Dopamine D2 Receptor Occupancy Estimated From Plasma Concentrations of Four Different Antipsychotics and the Subjective Experience of Physical and Mental Well-Being in Schizophrenia: Results From the Randomized NeSSy Trial.

BACKGROUND: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). METHODS: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. RESULTS: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. CONCLUSIONS: Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

Disparate effects of first and second generation antipsychotics on cognition in schizophrenia - Findings from the randomized NeSSy trial.

Cognitive impairment represents a core feature of schizophrenia. Uncertainty about demonstrable benefits of available antipsychotics on cognition remains an important clinical question relevant to patients' quality of life. The aim of our multi-center, randomized, double-blind "Neuroleptic Strategy Study" (NeSSy) was to compare the effectiveness of selected antipsychotics, conventionally classified as second- (SGAs) (haloperidol, flupentixol) and first generation antipsychotics (FGAs) (aripiprazole, olanzapine, quetiapine), on quality of life in schizophrenia. The effects on cognitive deficits represented a secondary outcome. We used an innovative double randomization for assignment of treatment group, and followed the patients with a neurocognitive test-battery upon six and 24 weeks of treatment. Psychopathology and quality of life were assessed using CGI, PANSS and SF-36. Assessment of cognitive performance was conducted in 114 of the 136 randomized patients. The SGA group (N = 62) showed beneficial effects of small to moderate effect size on cognition during the initial six weeks of treatment (executive functions, verbal fluency) and at 24 weeks (executive functions, working memory). In contrast, the FGA group (N = 52) showed moderately improved executive function, but a decline in verbal fluency at six weeks, with significant declines of moderate to large effect size in executive function, verbal learning and memory, and verbal fluency at 24 weeks. Our study indicates that SGAs present an advantage over FGAs regarding cognitive function during a medium-term treatment for schizophrenia. The results further emphasize a distinction between progression to detrimental effects of FGAs with prolonged treatment in contrast to more persistent cognitive benefits with SGA treatment.

Effects of first-generation antipsychotics versus second-generation antipsychotics on quality of life in schizophrenia: a double-blind, randomised study.

BACKGROUND: Whether or not second-generation antipsychotics (SGAs) represent an advantage over first-generation antipsychotics (FGAs) in the treatment of schizophrenia is not certain. Effectiveness studies published in the past 10 years have not unequivocally confirmed the superiority of SGAs over FGAs. We aimed to compare quality of life in patients with schizophrenia on an FGA strategy with those on an SGA strategy. METHODS: In the multicentre, randomised, double-blind Neuroleptic Strategy Study (NeSSy), we recruited participants (aged 18-65 years) with schizophrenia (ICD-10: F20.X) who required treatment initiation or a change in treatment, from 14 psychiatric university hospitals and state hospitals in Germany. Double randomisation allowed for restricted selection of a treatment within each antipsychotic drug group (FGA or SGA) for an individual patient: first, patients were assigned with a random number table to two of six possible drug pairs, each pair consisting of an FGA (haloperidol [3-6 mg] or flupentixol [6-12 mg]) given orally and an SGA (aripiprazole [10-20 mg], olanzapine [10-20 mg], or quetiapine [400-800 mg]) given orally, and the investigator then selected which pair was best suited to the patient; a second, double-blind random assignment allocated either the FGA or the SGA from the investigator-chosen pair to the patient. Treatment duration was 24 weeks. Primary outcomes were change from baseline to week 24 in quality of life (SF-36) and clinical global impression (CGI-I), analysed in all randomly assigned patients who received at least one dose of the study drug. Safety was assessed in a safety set, consisting of all randomly assigned patients who received at least one dose of the study drug, coinciding with the set of the efficacy analyses. The study is registered with ClinicalTrials.gov, number NCT01164059; German Clinical Trials Register, number DRKS00000304; WHO ICTRP, number U1111-1112-9727; and EudraCT, number 2009-010966-47. FINDINGS: Between April 1, 2010, and May 31, 2013, 149 patients were randomly assigned, 69 to FGA treatment and 80 to SGA treatment. 136 patients received at least one dose of study drug (63 in the FGA group, 73 in the SGA group). Mean area under the curve (AUC) values of SF-36 were significantly higher in the SGA group than in the FGA group (85·1 [SD 14·7] vs 79·7 [17·3], p=0·0112). Mean AUC values for CGI-I scores decreased in both groups, but were not significantly different between the two groups (3·39 [SD 0·89] in the FGA group vs 3·26 [0·92] in the SGA group, p=0·3423). 30 (48%) of 63 patients given FGAs had at least one adverse event compared with 42 (57%) of 73 patients given an SGA (p=0·3019); the most common were nervous system disorders (18 [60%] of 30 in the FGA group vs 19 [45%] of 42 in the SGA group) and psychiatric disorders (ten [33%] vs 16 [38%]). One patient died after cessation of study drug (olanzapine), most likely as a result of an illicit drug overdose. The increase in body-mass index (BMI) was significantly higher in the SGA group than in the FGA group (p=0·0021 at week 6 and p=0·0041 at week 24). INTERPRETATION: Improvement of patient-reported quality of life was significantly higher in patients with schizophrenia given SGAs than in those given FGAs, when treatment selection was individualised. This advantage, however, has to be weighed against the potential metabolic adverse effects of some SGAs. FUNDING: German Federal Ministry of Education and Research.

[Adaptive licensing - a threat to patient safety?]. / Adaptive Licensing - Gefahr für Patienten?

In 2014, a pilot project of the European licensing authority EMA was launched to explore new ways to license medicinal products. The intention of this project is to open up gradual ("adaptive") licensing pathways, with pharmaceutical developing preparations gaining market authorization on the basis of clearly lower-level evidence of effectiveness and risk of damage than before. Their market authorization shall, initially, be restricted, for example, to subpopulations of patients or to selected indications. When new data from subsequent become available, the extension of the authorization shall follow in a stepwise manner. Data from investigations using less valid methodology shall also find consideration, such as, for example data from uncontrolled studies. The experience with accelerated market access, which is already being offered by several drug authorities, may give rise to concerns about the use of procedures that keep drugs with a negative benefit-risk relation for the patients in the market for many years - apart from the costs for the healthcare system. It is unacceptable that manufacturers will be exempt from (strict) liability for these adaptively licensed pharmaceuticals. If patients suffer damage from taking these medications, they cannot even expect material compensation.

Patient-oriented randomisation: A new trial design applied in the Neuroleptic Strategy Study.

BACKGROUND: The 'gold standard' for clinical studies is a randomised controlled trial usually comparing specific treatments. If the scientific study expands to strategy comparison with each strategy including various treatments, the research problems are increasingly complicated. The strategy debate in the psychiatric community is the starting point for the development of our new design. It is widely accepted that second-generation antipsychotics are the therapy of choice in the treatment of schizophrenia. However, their general superiority over first-generation antipsychotics could not be demonstrated in recent randomised controlled trials. Furthermore, we are becoming increasingly aware that the experimental conditions of randomised controlled trials, as in the European First Episode Schizophrenia Trial and Clinical Antipsychotic Trials of Intervention Effectiveness Phase 1 studies, may be inappropriate for psychiatric treatments. The high heterogeneity in the patient population produces discrepancies between daily clinical perception and randomised controlled trials results. The patient-oriented approach in the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study reflects everyday clinical practice. The results, however, are highly dependent on the physicians' preferences. The goal of the design described here is to take an intermediate path between randomised controlled trials and clinical studies such as Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, combining the advantages of both study types. METHODS: The idea is to randomise two treatment pairs each consisting of one first-generation antipsychotic and one second-generation antipsychotic in a first step and subsequently, to involve the investigators in deciding for a pair most appropriate to the patients' needs and then to randomise the allocation to one drug (first-generation antipsychotic or second-generation antipsychotic) of that chosen pair. This idea was first implemented in the clinical trial, the Neuroleptic Strategy Study, with a randomised design comparing efficacy and safety of two different strategies: either to use first-generation antipsychotics (haloperidol and flupentixol) or second-generation antipsychotics (olanzapine, aripiprazole and quetiapine) in patients suffering from schizophrenia. RESULTS: In the course of the Neuroleptic Strategy Study, feasibility of this design was demonstrated. All aspects of the new design were implemented: randomisation process, documentation of responses from investigators as well as patients and drug logistic experience. In implementing the design, furthermore, we could investigate its theoretical properties. The physicians' preferences for specific drugs used for the respective patients were analysed. CONCLUSION: The idea of patient-oriented randomisation can be generalised. In light of the heterogeneity and complexity of patient-drug interaction, this design should prove particularly useful.

Declaration and Handling of Conflicts of Interest in Guidelines: A Study of S1 Guidelines From German Specialist Societies From 2010-2013.

BACKGROUND: Authors' conflicts of interest may affect the content of medical guidelines. In April 2010, the Association of Scientific Medical Societies in Germany (AWMF) issued recommendations on how such conflicts of interest should be dealt with. Most AWMF guidelines are so-called S1 guidelines developed by informal consensus in a group of experts. We now present the first study to date on the management of conflicts of interest in S1 guidelines. METHODS: On 2 December 2013, we selected the guidelines that had appeared from 1 November 2010 to 1 November 2013 among the 449 current S1 guidelines on the AWMF website. We extracted information about conflicts of interest from the guideline texts, reports, and/or conflict of interest statements and evaluated this information descriptively. RESULTS: There were 234 S1 guidelines in this category, developed by a total of 2190 experts. For 7% (16/234) of the guidelines and 16% (354/2190) of the experts, no individual conflict of interest statement could be found. Where conflict of interest statements were available, conflicts of interest were often declared--in 98% (213/218) of the guidelines and by 85% (1565/1836) of the authors. The most common type of conflict of interest was membership in a specialist society or professional association (1571/1836, 86%). Half of the experts acknowledged a financial conflict of interest (911/1836, 50%). Conflicts of interest were more common among experts contributing to guidelines that mainly concerned treatment with drugs or other medical products than in guidelines that did not have an emphasis of this type (397/663, or 60%, versus 528/1173, or 45%). The conflicts of interest were assessed in 11% (25/234) of the guidelines, with practical consequences in a single case. CONCLUSION: Conflicts of interest are often declared in the S1 guidelines of the AWMF, but they are only rarely assessed by external evaluators. Clear rules should be issued for how experts' declared conflicts of interest should be acted upon, whether they are of a financial nature or not.

Metamizole (dipyrone)-associated agranulocytosis. An analysis of German spontaneous reports 1990-2012.

PURPOSE: In 1986, the risk of agranulocytosis prompted German authorities to restrict the indications for metamizole use. After an initial decline, prescriptions increased from <20 million defined daily doses in 1990 to >140 million in 2012. Concurrently, spontaneous reports of agranulocytosis increased from about 10 in 1990 to >50 in 2012. In this study, reports were analyzed to identify targets for risk minimization measures. METHODS: Reports of suspected metamizole-induced agranulocytosis (neutrophils < 0.5 × 10(9) cells/l) between 1990 and 2012 were identified in the German spontaneous reporting database. Cases for which original reporting documents were available were eligible for analysis. Patient characteristics, indication, clinical course, and outcome were assessed. RESULTS: One hundred sixty-one reports were analyzed. The mean age of the patients was 56.8 years (11-93) and 64.6 % were female. Off-label use was identified in about 25 % of cases. Neutrophils fell below 100/µl in 63 and intercurrent infections developed in 109 cases. Thirty-eight patients (23.6 %) died. In two thirds of the cases, agranulocytosis occurred within 6 weeks of permanent or intermittent metamizole treatment, in 30.5 % within 7 days, including 18 cases of immediate onset after the first or second administration. CONCLUSION: The reported cases show severe clinical courses and are, to some extent, a result of off-label use. Due to the absence of individual risk factors and presence of variable onset patterns, risk minimization measures should focus on restricting use to defined clinical situations and providing concise risk information for patients and healthcare professionals.

Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration.

BACKGROUND: Neovascular age-related macular degeneration (AMD) is the leading cause of legal blindness in elderly populations of industrialised countries. Bevacizumab (Avastin®) and ranibizumab (Lucentis®) are targeted biological drugs (a monoclonal antibody) that inhibit vascular endothelial growth factor, an angiogenic cytokine that promotes vascular leakage and growth, thereby preventing its pathological angiogenesis. Ranibizumab is approved for intravitreal use to treat neovascular AMD, while bevacizumab is approved for intravenous use as a cancer therapy. However, due to the biological similarity of the two drugs, bevacizumab is widely used off-label to treat neovascular AMD. OBJECTIVES: To assess the systemic safety of intravitreal bevacizumab (brand name Avastin®; Genentech/Roche) compared with intravitreal ranibizumab (brand name Lucentis®; Novartis/Genentech) in people with neovascular AMD. Primary outcomes were death and All serious systemic adverse events (All SSAEs), the latter as a composite outcome in accordance with the International Conference on Harmonisation Good Clinical Practice. Secondary outcomes examined specific SSAEs: fatal and non-fatal myocardial infarctions, strokes, arteriothrombotic events, serious infections, and events grouped in some Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOC). We assessed the safety at the longest available follow-up to a maximum of two years. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE and other online databases up to 27 March 2014. We also searched abstracts and clinical study presentations at meetings, trial registries, and contacted authors of included studies when we had questions. SELECTION CRITERIA: Randomised controlled trials (RCTs) directly comparing intravitreal bevacizumab (1.25 mg) and ranibizumab (0.5 mg) in people with neovascular AMD, regardless of publication status, drug dose, treatment regimen, or follow-up length, and whether the SSAEs of interest were reported in the trial report. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and assessed the risk of bias for each study. Three authors independently extracted data.We conducted random-effects meta-analyses for the primary and secondary outcomes. We planned a pre-specified analysis to explore deaths and All SSAEs at the one-year follow-up. MAIN RESULTS: We included data from nine studies (3665 participants), including six published (2745 participants) and three unpublished (920 participants) RCTs, none supported by industry. Three studies excluded participants at high cardiovascular risk, increasing clinical heterogeneity among studies. The studies were well designed, and we did not downgrade the quality of the evidence for any of the outcomes due to risk of bias. Although the estimated effects of bevacizumab and ranibizumab on our outcomes were similar, we downgraded the quality of the evidence due to imprecision.At the maximum follow-up (one or two years), the estimated risk ratio (RR) of death with bevacizumab compared with ranibizumab was 1.10 (95% confidence interval (CI) 0.78 to 1.57, P value = 0.59; eight studies, 3338 participants; moderate quality evidence). Based on the event rates in the studies, this gives a risk of death with ranibizumab of 3.4% and with bevacizumab of 3.7% (95% CI 2.7% to 5.3%).For All SSAEs, the estimated RR was 1.08 (95% CI 0.90 to 1.31, P value = 0.41; nine studies, 3665 participants; low quality evidence). Based on the event rates in the studies, this gives a risk of SSAEs of 22.2% with ranibizumab and with bevacizumab of 24% (95% CI 20% to 29.1%).For the secondary outcomes, we could not detect any difference between bevacizumab and ranibizumab, with the exception of gastrointestinal disorders MedDRA SOC where there was a higher risk with bevacizumab (RR 1.82; 95% CI 1.04 to 3.19, P value = 0.04; six studies, 3190 participants).Pre-specified analyses of deaths and All SSAEs at one-year follow-up did not substantially alter the findings of our review.Fixed-effect analysis for deaths did not substantially alter the findings of our review, but fixed-effect analysis of All SSAEs showed an increased risk for bevacizumab (RR 1.12; 95% CI 1.00 to 1.26, P value = 0.04; nine studies, 3665 participants): the meta-analysis was dominated by a single study (weight = 46.9%).The available evidence was sensitive to the exclusion of CATT or unpublished results. For All SSAEs, the exclusion of CATT moved the overall estimate towards no difference (RR 1.01; 95% CI 0.82 to 1.25, P value = 0.92), while the exclusion of LUCAS yielded a larger RR, with more SSAEs in the bevacizumab group, largely driven by CATT (RR 1.19; 95% CI 1.06 to 1.34, P value = 0.004). The exclusion of all unpublished studies produced a RR of 1.12 for death (95% CI 0.78 to 1.62, P value = 0.53) and a RR of 1.21 for SSAEs (95% CI 1.06 to 1.37, P value = 0.004), indicating a higher risk of SSAEs in those assigned to bevacizumab than ranibizumab. AUTHORS' CONCLUSIONS: This systematic review of non-industry sponsored RCTs could not determine a difference between intravitreal bevacizumab and ranibizumab for deaths, All SSAEs, or specific subsets of SSAEs in the first two years of treatment, with the exception of gastrointestinal disorders. The current evidence is imprecise and might vary across levels of patient risks, but overall suggests that if a difference exists, it is likely to be small. Health policies for the utilisation of ranibizumab instead of bevacizumab as a routine intervention for neovascular AMD for reasons of systemic safety are not sustained by evidence. The main results and quality of evidence should be verified once all trials are fully published.

Does the pharmaceutical industry influence guidelines?: two examples from Germany.

BACKGROUND: The recommendations in clinical guidelines are based on clinical trial findings and expert opinion. The influence of drug companies on these two factors is illustrated with two examples. METHODS: A judicially ordered expert review revealed that the market authorization holder (MAH) of gabapentin manipulated study data. Gabapentin was, therefore, chosen as an example for this article to analyze whether manipulated data serve as a basis for recommendations in German clinical guidelines. A search was carried out for manipulated publications on gabapentin that found their way into guidelines published by the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). To analyze the possible effects of financial ties between guideline authors and drug companies, the S3 guideline on the treatment of psoriasis vulgaris with efalizumab was compared with guidelines whose authors had no conflicts of interest. One of the authors of this article had noted variable prescribing practices for psoriasis among dermatologists while carrying out an economic assessment for a German state Association of Statutory Health Insurance Physicians. RESULTS: The data that had been manipulated by the MAH of gabapentin served as a basis for recommendations to prescribe gabapentin in guidelines that were published by the AWMF. Efalizumab was judged more favorably in the S3 guideline than in a guideline issued by the National Institute of Health and Care Excellence: for example, the evidence for it was judged as good, the use of efalizumab for induction and combination therapy in psoriasis vulgaris was recommended, and efalizumab was said to improve patients' health-related quality of life. CONCLUSION: Public access to all trial data must be ensured so that independent evaluations are possible. We take the view that the responsibility for creating guidelines should be borne by authors and organizations that do not have any conflicts of interest.

Pathway-controlled fast-track rehabilitation after total knee arthroplasty: a randomized prospective clinical study evaluating the recovery pattern, drug consumption, and length of stay.

PURPOSE: To investigate fast-track rehabilitation concept in terms of a measurable effect on the early recovery after total knee arthroplasty (TKA). METHODS: This was an open, randomized, prospective clinical study, comparing the fast-track rehabilitation--a pathway-controlled early recovery program (Joint Care(®))--with standard postoperative rehabilitation care, after TKA. Overall, 147 patients had TKA (N = 74 fast-track rehabilitation, N = 73 standard rehabilitation). The fast-track rehabilitation patients received a group therapy, early mobilization (same day as surgery) and 1:1 physiotherapy (2 h/day). Patient monitoring occurred over 3 months (1 pre- and 4 post-operative visits). The standard rehabilitation group received individual postoperative care according to the existing protocol, with 1:1 physiotherapy (1 h/day). The cumulative American Knee Society Score (AKSS) was the primary evaluation variable, used to detect changes in joint function and perception of pain. The secondary evaluation variables were WOMAC index score, analgesic drug consumption, length of stay (LOS), and safety. RESULTS: After TKA, patients in the fast-track rehabilitation group showed enhanced recovery compared with the standard rehabilitation group, as based on the differences between the groups for the cumulative AKSS (p = 0.0003), WOMAC index score (<0.0001), reduced intake of concomitant analgesic drugs, reduced LOS (6.75 vs. 13.20 days, p < 0001), and lower number of adverse events. CONCLUSION: For TKA, implementation of pathway-controlled fast-track rehabilitation is achievable and beneficial as based on the AKSS and WOMAC score, reduced intake of analgesic drugs, and reduced LOS.

EVITA: a tool for the early evaluation of pharmaceutical innovations with regard to therapeutic advantage.

BACKGROUND: New drugs are generally claimed to represent a therapeutic innovation. However, scientific evidence of a substantial clinical advantage is often lacking. This may be the result of using inadequate control groups or surrogate outcomes only in the clinical trials. In view of this, EVITA was developed as a user-friendly transparent tool for the early evaluation of the additional therapeutic value of a new drug. METHODS: EVITA does not evaluate a new compound per se but in an approved indication in comparison with existing therapeutic strategies. Placebo as a comparator is accepted only in the absence of an established therapy or if employed in an add-on strategy on top. The evaluation attributes rating points to the drug in question, taking into consideration both therapeutic benefit and risk profile. The compound scores positive points for superiority in efficiency and/or adverse effects as demonstrated in randomized controlled trials (RCTs), whilst negative points are awarded for inferiority and/or an unfavorable risk profile. The evaluation follows an algorithm considering the clinical relevance of the outcomes, the strength of the therapeutic effect and the number of RCTs performed. Categories for therapeutic aim and disease severity, although essential parts of the EVITA assessment, are attributed but do not influence the EVITA score which is presented as a color-coded bar graph. In case the available data were unsuitable for an EVITA calculation, a traffic-type yield sign is assigned instead to criticize such practice. The results are presented online http://www.evita-report.de together with all RCTs considered as well as the reasons for excluding a given RCT from the evaluation. This allows for immediate revision in response to justified criticism and simplifies the inclusion of new data. RESULTS: As examples, four compounds which received approval within the last years were evaluated for one of their clinical indications: lenalidomide, pioglitazone, bupropion and zoledronic acid. Only the first achieved an EVITA score above zero indicating therapeutic advantage. CONCLUSIONS: The strength of EVITA appears to lie in its speedy assessment of the potential therapeutic advantage of a new drug for a given indication. At the same time, this approach draws attention to the typical deficits of data used for drug approval. EVITA is not intended to replace classical health technology assessment reports but rather serves as a screening tool in the sense of horizon scanning.

Off-label use of prescription drugs in childhood and adolescence: an analysis of prescription patterns in Germany.

BACKGROUND: Not all drugs prescribed for children and adolescents are certified for use in these age groups. The present study describes the extent of off-label prescriptions in the outpatient sector and identifies deficits in the quality of product information. METHODS: This analysis is based on patient-specific but pseudonymized drug prescription data for approximately 289,000 0- to 16-year-old members of the Gmünder Ersatzkasse, a German statutory health insurance provider, in the year 2002. For each substance prescribed, information regarding the youngest certified age group was derived from the product data. RESULTS: Of the 1,429,981 prescribed drug packages (726 active substances), 87.4% (66.1% of active substances) were prescribed in accordance with their license and 3.2% (15.7% of active substances) were prescribed off-label. For 9.4% of prescriptions (18.2% of active substances) the licensing status could not be established. For neonates and infants the proportion of licensed prescriptions was below average, at 42.5% and 82.8% of the prescribed packages (20.0% and 38.6% of active substances) respectively. After infancy, prescriptions were predominantly in accordance with licensed use. Deficits were seen in the indication groups "alimentary tract and metabolism," "respiratory system," "dermatologicals," and "sensory organs." CONCLUSIONS: The methodology enables characterization of off-label prescription and identification of fields where further research is needed. With regard to the EU regulation on medicinal products for pediatric use, this could assume increasing importance and contribute to the development of appropriate and safe medicines for children.

[Off-label use of drugs in paediatrics causes uncertainty]. / Unsicherheit in der Pädiatrie durch Off-label-Use von Arzneimitteln.

The off-label use of drugs in paediatrics is a common practice casting doubts on the adequate safety of drug therapy. Regulatory initiatives of European and national legislators aim to address this paucity of clinical drug trials in paediatrics through clarifying regulations and incentives in pharmaceutical law, thereby promoting an increase in the approval of paediatric drugs, the improvement of drug and thus treatment safety. This paper describes the present situation in paediatrics and the legal status of off-label use in pharmaceutical law, medical malpractice law and statutory health insurance law.

An illicit love affair during the Third Reich: who is my grandfather?

More than 60 years after an illicit love affair had occurred between Erika H, wife of a Wehrmacht soldier, and a Polish slave worker during World War II, we could clarify the blood relationships of her daughter Uta. When Erika H had become pregnant both of the men could have fathered the child. Erika H was found guilty of fraternization and imprisoned at Ravensbrück concentration camp. She gave birth to Uta and died there in 1944. Uta survived the war as did Erika's husband Gustav, who accepted Uta as his child. Blood samples from family members were taken and DNA extracted. A panel of 16 short tandem repeat (STR) loci were amplified and separated by capillary electrophoresis and the likelihoods calculated using the MLINK software. The combined genotypes yielded a cumulative likelihood ratio of over 200,000 against paternity of Gustav H. This case serves to illustrate the utility of STR profiles for complex deficiency kinship analysis.

Hospitalization rates of generic metoprolol compared with the original beta-blocker in an epidemiological database study.

PURPOSE: A less favourable galenic profile of generic formulations of the beta-blocker metoprolol raised the concern of a higher risk for serious cardiovascular (CV) events. We assessed hospital admission rates for CV diseases and prescription prevalences of various drugs using claims data of statutory health insurances (SHIs) to compare the incidence of serious CV events among users of original and generic metoprolol. Index events included hospitalization due to myocardial infarction, hypertensive crisis and stroke. METHODS: Data files of three SHIs were linked with dispensing data of drug prescriptions from each pharmacy's electronic data processing centre on an individual basis. Incidences of hospital admissions among patients receiving original metoprolol and among patients treated with the generic equivalent were compared by logistic regression, stratified for Bremen and the rest of Northern Germany. Risk estimates and confidence intervals were adjusted for confounders. RESULTS: A total of 49,673 patients receiving metoprolol were identified within a cohort of 3,649,285 insurance members. While the crude analysis revealed a higher risk for index events in patients receiving the generic drug (Bremen: RR 1.45; Northern Germany: RR 1.14), no elevated risk remained after confounder adjustment (Bremen: OR 1.06; Northern Germany: OR 1.04). Among co-morbid conditions considered as confounders, a previous CV event and an elevated thromboembolic risk exerted the strongest effect on index events. CONCLUSIONS: SHI data are a valuable source for pharmacoepidemiology and health services research in Germany. Incidence rates of serious CV events did not reveal any noticeable differences between the original and the generic group after confounder adjustment.