A patient-centred web-based adverse drug reaction reporting system identifies not yet labelled potential safety issues.

PURPOSE: Reporting of adverse drug reactions (ADRs) by patients is essential for a comprehensive risk-benefit evaluation of drugs after marketing, but only few data are available regarding patient-centred web-based ADR reporting systems. Hence, we aimed to analyze ADRs reported by patients with a particular emphasis on novel drugs and serious ADRs not yet labelled in the respective summary of product characteristics (SPC). METHODS: All ADR reports received by a web-based, patient-centred platform ( www.nebenwirkungen.de ) between April 1, 2019, and September 1, 2020, were descriptively analyzed. ADRs and drugs were coded automatically according to MedDRA and ATC classification system. SPC labelling of reported ADRs for novel drugs marketed since 2015 was checked manually. RESULTS: In total, 13,515 patient reports including 29,529 ADRs were received during the study period (serious ADRs [SADRs] n = 1,318; 4.5%). Women were affected in more than two-thirds of ADR reports. The most common patient-reported ADRs were nausea, dizziness and headache, whereas arrhythmia, intestinal obstruction and erectile dysfunction were the most frequent SADRs. Ciprofloxacin, levothyroxine and venlafaxine were the compounds most frequently suspected for causing both ADRs and SADRs. Regarding novel compounds, 289 reports including 739 ADRs were received (mainly fatigue, headache and myalgia). Three hundred thirty-one (44.8%) out of those ADRs were not yet labelled in the respective SPC, whereof twelve were SADRs. CONCLUSION: The majority of patient-reported ADRs were non-serious. However, a relevant number of non-labelled even serious ADRs was reported for novel compounds by patients. Despite well-known limitations of patient-reported ADRs, this web-based ADR reporting system contributes to the identification of new ADRs and thus can help to improve patients' safety complementing other pharmacovigilance instruments.

Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.

BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce. METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted. RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)). CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).

Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction.

PURPOSE: Results from observational studies on inhaled long-acting beta-2-agonists (LABA) and acute myocardial infarction (AMI) risk are conflicting, presumably due to variation in methodology. We aimed to evaluate the impact of applying a common study protocol on consistency of results in three databases. METHODS: In the primary analysis, we included patients from two GP databases (Dutch-Mondriaan, UK-CPRD GOLD) with a diagnosis of asthma and/or COPD and at least one inhaled LABA or a "non-LABA inhaled bronchodilator medication" (short-acting beta-2-agonist or short-/long-acting muscarinic antagonist) prescription between 2002 and 2009. A claims database (USA-Clinformatics) was used for replication. LABA use was divided into current, recent (first 91 days following the end of a treatment episode), and past use (after more than 91 days following the end of a treatment episode). Adjusted hazard ratios (AMI-aHR) and 95 % confidence intervals (95 % CI) were estimated using time-dependent multivariable Cox regression models stratified by recorded diagnoses (asthma, COPD, or both asthma and COPD). RESULTS: For asthma or COPD patients, no statistically significant AMI-aHRs (age- and sex-adjusted) were found in the primary analysis. For patients with both diagnoses, a decreased AMI-aHR was found for current vs. recent LABA use in the CPRD GOLD (0.78; 95 % CI 0.68-0.90) and in Mondriaan (0.55; 95 % CI 0.28-1.08), too. The replication study yielded similar results. Adjusting for concomitant medication use and comorbidities, in addition to age and sex, had little impact on the results. CONCLUSIONS: By using a common protocol, we observed similar results in the primary analysis performed in two GP databases and in the replication study in a claims database. Regarding differences between databases, a common protocol facilitates interpreting results due to minimized methodological variations. However, results of multinational comparative observational studies might be affected by bias not fully addressed by a common protocol.

Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV.

Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.

Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia.

In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. 'Death due to CML' was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate- and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long-term antileukemic efficacy and risk-adapted treatment.

Seasonal changes in prescribing of long-acting beta-2-agonists-containing drugs.

BACKGROUND: For patients with asthma, COPD, or asthma-COPD overlap syndrome (ACOS), inter-country comparisons of seasonal changes in drug prescriptions are scarce or missing. Hence, we aimed to compare seasonal changes in prescription rates of long-acting beta-2-agonist (LABA) in four European countries. METHODS: A common study protocol was applied to six health care databases (Germany, Spain, the Netherlands (2), and the UK (2)) to calculate age- and sex-standardized point prevalence rates (PPRs) of LABA-containing prescriptions by the 1st of March, June, September, and December of each year during the study period 2002-2009. Seasonal variation of PPRs was quantified using seasonal indexes (SIs; based on the ratio-to-moving-average-method) and SIs averaged over the study period (aSI) stratified by sex, age, and indication (asthma, COPD, or ACOS). RESULTS: There was a moderate seasonal change in LABA-containing prescriptions which was more pronounced in asthma or COPD patients compared to ACOS patients. For asthma and ACOS patients, highest seasonal variation was found for patients living in Spain (aSI: 87.3-110.7, aSI: 93.2-103.1) whereas for COPD highest seasonal variation was revealed for the NPCRD database (the Netherlands) (aSI: 92.2-105.6). Regarding age and sex, highest seasonal variation was found in Spanish boys under 10 years of age having a diagnosis of asthma. CONCLUSIONS: By applying a common analysis in six databases, we could observe moderate overall seasonal changes in LABA-containing prescription rates in patients with asthma, COPD, or ACOS.

The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries.

This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.

Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV.

Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% major molecular remission and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.

Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib.

UNLABELLED: Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection. RESULTS: (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.

Erythropoietin-induced treatment costs in patients suffering from renal anemia - a comparison between biosimilar and originator drugs.

OBJECTIVES: Renal anemia is a serious concern for morbidity and lower quality-of-life of patients suffering from chronic kidney disease resulting in a high economic burden when administering erythropoiesis-stimulating agents (ESAs). The aim of this study was to estimate erythropoietin-induced treatment costs in patients suffering from renal anemia undergoing dialysis treated with originator or biosimilar drugs. METHODS: A retrospective analysis was undertaken of ESA-related pharmacotherapy between January 1, 2008 and December 31, 2010 based on treatment and pharmacy claims data of 16,895 dialysis patients contained in the database of the Association of Statutory Health Insurance Physicians, Bavaria. All patients received an ESA treatment (ATC code B03XA) and chronic maintenance hemodialysis due to chronic kidney disease stage 5. RESULTS: Total drug expenditures for ESA-originators and biosimilars amounted to € 78.447 million for the 3-year study period. In hemodialysis patients cumulative defined daily doses (DDDs) were 7,727,782.14. Mean costs per DDD were € 10.79 (originators) and € 8.56 (biosimilars). A biosimilar substitution quota of 50% provides a savings potential of € 6.14 million [range € 3.07-9.22 million (25-75% quota)]. CONCLUSION: A more common biosimilar prescription in renal anemia patients suffering from chronic kidney disease provides a noteworthy economic savings potential.

In-hospital fall-risk screening in 4,735 geriatric patients from the LUCAS project.

OBJECTIVES: In-hospital falls in older patients are frequent, but the identification of patients at risk of falling is challenging. Aim of this study was to improve the identification of high-risk patients. Therefore, a simplified screening-tool was developed, validated, and compared to the STRATIFY predictive accuracy. DESIGN: Retrospective analysis of 4,735 patients; evaluation of predictive accuracy of STRATIFY and its single risk factors, as well as age, gender and psychotropic medication; splitting the dataset into a learning and a validation sample for modelling fall-risk screening and independent, temporal validation. SETTING: Geriatric clinic at an academic teaching hospital in Hamburg, Germany. PARTICIPANTS: 4,735 hospitalised patients ≥65 years. MEASUREMENTS: Sensitivity, specificity, positive and negative predictive value, Odds Ratios, Youden-Index and the rates of falls and fallers were calculated. RESULTS: There were 10.7% fallers, and the fall rate was 7.9/1,000 hospital days. In the learning sample, mental alteration (OR 2.9), fall history (OR 2.1), and insecure mobility (Barthel-Index items 'transfer' + 'walking' score = 5, 10 or 15) (OR 2.3) had the most strongest association to falls. The LUCAS Fall-Risk Screening uses these risk factors, and patients with ≥2 risk factors contributed to the high-risk group (30.9%). In the validation sample, STRATIFY SENS was 56.8, SPEC 59.6, PPV 13.5 and NPV 92.6 vs. LUCAS Fall-Risk Screening was SENS 46.0, SPEC 71.1, PPV 14.9 and NPV 92.3. CONCLUSIONS: Both the STRATIFY and the LUCAS Fall-Risk Screening showed comparable results in defining a high-risk group. Impaired mobility and cognitive status were closely associated to falls. The results do underscore the importance of functional status as essential fall-risk factor in older hospitalised patients.

Lenalidomide does not increase AML progression risk in RBC transfusion-dependent patients with Low- or Intermediate-1-risk MDS with del(5q): a comparative analysis.

Data comparing long-term outcomes in lenalidomide-treated and untreated patients with myelodysplastic syndromes (MDS) with del(5q) are limited. We evaluated clinical outcomes of 295 lenalidomide-treated patients from two clinical trials (MDS-003 and MDS-004) and 125 untreated red blood cell (RBC) transfusion-dependent patients with del(5q) Low- or Intermediate-1 (Int-1)-risk MDS from a large multicenter registry. Risk factors for acute myeloid leukemia (AML) progression and mortality were assessed using Cox proportional hazards models with left truncation to adjust for study entry differences between cohorts. Baseline characteristics were well balanced across cohorts, except for a higher RBC transfusion burden in lenalidomide-treated patients (median, 6 vs 2 units/8 weeks). Median follow-up was 4.3 years from first dose for lenalidomide-treated patients and 4.6 years from diagnosis for untreated patients. Two-year cumulative AML progression incidences were 6.9% (95% confidence interval (CI): 3.3-13.9) and 12.1% (95% CI: 7.0-20.3) and 2-year overall survival (OS) probabilities were 89.9% (95% CI: 84.1-96.0) and 74.4% (95% CI: 66.1-83.7), respectively. AML progression risk was similar in both cohorts (hazard ratio (HR) 0.969, P=0.930); however, lenalidomide treatment was associated with significant improvement in survival (HR 0.597, P=0.012), after adjusting for all other covariates. In conclusion, lenalidomide treatment does not increase AML progression risk, but instead confers a possible survival benefit in RBC transfusion-dependent patients with del(5q) Low- or Int-1-risk MDS.

Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML).

In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels >10% according to the international scale (BCR-ABL(IS)) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with >1-10% BCR-ABL(IS) (41% of pts; 5-year OS: 94%; P=0.012) and from a group with ≤1% BCR-ABL(IS) (31% of pts; 5-year OS: 97%; P=0.004). Cytogenetics identified high-risk pts by >35% Philadelphia chromosome-positive metaphases (Ph+, 27% of pts; 5-year OS: 87%) compared with ≤35% Ph+ (73% of pts; 5-year OS: 95%; P=0.036). At 6 months, >1% BCR-ABL(IS) (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with ≤1% (63% of pts; 5-year OS: 97%; P<0.001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks.

Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): a multicenter study.

Myelodysplastic syndromes (MDS) with del(5q) are considered to have a benign course of the disease. In order to address the issue of the propensity of those patients to progress to acute myeloid leukemia (AML), data on 381 untreated patients with MDS and del(5q) characterized by low or intermediate I International Prognostic Scoring System (IPSS) risk score were collected from nine centers and registries. Median survival of the entire group was 74 months. Transfusion-dependent patients had a median survival of 44 months vs 97 months for transfusion-independent patients (P<0.0001). Transfusion need at diagnosis was the most important patient characteristic for survival. Of the 381 patients, 48 (12.6%) progressed to AML. The cumulative progression rate calculated using the Kaplan-Meier method was 4.9% at 2 years and 17.6% at 5 years. Factors associated with the risk of AML transformation were high-risk World Health Organization adapted Prognostic Scoring System (WPSS) score, marrow blast count >5% and red-cell transfusion dependency at diagnosis. In conclusion, patients with MDS and del(5q) are facing a considerable risk of AML transformation. More detailed cytogenetic and molecular studies may help to identify the patients at risk of progression.

[Hospital admission due to adverse drug events (ADE): an analysis of German routine hospital data of 2006]. / Stationäre Aufnahmen wegen unerwünschter Arzneimittelereignisse (UAE): Analyse der DRG-Statistik 2006.

BACKGROUND: In developed countries 1-5% of all hospital admissions are due to adverse drug events (ADE). An ADE is defined as an injury resulting from medical intervention related to a drug. The established reporting systems and study designs only capture selective data. The objective of the current analysis was to evaluate the rate, distribution and correlations of ADE related admissions by using German routine data. METHODS: ADEs were identified by an array of 502 specified codes of the ICD-10-GM. The evaluation included only verified codes and was carried out by remote queries of the German DRG-Statistics 2006. Hospital admission due to an ADE was identified via the primary diagnosis. RESULTS: Of all hospital admissions 0.92% were revealed to be certainly caused by an adverse drug event. The average age between affected and non-affected was nearly identical for women 53.48 vs. 53.67 years, for men it was reduced by 4 years (48.38 years). The average hospital stay was lower for cases with an ADE, being reduced by 1.3 days for women (6.26 days vs. 7.55 days) and 1.5 days for men (5.91 days vs. 7.42 days). While mortality with an odds ratio (OR) of 0.59 (95% CI 0.57-0.62) was lower in ADE cases, the rate of emergency admissions due to ADE was increased, the OR being 3.10 (95% CI 3.07-3.13). The wards with excess rates of ADE cases were internal medicine, paediatrics, dermatology, intensive care and neurology. CONCLUSIONS: Younger age, reduced hospital stay and lower mortality of ADE cases are contrary to findings in the relevant literature. The DRG-Statistics also comprise populations which often are excluded in established study designs, in particular, children and cases due to medication errors, overdose, poisoning and allergic reactions. As these cases respond easily to prevention and are of significant interest to pharmacovigilance, the use of routine data is valuable for more intense research of ADE.

The LUCAS* consortium: objectives of interdisciplinary research on selected aspects of ageing and health care for older people in an urban community.

BACKGROUND: Decline in functional competence is a major determinant of older persons' needs, the development of dependency, use of care, clinical outcome and mortality. The interactions between rising life expectancy and changes in morbidity and disability warrant interdisciplinary research on functional disability, health promotion and prevention. The LUCAS (Longitudinal Urban Cohort Ageing Study) research consortium was established to study particular aspects of functional competence, its changes with ageing, to detect preclinical signs of functional decline, and to address questions on how to maintain functional competence and to prevent adverse outcome. The questions originate from problems encountered in practical health care provision in different settings, i.e. community, hospital and nursing home. METHODS: The subprojects apply a longitudinal cohort follow-up study, an embedded randomised controlled intervention, cross-sectional comparative, and prospective intervention studies. CONCLUSION: The results will provide instruments to screen for preclinical signs of functional decline and concrete recommendations to sustain independence and prevent adverse outcomes in older age in daily practice.

Recommendations to meet statistical challenges arising from endpoints beyond overall survival in clinical trials on chronic myeloid leukemia.

The aim of this work was to provide guidelines for appropriate statistical analyses regarding most common endpoints in clinical trials on chronic myeloid leukemia: hematologic, cytogenetic and molecular results, failure-free and event-free survival, and progression-free and overall survival. The reasons for the specified recommendations are explained and important issues are outlined by comprehensive examples. Particular attention is paid to the warning of the application of suboptimal methods that may lead to seriously biased results and conclusions. In the presence of a competing risk like death, Kaplan-Meier analysis should not be applied for time-to-remission endpoints. The appropriate method to estimate the probabilities of a time-to-remission endpoint is the calculation of its cumulative incidence function. However, the exact date of remission is hardly known. Detection of remission depends strongly on evaluation frequencies. Complex composite endpoints comprising many events with considerably heterogeneous severity imply difficulties with interpretation. Time-to-remission and complex composite endpoints are not recommended for primary judgment on efficacy. It is rather advisable to investigate remission status at a fixed time point as a primary endpoint, followed by progression-free and overall survival. For patients with the intended remission success at the time point of interest, relapse-free survival provides an additional primary outcome.