[Covid-19: Twin Method for Verifying Real-World Effectiveness Under Everyday Conditions]. / Covid-19: Twinmethode zum Nachweis der Real-World Effectiveness (RWE) unter Alltagsbedingungen.

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.

Recommendations for cancer screening would be different if we measured endpoints that are valid, reliable, specific, and important to patients.

BACKGROUND: 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. REVIEW: 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. SYNTHESIS: 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.

End-of-life perceptions among physicians in intensive care units managed by anesthesiologists in Germany: a survey about structure, current implementation and deficits.

BACKGROUND: Structural aspects and current practice about end-of-life (EOL) decisions in German intensive care units (ICUs) managed by anesthesiologists are unknown. A survey among intensive care anesthesiologists has been conducted to explore current practice, barriers and opinions on EOL decisions in ICU. METHODS: In November 2015, all members of the German Society of Anesthesiology and Intensive Care Medicine (DGAI) and the Association of German Anesthesiologists (BDA) were asked to participate in an online survey to rate the presence or absence and the importance of 50 items. Answers were grouped into three categories considering implementation and relevance: Category 1 reflects high implementation and high relevance, Category 2 low and low, and Category 3 low and high. RESULTS: Five-hundred and forty-one anesthesiologists responded. Only four items reached ≥90% agreement as being performed "yes, always" or "mostly", and 29 items were rated "very" or "more important". A profound discrepancy between current practice and attributed importance was revealed. Twenty-eight items attributed to Category 1, six to Category 2 and sixteen to Category 3. Items characterizing the most urgent need for improvement (Category 3) referred to patient outcome data, preparation of health care directives and interdisciplinary discussion, standard operating procedures, implementation of practical instructions and inclusion of nursing staff and families in the process. CONCLUSION: The present survey affirms an urgent need for improvement in EOL practice in German ICUs focusing on advanced care planning, distinct aspects of changing goals of care, implementation of standard operating procedures, continuing education and reporting of outcome data.

The analysis of factors affecting municipal employees' willingness to report to work during an influenza pandemic by means of the extended parallel process model (EPPM).

BACKGROUND: The management of pandemics with highly infectious diseases in modern urban habitats depends largely on the maintenance of public services. Understanding the factors that influence municipal employees' willingness to come to work during a pandemic is therefore a basic requirement for adequate public health preparedness. In this study the extended parallel process model (EPPM) is applied to investigate how the readiness of municipal employees to report to work during an influenza pandemic (IP) is affected by individual attitudes and environmental conditions. METHODS: 1.566 employees of a major German city participated in a cross-sectional online survey. The questions of the survey covered the dimensions of risk perception, role competence, self-efficacy, role importance, sense of duty, and willingness to report to work in the case of an IP. Data were analysed by means of path analyses. RESULTS: Data suggest that up to 20% of the public service workers were not willing to come to work during an IP. Willingness to report to work was increased by the perception of a high working role competence, a high assessment of role importance, high self-efficacy expectations, and a high sense of duty. Negative effects on willingness to report to work were identified as the perception of a high risk to become infected at work and the perceived risk to infect family members. The decomposition of direct and indirect effects provided important insights into the interrelationships between model variables. CONCLUSIONS: Measures to increase municipal workers' willingness to report to work in case of an infectious pandemic should include communication strategies to inform employees clearly about their particular tasks during such critical events and training exercises to increase their confidence in their competences and skills to fulfil these tasks.

Comparative effectiveness is the common denominator in health services research: experimental effects are promising, real-world effects are compelling.

BACKGROUND: Sir Archibald Cochrane and Sir Austin Bradford Hill requested 80 years ago answers to three questions (Can it work? Does it work? Is it worth it?) before a new intervention is implemented in day-to-day healthcare. A critical analysis of currently accepted answers identified a terminology conflict that inherits the risk of misleading interpretations and inappropriate decisions. CONTENT: For detection of the terminology problem and the development of the solutions was possible through three recommendations (the "Ulm heritage"): (1) Albert Einstein (*1879 in Ulm/Germany) predicted, "A problem cannot be solved with the way of thinking that caused it"; (2) The "hochschule für gestaltung ulm (Academy of Design, 1953-1968)" disseminated the rules of American designers and architects e.g., "Form Follows Function"; and (3) requested to "design not only individual but universally valid solutions with socio-political relevance". SUMMARY: Our data confirms the power of the FFF rule, the pros and cons of value judgments, the complexity of healthcare decisions, the difference between scientific statements and political decisions, and the effects of interprofessional collaboration. OUTLOOK: "Efficacy" offers promising "Proofs of Principle (PoP)" while "effectiveness" describes "Real-World Effectiveness (RWE)". That is why the results obtained are always more important than hypotheses.

Validity of the MAGIC study: sufficient for recommendations?

According to the recommendations of the German S3 guideline, perioperative chemotherapy is an integral part of the treatment concept for advanced gastric cancer. The leading trial which examined the effects of perioperative chemotherapy is the MAGIC study. An examination of the validity of this study with a standardized method revealed shortcomings in the six areas: design, protocol, selection of patients, randomization / homogeneity of patient groups, quality of the surgical care and the statistical evaluation. These shortcomings and their influence on the study results are described in this paper to reveal the importance of these effects for discussion in guidelines committees.

Visual AIDS for multimodal treatment options to support decision making of patients with colorectal cancer.

BACKGROUND: A variety of multimodal treatment options are available for colorectal cancer and many patients want to be involved in decisions about their therapies. However, their desire for autonomy is limited by lack of disease-specific knowledge. Visual aids may be helpful tools to present complex data in an easy-to-understand, graphic form to lay persons. The aim of the present study was to evaluate the treatment preferences of healthy persons and patients using visual aids depicting multimodal treatment options for colorectal cancer. METHODS: We designed visual aids for treatment scenarios based on four key studies concerning multimodal treatment of colorectal cancer. The visual aids were composed of diagrams depicting outcome parameters and side effects of two treatment options. They were presented to healthy persons (n = 265) and to patients with colorectal cancer (n = 102). RESULTS: Most patients and healthy persons could make immediate decisions after seeing the diagrams (range: 88%-100%). Patients (79%) chose the intensive-treatment option in the scenario with a clear survival benefit. In scenarios without survival benefit, all groups clearly preferred the milder treatment option (range: 78% - 90%). No preference was seen in the scenario depicting equally intense treatment options with different timing (neoadjuvant vs. adjuvant) but without survival benefit. CONCLUSIONS: Healthy persons' and patients' decisions using visual aids seem to be influenced by quality-of-life aspects rather than recurrence rates especially in situations without survival benefit. In the future visual aids may help to improve the management of patients with colorectal cancer.

Measuring Health-Related Quality of Life in Randomised Controlled Trials: Expected and Reported Results Do Not Match.

Purpose: 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.

Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials.

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.

Lessons learned from prevention programs: different endpoints should be used in secondary and tertiary prevention.

It is mandatory to compare cost and consequences of healthcare services if public support is requested. This request will apply to all healthcare services including prevention. As the demand for health care will always exceed the available resources, methods that make it possible to select the "best" programs for implementation have to be developed. The selection of the "best" programs is not easy because there exist so far no generally accepted quality criteria that can be used to identify the "best" prevention programs.Based on a model on structural and functional properties of a disease, it is concluded that the traditional outcomes of treatment and prevention may be useful for the evaluation of tertiary prevention programs, but not of secondary prevention programs. Neither the traditional endpoints of treatment studies nor traditional surrogate parameters are useful for the evaluation of secondary prevention programs.Using the assumptions of the model and a list of available data in secondary prevention programs we recommend to assess five indicators for description of the value of a secondary prevention program: quality of life, surrogates for life expectancy, the perspective of the assessor, the conditions of assessment, and finally the payment. As each of these five items offers two possible values prevention programs may be classified into 32 different groups.

Efficacy and effectiveness studies of depression are not well-differentiated in the literature: a systematic review.

BACKGROUND: In the literature on the treatment of depression, efficacy and effectiveness research have different purposes and should apply different research methodologies. OBJECTIVE: The 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 SELECTION: Studies indexed as efficacy AND 'real-world' AND depression or effectiveness AND 'real-world' AND depression in PubMed up to 18 May 2019. FINDINGS: 27 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. CONCLUSIONS: Efficacy 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.

Covid-19 pandemic lessons: uncritical communication of test results can induce more harm than benefit and raises questions on standardized quality criteria for communication and liability.

BACKGROUND: The 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. METHOD: The 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. RESULTS: The 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'. CONCLUSIONS: Communication of test results caused perceived anxiety but not perceived safety in 80% of the investigated tests. Medical tests - whether true or false - generate strong psychological messages. In the case of COVID-19 tests may induce more perceived anxiety than safety. Risk communication has to balance objective and subjective risks.

Preferences of diabetes patients and physicians: a feasibility study to identify the key indicators for appraisal of health care values.

BACKGROUND: Evidence-based medicine, the Institute of Medicine (IOM) and the German Institute for Quality and Efficiency in Health Care (IQWiG), support the inclusion of patients' preferences in health care decisions. In fact there are not many trials which include an assessment of patient's preferences. The aim of this study is to demonstrate that preferences of physicians and of patients can be assessed and that this information may be helpful for medical decision making. METHOD: One of the established methods for assessment of preferences is the conjoint analysis. Conjoint analysis, in combination with a computer assisted telephone interview (CATI), was used to collect data from 827 diabetes patients and 60 physicians, which describe the preferences expressed as levels of four factors in the management and outcome of the disease. The first factor described the main treatment effect (reduction of elevated HbA1c, improved well-being, absence of side effects, and no limitations of daily life). The second factor described the effect on the body weight (gain, no change, reduction). The third factor analyzed the mode of application (linked to meals or flexible application). The fourth factor addressed the type of product (original brand or generic product). Utility values were scaled and normalized in a way that the sum of utility points across all levels is equal to the number of attributes (factors) times 100. RESULTS: The preference weights confirm that the reduction of body weight is at least as important for patients--especially obese patients--and physicians as the reduction of an elevated HbA1c. Original products were preferred by patients while general practitioners preferred generic products. CONCLUSION: Using the example of diabetes, the difference between patients' and physicians' preferences can be assessed. The use of a conjoint analysis in combination with CATI seems to be an effective approach for generation of data which are needed for policy and medical decision making in health care.

Development of the Berlin Symptom Checklist Ovary (BSCL-O) for the measurement of quality of life of patients with primary and recurrent ovarian cancer: results of a phase I and II study.

GOALS OF WORK: Quality of life (Qol) represents a relevant end point in the clinical management of advanced ovarian cancer (AOC). However, there exist only a few specific instruments which have been designed for patients with ovarian cancer. The aim of this study was to develop a systematic checklist (Berlin Symptom Checklist Ovary (BSCL-O)) as an instrument of Qol for patients with AOC and to discriminate between the frequency and the importance of symptoms. PATIENTS AND METHODS: The main symptoms were identified in a phase I study via free interviews of five patients with ovarian cancer (OC) as well as five medical doctors, family dependent, and care workers. In the phase II study, the capability of BSCL-O was evaluated by questionnaire-guided interviews of 200 patients with primary OC, recurrent OC, metastasized breast cancer, and benign ovarian tumors. MAIN RESULTS: In phase I, 36 main symptoms were identified. In phase II, 7,200 answers from 98.5% of all patients were evaluable. Of the 36 symptoms of the BSCL-O, 23 revealed clinical relevance. There was a correlation of frequency and importance of symptoms (p < 0.05). The symptoms of the BSCL-O were deemed twice as strenuous in patients with recurrent OC. CONCLUSIONS: The BSCL-O can measure Qol of patients with OC. The BSCL-O is being validated in a phase III study.

The terminology conflict on efficacy and effectiveness in healthcare.

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.

Predictors of successful cancer prevention programs.

Finding the optimal use of health-care resources requires the reliable estimation of costs and consequences. Acquiring these estimates may not be difficult for some common treatments. More difficult is the optimization of resources in the area of diagnostics. Only a few attempts have been made to optimize the use of resources in the area of prevention. Several aspects have to be considered when optimizing the resources for prevention: (1) participation rates in structured prevention programs are low, (2), acquiring data on follow-up and outcomes is difficult, (3) there are concerns about the quality of information available to public, and (4), the public is often unaware of scientific assessments of prevention programs. As prevention programs are costly long-term projects, a strategy to select these programs according to possible predictors of success might be useful. The few analyses of cancer prevention in the literature have been directed towards the most common malignant diseases (as assessed by incidence) such as cancer of the breast, colon, lung and prostate. We argue that incidence is a poor marker for selecting secondary prevention programs. Incidence may be a misleading indicator for two reasons: incidence of disease does not predict efficiency of management or good health outcomes, and incidence does not separate clinically significant from non-significant disease. The traditional strategy is based on the assumption that more screening increases the chance of cure. We propose an alternative outcomes model that suggests better disease management justifies new prevention programs. Indicators for better disease management are effective and efficient treatments as well as high-quality screening (sensitivity and specificity) techniques and possibly "side-effects of prevention programs," which provide early signs of success to motivate the patient's participation, to keep up with the program and finally to succeed.