health services with conditional approval. The PCT uses the Bayesian principle instead of randomization. It enables care under non-standardized everyday conditions and, by describing the endpoint-specific risks of each individual patient and by classifying the interventions, creates an unbiased evaluation in a non-experimental, but risk-stratified and controlled study. Patients expect a timely solution to their health problems. Until now, science has required sufficiently well-founded results before approving an innovation. The Covid-19 pandemic has shown that the demand for immediate and best possible care can be met through the conditional approval of a new care principle. With the PCT, we describe a procedure with which, after conditional approval, the missing data can be collected in order to successfully complete the approval process.Die positive Seite der Covid-19-Pandemie ist die Stimulation von Innovationen. Als Beispiel diskutieren wir das Pragmatic Controlled Trial (PCT), eine Twinstudie, mit der die Real-World Effectiveness (RWE) von Gesundheitsleistungen unter den nicht standardisierten Bedingungen des Versorgungsalltags bestätigt werden kann. Der Nachweis der RWE kann generell für Gesundheitsleistungen mit bedingter Zulassung bedeutend werden. Das PCT verwendet das Bayes-Prinzip anstelle einer Randomisierung. Es ermöglicht die Versorgung unter nicht standardisierten Alltagsbedingungen und die unverzerrte Evaluation unter standardisierten Bedingungen. Letztere wird durch die Beschreibung der endpunkt-spezifischen Risiken jedes individuellen Patienten und durch die Klassifikation der Interventionen in einer nicht-experimentellen, aber risiko-stratifizierten und kontrollierten Studie gewährleistet. Patienten erwarten eine zeitnahe Lösung ihrer Gesundheitsprobleme. Bisher verlangt die Wissenschaft vor der Zulassung einer Innovation hinreichend fundierte Versuchsergebnisse. Die Covid-19-Pandemie hat gezeigt, dass die Forderung nach sofortiger und bestmöglicher Versorgung durch die bedingte Zulassung eines neuen Versorgungsprinzips erfüllt werden kann. Mit dem PCT beschreiben wir ein Verfahren, mit dem nach einer bedingten Zulassung die noch ausstehenden Daten erhoben werden können, um den Zulassungsprozess erfolgreich abzuschließen.

BackgroundThe COVID-19 pandemic is characterized by both health and economic risks. A ‘safety loop’ model postulates risk-related decisions are not based on objective and measurable risks but on the subjective perception of those risks. We here illustrate a quantification of the difference between objective and subjective risks.MethodThe objective risks (or chances) can be obtained from traditional 2 × 2 tables by calculating the positive (+LR) and negative (-LR) likelihood ratios. The subjective perception of objective risks is calculated from the same 2 × 2 tables by exchanging the X- and Y-axes. The traditional 2 × 2 table starts with the hypothesis, uses a test and a gold standard to confirm or exclude the investigated condition. The 2 × 2 table with inverted axes starts with the communication of a test result and presumes that the communication of bad news (whether right or false) will induce ‘perceived anxiety’ while good news will induce ‘perceived safety’. Two different functions (confirmation and exclusion) of both perceptions (perceived anxiety and safety) can be quantified with those calculations.ResultsThe analysis of six published tests and of one incompletely reported test on COVID-19 polymerase chain reactions (completed by four assumptions on high and low sensitivities and specificities) demonstrated that none of these tests induces ‘perceived safety’. Eight of the ten tests confirmed the induction of perceived anxiety with +LRs (range 3.1 – 5900). In two of these eight tests a -LR (0.25 and 0.004) excluded the induction of perceived safety.ConclusionsCommunication of test results caused perceived anxiety but not perceived safety in 80% of the investigated tests. Medical tests – whether right or false – generate strong psychological messages. In the case of COVID-19 tests may induce more perceived anxiety than safety.

Background: Evidence-Based healthcare deals basically with published clinical trials to guide the decision making on what treatment to use for any specific conditions.Aims: The present paper assessed the inclusion and exclusion criteria used in clinical trials of cervical cancer aiming at establishing a clear distinction between each criterion.Methods: We performed a bibliographical search in pubmed with the terms cervical cancer and treatment or therapy filtered for clinical trials with human subjects for the last ten years. A total of 30 papers were used extracting and classifying the inclusion and exclusion category according to the characteristic they described. Results: We found no clear parameter to establish which criteria could exclusively serve as inclusion or exclusion across the papers, about 56% of the categories identified were found either listed as inclusion or exclusion criteria or even as both in some cases.Conclusions: The key issue of selection criteria is not in its form but in its function, the first point to consider is if the trial is experimental (focused on efficacy and proof of principle) or observational (pragmatic trials, focused on effectiveness and real world conditions). We suggest, inclusion criteria should be broad, focused on the investigated condition; exclusion criteria should apply only to the subset of this “included” population, and do not take part in observational studies. These conclusions do not serve only for researchers but should affect practitioners and policy makers to correctly compare the results of investigated treatment.

Designers and architects created the rule ‘form follows function (FFF)’ for their own profession. Our paper demonstrates that this FFF rule applies equally well to the designers of clinical studies. Four examples present are as follows: disregarding this FFF rule causes an inconsistent terminology to differentiate between efficacy and effectiveness, inconsistent differentiation of efficacy and effectiveness interferes with the consistent interpretation of the results of clinical studies, inconsistent interpretation of clinical studies results in an unexpectedly variance of recommendations in clinical guidelines and the fusion of the FFF designer rule and of the demands of Cochrane and Bradford Hill (‘can it work?’, ‘does it work?’ and ‘is it worth it?’) avoids the terminology problem and its misleading consequences. This strategy is presented.

BackgroundIn the literature on the treatment of depression, efficacy and effectiveness research have different purposes and should apply different research methodologies.ObjectiveThe purpose of the study was to review characteristics of depression treatment studies identified using efficacy or effectiveness search terms. We considered subject inclusion and exclusion criteria; numbers of subjects enrolled and the proportion in the primary analyses; inclusion of a Consolidated Standards of Reporting Trials (CONSORT) flow diagram; use of random assignment; use of placebo control conditions; lengths of treatment and follow-up; primary outcome variable; trial registration; journal impact factor.Study selectionStudies indexed as efficacy AND ‘real-world’ AND depression or effectiveness AND ‘real-world’ AND depression in PubMed up to 18 May 2019.Findings27 studies met the inclusion criteria: 13 effectiveness studies, 6 efficacy studies and 8 studies indexed as both effectiveness and efficacy. Studies identified as effectiveness, efficacy, or both differed on three outcome measures: the inclusion criteria were lengthier for efficacy than for effectiveness studies; efficacy studies were more likely to have a placebo control condition than effectiveness studies; and the journal impact factor was lower for effectiveness studies than for studies from the efficacy search or studies identified by both searches.ConclusionsEfficacy and effectiveness research hypothetically use different methodologies, but the efficacy and effectiveness literatures in the treatment of depression were comparable for most of the coded characteristics. The lack of distinguishable characteristics suggests that variably applied terminology may hinder efforts to narrow the gap between research and practice.PROSPERO registration number#CRD42019136840.

Despite enthusiasm for cancer screening, systematic reviews consistently fail to show that screening reduces all-cause mortality. This narrative review explores conceptual issues, and inconsistencies between evidence and opinion about screening. We examined the interpretation of screening studies in relation to three intellectual traditions: (1) The relationship between prevention and cure; (2) Confirmation bias and the challenge of incorporating new data: less care may produce better outcomes than more care; (3) The answers to three structured questions about efficacy, effectiveness, and value of treatments proposed by Sir Archie Cochrane and Sir Austin Bradford Hill. When considering extensions of life expectancy or all-cause mortality, systematic reviews typically show cancer screening to have only small effects and often non-significant effects on all-cause mortality. Early diagnosis does not assure application of an intervention that alters the pathway toward demise. The interpretation of screening results is also affected by several known biases. Investigators and advocates are encumbered by an over focus on studies designed to determine if a treatment can work under ideal circumstances. To advance the field, we need a greater emphasis on evaluations that ask ‘Does the treatment work under real-world conditions?’, and ‘Is the treatment worth it?’ in terms of outcomes that are meaningful to patients.

Die klinische Ökonomik lässt sich einordnen zwischen den Kernfächern der Medizin und der Epidemiologie, der Ethik, den Wirtschaftswissenschaften und der Jurisprudenz. Durch die klinische Ökonomik wird eine Reihe bisher unbeachteter ethischer Konflikte aufgedeckt, von deren Lösung letztlich die Autonomie des Fachs Medizin abhängen wird.

Hintergrund: Praventionsprogramme sollten nur empfohlen werden, wenn sie leisten, was sie zu leisten versprechen. Deshalb haben wir die Variation und Validitat der Empfehlungen zum Darmkrebs-Screening von 9 Organisationen gepruft. Methoden: Angaben zum Screening-Alter, chemischen Stuhltest (gFOBT), immunologischen Stuhltest (FIT), DNA-Stuhltest, Sigmoidoskopie, Koloskopie, Doppelkontrastuntersuchung/Barium-Doppelkontrasteinlauf und zur virtuellen Koloskopie/CT-Kolonografie wurden in 3 Schritten analysiert. 1) Erfassung aller Referenzen, die von den 9 Organisationen ausgewahlt wurden, 2) Zuordnung der Referenzen zur Mortalitat, Inzidenz und Sensitivitat/Spezifitat und 3) Bewertung der Validitat bei Mortalitatsstudien. Ergebnisse: Der Nachweis von okkultem Blut wird als einzige Screening-Methode von allen 9 Organisationen empfohlen. Die Koloskopie wird von 7 Organisationen empfohlen. Von 33 Referenzen zur Begrundung des Screenings hatten 15 andere Endpunkte als die Mortalitat. Eine Publikation war eine Metaanalyse. Elf von 17 Veroffentlichungen untersuchten den chemischen Stuhltest, 3 die Sigmoidoskopie und je eine Studie den immunologischen Stuhltest, die Koloskopie oder generell die Diagnostik des Darmes. Durchschnittlich wurden in allen Studien 2 von 9 Validitatskriterien vollstandig, 5 teilweise und 2 nicht erfullt. In 2 Veroffentlichungen war keines der Validitatskriterien vollstandig erfullt. Schlussfolgerungen: Die Analyse der Empfehlungen zum Darmkrebs-Screening zeigte, dass 9 Organisationen unterschiedliche Ziele verfolgen und unterschiedliche Empfehlungen aussprechen. Die gewissenhafte und aufwendige Prufung der wissenschaftlichen Studien zur Mortalitat, die diesen Empfehlungen zugrunde liegen, weisen erhebliche Mangel auf und konnen damit die internationalen Empfehlungen zum Darmkrebs-Screening nicht hinreichend begrunden. Sinnvoll ware, uber die zu erhebenden Daten einen Konsensus herbeizufuhren, mit welchem eine belastbare Basis fur Versorgungsentscheidungen generiert werden kann.

The description of results in clinical trials is an unsolved problem.1 The low quality of some clinical trials and the low output of useful data for healthcare decisions is a problem for clinicians and patients alike. Statisticians doing systematic reviews or meta-analysis try to solve this problem by establishing lower p-value thresholds (for example, changing from 0.05 to 0.005). That results in the acceptance of fewer, larger and more carefully designed studies in order to be considered to have sufficient power.2 The problem is that good useful information might get suppressed using stricter p-value thresholds. This is an especially difficult problem in quality of life (QoL) studies which, by their very nature, are smaller and less powerful. QoL researchers believe that the answer to poor quality is to review more studies that describe meaningful positive outcomes that contribute to the improvement of healthcare.3 What is often missing is a general discussion about the selection criteria. Choosing selection criteria is not easy. On one hand, wide inclusion criteria should be chosen in order to demonstrate safety and effectiveness for a large group of patients. On the other hand, there are many ethical and scientific reasons to define exclusion criteria.4 The resulting subjective selection of inclusion and exclusion criteria should be a balance of these two considerations. In this report, we analyse the information provided by the description of inclusion and exclusion criteria. We demonstrate that valuable information on the investigated study population can be provided by a complete and precise description of the inclusion and exclusion criteria that is not present in all publications. Furthermore, we propose that researchers can derive important information on the homogeneity/heterogeneity of different study populations from completely reported inclusion and exclusion criteria. This study builds on on the data of research done …

Sir Archie Cochrane and Sir Austin Bredford Hill requested to answer three short questions before implementing a new healthcare service into daily clinical practice: C AN IT WORK? D OES IT WORK? I S IT WORTH IT? For implementation of this 3-step-CDI-strategy we propose the consecutive completion of three different types of studies. First, a Randomised Controlled Trial (RCT) to confirm that it CAN WORK, i.e. to demonstrate efficacy under Ideal Study Conditions (ISC). Second, a Pragmatic Controlled Trial (PCT) to confirm that it DOES WORK, i.e. to demonstrate effectiveness under Real World Conditions (RWC). Third, a Complete Economic or Cost-Effectiveness-Analysis (CEA) to demonstrate that IT IS WORTH IT, i.e. to demonstrate the value [needless to say] under RWC from the patient and the societal perspectives. Unfortunately, there exist still different concepts on the appropriateness of different tools (RCT, PCT, CEA) for assessment of different effects (efficacy, effectiveness, value) under different conditions (ISC, RWC). There is probably no rational condition between the two ‘extremes’ of ICS and RWC. One may measure effects either under ISCs or RWCs. Both conditions and the interventions under these conditions can be distinguished clearly by five criteria. The goal of the intervention, the respect of patient autonomy, the legitimised application of the intervention, the application of not legitimised interventions, and finally the value generated by the intervention. These details will be presented in four tables. First, the tree requests of Sir Archie Cochrane and Sir Austin Bredford Hill. Second, the 3-step-CDI-approach we propose. Third, the description of differences of efficacy, effectiveness, and value, and finally and fourth, the detailed differences in the 14 steps of a RWC, PCT or RCT. The function of this 3-step-CDI-approach is a prototype of the more practicable ICE-3-step-tool that will be presented at the next meeting.

The purpose of this study was to determine if international guidelines differ in their recommendations concerning additive therapy for advanced, but potentially curable, gastric cancer. A systematic search of the English and German literature was conducted in the databases Medline, Cochrane Database, Embase, and PubMed. The search terms used were 'guidelines gastric cancer,' 'guidelines stomach cancer,' and 'Leitlinien Magenkarzinom.' Six different guidelines published after January 1, 2010, in which the tumors were classified according to the seventh edition of the TNM system (2010), were identified. Although the examined guidelines were based on the same study results, their recommendations concerning accompanying therapy for gastric cancer differ considerably. While perioperative chemotherapy is recommended in Germany, Great Britain, and large parts of Europe, postoperative adjuvant radiochemotherapy or perioperative chemotherapy is recommended in the USA and Canada. In Japan, postoperative adjuvant chemotherapy is recommended.The results of identical studies were interpreted differently in different countries. Since considerable effort is required for each country to separately test relevant studies for their validity and suitability, an international cooperation could simplify the creation of a common basis for guidelines and contribute to improved comparability of international guidelines.

The term "prevention" is used with several different meanings. Mistakes can be avoided by using different word for different contents. In addition to clear definitions the most frequent forms of bias have to be avoided. These forms are related to the five dimensions such as targets and endpoints as well as methods of screening, diagnostic, and finally treatment. Unless the appropriate items are selected in all five dimensions the results of the prevention strategy will not provide valid information.

Die randomisierte kontrollierte Studie (RCT) gilt als Goldstandard zur Gewinnung angemessener Evidenz für Therapieentscheidungen. Idealtypische Studien werden auch als Explanatory Trials bezeichnet, um sie von Studien unter Alltagsbedingungen (Pragmatic Trials) zu unterscheiden. Bei Einhaltung aller für die Durchführung dieser Studien geforderten Qualitätskriterien können die vier wesentlichen Formen systematischer Fehler (Selection Bias, Performance Bias, Attrition Bias und Detection Bias) vermieden und die interne Validität von Studien gewährleistet werden. Wenn die interne Validität einer Studie bestätigt wird, ist davon auszugehen, dass die innerhalb der Studie angestellten Vergleiche weitgehend frei von systematischen Fehlern sind. Die externe Validität besagt, dass in einer Studie di e Eigenschaften der Grundgesamtheit reflektiert werden, für welche die Ergebnisse der Studie gültig sein sollen. Da eine gute randomisierte Studie eine möglichst exakt definierte und homogene Population von Probanden enthält, kann sie per definitionem nahezu keine externe Validität, d. h. externe Gültigkeit, haben. Der Nachweis der externen Validität ist aber ebenso bedeutend wie der Nachweis der internen Validität, weil Erkenntnisse, die in randomisierten Studien gewonnen werden, nur wertvoll sind, wenn sie auch bei Patienten unter Alltagsbedingungen mit Erfolg angewandt werden können. Eine Verletzung dieser letztgenannten Forderung wird auch als Sampling Bias bezeichnet. Zur Gewährleitung der internen und externen Evidenz scheint ein Zwei-Schritt-Verfahren sinnvoll. Im ersten Schritt wir d die Wirkung eines Therapieprinzips idealtypisch in einem Explanatory Trial ohne Anspruch auf externe Validität nachgewiesen. Im zweiten Schritt wird der Nutzen für die untersuchten Patientengruppen unter Alltagsbedingungen (Pragmatic Trial) geprüft. Designs und etablierte Methoden zur Auswertung dieser Studien werden diskutiert. Das Zwei-Schritt-Verfahren bietet gegenüber den bisherigen Verfahren drei Vorteile: Das Risiko, die Ergebnisse von RCTs zu überinterpretieren, wird reduziert, weil Explanatory Trials lediglich die Wirkung unter Idealbedingungen nachweisen können. Der vom Gesetzgeber geforderte Nachweis des Nutzens kann durch Pragmatic Trials, welche die externe Validität berücksichtigen, erbracht werden. Möglicherweise lassen sich Fortschritte des Erkenntnisgewinns nur erzielen, wenn in kontrollierten pragmatischen Studien Methoden angewandt werden, bei denen der Einfluss der beabsichtigten Intervention (Therapie) mit jenem unbeabsichtigter Interventionen (Confounder) verglichen wird. Beispiele solcher Methoden sind das Propensity Score Matching und Strukturgleichungsmodelle. Die Entscheidung über die ideale Auswertungsmethode ist von den Bedingungen und den Variablen der Studie abhängig.

Aims: The Surviving Sepsis Campaign (SSC) guidelines aimed to reduce heterogeneity of conventional therapy and mortality. The present study was performed in septic shock to describe the adherence to the 2008 SSC guidelines, confounding factors, and limitations. Study Design: Prospective observational study. Place and Duration of Study: Clinic of Anaesthesiology, University Hospital Medical School, and Clinical Economics at the Institute of History, Philosophy and Ethics in Medicine, University of Ulm, between January 2008 and June 2009. Methodology: The adherence to 36 items of the 6-hour and 24-hour bundles of the 2008 SSC guidelines was investigated in 98 surgical patients with septic shock. Results: The adherence to the 36 items varied between 0% and 95%. Besides the categories “adherent“ and “nonadherent“, additional categories “partially adherent“, “notapplicable“ and “unknown“ were used. None of the single items alone was essential for survival. Patients with septic shock on admission (n=68) had significantly higher SOFA scores (degree of organ dysfunctions) compared to patients developing septic shock in the ICU (n = 30). Conclusion: As many confounders are limiting the adherence to complex guidelines, Research Article British Journal of Medicine & Medical Research, 3(1): 94-107, 2013 95 the complete adherence will hardly be possible in severe diseases such as septic shock. Our results suggest that efforts associated with early diagnosis and active encouragement outside the ICU are necessary to improve applicability and adherence to the SSC guidelines in patients with septic shock in order to reduce the time lag of diagnosis and treatment, which may be reached by focusing on few essential points.

Background and aims Liver resection (LR) and transplantation are the most reliable treatments for hepatocellular carcinoma (HCC). Aim was to compare different guidelines regarding indication for resection and transplantation because of HCC with and without underlying cirrhosis. Methods We compared the following guidelines published after 1 January 2010: American (American Association for the Study of Liver Diseases (AASLD)), Spanish (Sociedad Espanola de Oncologia Medica (SEOM)), European (European Association for the study of liver-European Organization for Research and Treatment of Cancer (EASL-EORTC) and European Society for Medical Oncology-European Society of Digestive Oncology (ESMO-ESDO)), Asian (Asian Pacific Association for the Study of Liver (APASL)), Japanese (Japan Society of Hepatology (JSH)), Italian (Associazione Italiana Oncologia Medica (AIOM)) and German (S3) guidelines. Results All guidelines recommend resection as therapy of choice in healthy liver. Guidelines based on the Barcelona Clinic Liver Cancer staging system recommend resection for single HCC

Clinical Economics emerged from the field of medical oncology where the need of balancing harm and benefit is most obvious. It is explained that the principle of complete economic analyses in health care include both non-monetary (values) and monetary dimensions (budgets). Including the perspectives of individual patients, of doctors and of managers are equally important when decisions have to be made. Clinical Economics offers solutions to five major challenges of health care assessment and provision.

The term "prevention" is used with several different meanings. Mistakes can be avoided by using different word for different contents. In addition to clear definitions the most frequent forms of bias have to be avoided. These forms are related to the five dimensions such as targets and endpoints as well as methods of screening, diagnostic, and finally treatment. Unless the appropriate items are selected in all five dimensions the results of the prevention strategy will not provide valid information.

Dear Editor, In April 2015, an article of Ferraresi et al. [1] was published, which stated that the use of red and near-infrared LEDT was effective in the prevention of muscle damage (CK) in professional volleyball players during official matches. We congratulate the authors for pioneering in investigating Breal world^ application of phototherapy in sports and would address some points discussed in our group, some of them against CONSORT statement [2]

Scientists and politicians in all health care systems have not yet been able to agree on a uniformly accepted definition of the benefit of pharmaceutical products. Even if we cannot solve the problem we may contribute to understand it. To this end, we have compiled the methods used in various scientific disciplines to describe benefit and built a theoretical framework for these methods. The framework includes the aims, the subject matter measured, and the risks of a measurement as well as a possible sequence for the application of the methods as part of the benefit assessment. It includes six steps. Each of these steps contributes specific information to the benefit assessment. Because it is impossible to apply all of these steps and methods under real world conditions a sensible selection has to be made on which methods to consider or disregard. We assume that this selection depends on the selected objectives and the selection of objectives depends on values such as justice or utility. Consequently we propose to address as a first step the discussion about values before objectives can be defined and appropriate tools can be selected.

Rationale, aims and objectives Having a quick, practical, educational tool designed for busy child-care professionals to check whether systematic reviews (SRs) contain valid information would help them regularly update their evidence-based knowledge and apply it to their patients. Continuing our annual workshop courses encouraging paediatric hospital professionals to use evidence-based information, in a preliminary study, we compared the commonly used Critical Appraisal Skill Programme (CASP) questionnaire for appraising overall internal validity in SRs with a new, practical tool designed to check internal validity quickly. Method During a course in 2010, two ‘teacher-brokers’ taught experienced paediatric hospital professionals to use and compare the CASP and the new practical tool to appraise a Cochrane SR on beclomethasone for asthma in children by assessing internal validity only from the two most weighted randomized controlled trials in the forest plot. At 15 days and 6 months, participants then answered questionnaires designed to assess qualitative data including feelings about working together, memorization and possibly provide feedback for Cochrane reviewers. Results Using the CASP, participants agreed that the Cochrane SR analysed contained overall valid results. Conversely, using the new quick tool, they found poor internal validity. Participants worked well together in a group, took less time to apply the new tool than the CASP (1 vs. 2.5 hours) and provided Cochrane feedback. Conclusions Our quick practical tool for teaching critical appraisal encourages busy child-care hospital professionals to work together, carefully check validity in SRs, apply the findings in clinical practice and provide useful feedback for Cochrane reviewers.

Clinical economics strives to support healthcare decisions by economic considerations. Making economic decisions does not mean saving costs but rather comparing the gained added value with the burden which has to be accepted. The necessary rules are offered in various disciplines, such as economy, epidemiology and ethics. Medical doctors have recognized these rules but are not applying them in daily clinical practice. This lacking orientation leads to preventable errors. Examples of these errors are shown for diagnosis, screening, prognosis and therapy. As these errors can be prevented by application of clinical economic principles the possible consequences for optimization of healthcare are discussed.

Aim Health care is no longer a national topic as the results of health care research as well as health care services are shared across countries and continents. The common feature in almost any of these countries is the perceived limitation of health care resources and the discussions about health care expenditures which strongly depend on the definition of health care values.

Background: Applying the principles of Evidence Based Health Care (EBHC) in an academic environment we became aware of important differences between medical students and the users of clinical research. The latter may be clinicians, educators, guideline developers, or industry managers. These users are adapted to the system and have some kind of conflict of interest: they are either biased by patients’ demands, by main stream thinking, by medical standards and/or by economic interests. All are under time pressure, want to avoid conflicts with their employer and the analysis of scientific reports may not really be their main focus. Medical students were not exposed to these confounders. Methods: Medical students under professional supervision completed critical assessments of more than 100 published studies. Their analyses were limited to identification of mistakes, bias and errors using a check list of potential weaknesses in design and conduct but included the feedback to the academic supervisors. Results: Medical students trained in Evidence Based Medicine are capable of identifying problems in clinical trials by the systematic application of an assessment checklist. Conclusion: In our approach we demonstrate that students can assist health care professionals and academic teachers with the assessment of clinical evidence. The premise of the approach is that the final appraisals, which involve consideration of clinical, practical and value issues, necessarily reside with the academic teachers, writers of guidelines or industry managers who constitute the active users of research.

Safety of healthcare is one of the most important values of patients. Public safety and security are important aspects to all, as demonstrated by the 2011 disaster in Japan. This comment describing 5 valences of safety and security may contribute to the necessary discussion about human values. These valences are related to system theory, intentionality, locus of control, situation andpersonality, and modeling capability. It is also suggested that different values such as safety/security, utility/benefit, and justice/equity may be structured by similar valences.

What's known on the subject? and What does the study add? Targeted agents have greatly changed the therapeutic landscape in RCC. A substantial number of trials have been published in recent years. The current review summarises and analyses the available data to date. OBJECTIVE • To estimate the effects of drugs with molecular targets on patients with advanced renal cell cancer (RCC). PATIENTS AND METHODS • MEDLINE, EMBASE, and the Cochrane Collaboration Library were systematically searched on-line through to June 2011 to identify eligible randomised trials. We also searched abstract reports from major oncology and urology meetings. • We included randomised trials that tested a targeted agent and reported at least one outcome by allocation on an intent-to-treat basis. Completeness of ascertainment and risk of bias were assessed. • Our primary outcome was progression-free survival (PFS). RESULTS • In all, 28 studies met our inclusion criteria and 10 were placebo-controlled. Two studies were too small to assess, and five early studies used nonspecific anti-angiogenic agents with poor activity. In all, 15 studies, in 5587 patients, tested anti-vascular epithelial growth factor (VEGF) agents: bevacizumab (BEV), sorafenib, sunitinib, pazopanib, tivozanib, or axitinib. Three studies, in 1147 patients, tested the mammalian target of rapamycin (mTOR) inhibitors, temsirolimus or everolimus. Two studies included epidermal growth factor receptor (EGFR) inhibitors, and one tested the combination of temsirolimus plus BEV. • In treatment-naive patients with mostly good–moderate prognostic risk, in separate trials oral sunitinib (one trial) and intravenous BEV plus subcutaneousinterferon-α (two trials) improved PFS compared with the previous standard of care interferon-α within randomised phase III trials. Sorafenib did not improve PFS over interferon-α in the first-line setting and the addition of cytokines did not improve sorafenib efficacy. In poor-risk patients, the mTOR inhibitor temsirolimus improved PFS and overall survival (OS). The studies of other VEGF inhibitors have used placebo controls no longer appropriate in this setting, although pazopanib is an approved option. • Several trials examined agents in the second-line setting. After cytokine therapy, sorafenib (one study) and pazopanib (one study) prolonged PFS over placebo. A preliminary report of the investigational VEGF receptorinhibitor axitinib gave superior PFS to sorafenib after either prior cytokine or prior sunitinib treatment. After cancer progression ≤6 months of sunitinib and/or sorafenib therapy, everolimusprolonged PFS. • OS was marginally improved in several studies. A more substantial effect on OS may have been diluted by crossover from control therapy to the investigational arm and/or by other anti-angiogenic agents after trial closure. Patient-reported outcomes were considered unreliable in trials without ‘blinding’. • A clear cell RCC (ccRCC) component was required for most trials, and information for non-ccRCCs is consequently limited CONCLUSIONS • Agents targeting VEGF and mTOR pathways improve PFS in both first-line and second-line settings. These treatments rarely yield complete responses and thus are not curative. • No placebo-controlled trial has reported a health-related quality of life benefit.

Die Finanzierung klinischer Studien durch die pharmazeutische Industrie ist international wie auch hier in Deutschland ein hinreichend diskutiertes Thema. Es bedarf keiner weiteren Bestatigung, dass die bekannten Unzulanglichkeiten inakzeptabel sind. Ebenso wenig ist aber zu diskutieren, dass die pharmazeutische Industrie und die medizinische Wissenschaft aufeinander angewiesen sind. Weder die Vermarktung der Industrieprodukte noch die Forschung und Lehre der klinischen Wissenschaftler wurde ohne diese Kooperation funktionieren. Deshalb benotigen alle Partner konsensfahige und zielfuhrende Vorschlage. Diese zu erarbeiten, ist das Ziel der vorliegenden Diskussion. Um diese Diskussion zu strukturieren, haben wir die folgenden Fragen angeschnitten: Ist den Ergebnissen von Studien, die durch die Industrie finanziert wurden, immer zu misstrauen? Dabei sollte bedacht werden, dass in Deutschland alle Studien, die zur Zulassung eines Arzneimittels fuhrten, durch die Industrie unterstutzt wurden. Sind wir uns daruber im Klaren, was durch die explizite und oft berechtigte Kritik erreicht werden soll? Was ist zu veranlassen, um eine hohere Validitat der publizierten Daten zu erreichen und wie konnten konsensfahige und zielfuhrende Vorschlage aussehen? Die Diskussion ware unvollstandig, wenn wir uns davor drucken, die entscheidende Frage zu beantworten, ob wir uns der Herausforderung stellen, die Forschung und Lehre mit Finanzierung durch die pharmazeutische Industrie durchzufuhren oder diese Art der Kooperation und Forderung ablehnen.