Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data.

OBJECTIVE: To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes. DESIGN: Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data. DATA SOURCES: Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks. RESULTS: 45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included. CONCLUSIONS: For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.

Risk-taking propensity and (un)healthy behavior in Germany.

BACKGROUND: Earlier research in South Africa (Szrek et al., 2012) confirmed the one-item Dohmen measure (Dohmen et al., 2011) to be a significant predictor of risky health behavior. METHODS: The present study investigated the relationship of the Dohmen measure with other measures of risk-taking propensity (e.g., Domain-Specific Risk-Taking scale), and its predictive power for smoking, problematic drinking, problematic car driving, and problematic sexual behavior, in a sample of 63 patients of psychiatric clinics and 102 healthy participants in Germany. RESULTS: The Dohmen measure was significantly positively related to other involved instruments. It served as predictor of two of the four investigated risky health activities (i.e., smoking, problematic drinking). CONCLUSIONS: The Dohmen measure seems to be a valid and time efficient instrument to assess general risk-taking propensity, as well as specific propensity for smoking and problematic drinking in Germany.

Inactivation kinetics of invertase in honey and honey-glucose syrup formulations: effects of temperature and water activity.

BACKGROUND: The high viscosity and stickiness of honey in its natural state causes handling difficulties, therefore the demand for honey powder is continuously increasing. Powder preparation has to be performed gently because of the thermo- and oxidation- sensitive nature of honey. The aim of this study was to determine the degradation of invertase during drying as an indirect measure of the retention of valuable honey nutrients. RESULTS: The reaction kinetics were estimated in polyfloral honey and honey-glucose syrup (GS) formulation and the impact of temperature (40-70°C) and water activity (aw 0.23-0.81) was established. The honey-GS formulation (55:45 w/w) was intended for the preparation of high-grade honey powders using the vacuum-drying method. Invertase inactivation at temperatures below 60°C followed first-order kinetics. At 60°C high dilution (aw 0.81) and at 70°C, heterogeneous inactivation behaviour was observed. The best fit of invertase heterogeneous inactivation kinetic was achieved with the Cerf two-fraction model. The GS addition showed a stabilizing effect on invertase during thermal degradation. CONCLUSION: The data on invertase inactivation gathered here can be utilized to select optimal parameters for honey vacuum-drying and other thermal processes in order to achieve maximum invertase retention. © 2016 Society of Chemical Industry.

Information on new drugs at market entry: retrospective analysis of health technology assessment reports versus regulatory reports, journal publications, and registry reports.

BACKGROUND: When a new drug becomes available, patients and doctors require information on its benefits and harms. In 2011, Germany introduced the early benefit assessment of new drugs through the act on the reform of the market for medicinal products (AMNOG). At market entry, the pharmaceutical company responsible must submit a standardised dossier containing all available evidence of the drug's added benefit over an appropriate comparator treatment. The added benefit is mainly determined using patient relevant outcomes. The "dossier assessment" is generally performed by the Institute for Quality and Efficiency in Health Care (IQWiG) and then published online. It contains all relevant study information, including data from unpublished clinical study reports contained in the dossiers. The dossier assessment refers to the patient population for which the new drug is approved according to the summary of product characteristics. This patient population may comprise either the total populations investigated in the studies submitted to regulatory authorities in the drug approval process, or the specific subpopulations defined in the summary of product characteristics ("approved subpopulations"). OBJECTIVE: To determine the information gain from AMNOG documents compared with non-AMNOG documents for methods and results of studies available at market entry of new drugs. AMNOG documents comprise dossier assessments done by IQWiG and publicly available modules of company dossiers; non-AMNOG documents comprise conventional, publicly available sources-that is, European public assessment reports, journal publications, and registry reports. The analysis focused on the approved patient populations. DESIGN: Retrospective analysis. DATA SOURCES: All dossier assessments conducted by IQWiG between 1 January 2011 and 28 February 2013 in which the dossiers contained suitable studies allowing for a full early benefit assessment. We also considered all European public assessment reports, journal publications, and registry reports referring to these studies and included in the dossiers. DATA ANALYSIS: We assessed reporting quality for each study and each available document for eight methods and 11 results items (three baseline characteristics and eight patient relevant outcomes), and dichotomised them as "completely reported" or "incompletely reported (including items not reported at all)." For each document type we calculated the proportion of items with complete reporting for methods and results, for each item and overall, and compared the findings.Results 15 out of 27 dossiers were eligible for inclusion and contained 22 studies. The 15 dossier assessments contained 28 individual assessments of 15 total study populations and 13 approved subpopulations. European public assessment reports were available for all drugs. Journal publications were available for 14 out of 15 drugs and 21 out of 22 studies. A registry report in ClinicalTrials.gov was available for all drugs and studies; however, only 11 contained results. In the analysis of total study populations, the AMNOG documents reached the highest grade of completeness, with about 90% of methods and results items completely reported. In non-AMNOG documents, the rate was 75% for methods and 52% for results items; journal publications achieved the best rates, followed by European public assessment reports and registry reports. The analysis of approved subpopulations showed poorer complete reporting of results items, particularly in non-AMNOG documents (non-AMNOG versus AMNOG: 11% v 71% for overall results items and 5% v 70% for patient relevant outcomes). The main limitation of our analysis is the small sample size. CONCLUSION: Conventional, publicly available sources provide insufficient information on new drugs, especially on patient relevant outcomes in approved subpopulations. This type of information is largely available in AMNOG documents, albeit only partly in English. The AMNOG approach could be used internationally to develop a comprehensive publication model for clinical studies and thus represents a key open access measure.

Early benefit assessment of new drugs in Germany - results from 2011 to 2012.

Rising drug costs in Germany led to the Act on the Reform of the Market for Medicinal Products (AMNOG) in January 2011. For new drugs, pharmaceutical companies have to submit dossiers containing all available evidence to demonstrate an added benefit versus an appropriate comparator therapy. The Federal Joint Committee (G-BA), the main decision-making body of the statutory healthcare system, is responsible for the overall procedure of "early benefit assessment". The Institute for Quality and Efficiency in Health Care (IQWiG) largely conducts the dossier assessments, which inform decisions by the G-BA on added benefit and support price negotiations. Of the 25 dossiers (excluding orphan drugs) assessed until 31 December 2012, 14 contained sufficient data from randomized active-controlled trials investigating patient-relevant outcomes or at least acceptable surrogates; 11 contained insufficient data. The most common indications were oncology (6) and viral infections (4). For the 14 drugs assessed, the extent of added benefit was rated as minor, considerable, and non-quantifiable in 3, 8, and 2 cases; the remaining drug showed no added benefit. Despite some shortcomings, for the first time it has been possible in Germany to implement a systematic procedure for assessing new drugs at market entry, thus providing support for price negotiations and informed decision-making for patients, clinicians and policy makers.

High prevalence of Clostridium botulinum types A and B in honey samples detected by polymerase chain reaction.

A test protocol for reliable detection of Clostridium botulinum types A and B spores in honey by polymerase chain reaction (PCR) was developed and used for a prevalence survey of C. botulinum spores in 190 honey samples. The inhibiting effects of honey on microbial growth and PCR analysis were overcome by using a method of supernatant filtration (SF) in the preparation of the samples before enrichment and PCR. By using this method, an inoculum of 0.1 spore of C. botulinum/g honey could be detected. In the prevalence survey, spores of C. botulinum were detected in 8 (7%) of the 114 Finnish and in 12 (16%) of the 76 imported honey samples. The quantity of spores in PCR-positive samples varied from less than 18 to 140 spores/kg. Neurotoxin gene sequences corresponding to C. botulinum type A were detected in 17 samples and proteolytic type B in 12 samples by PCR analysis. Both types A and B were detected in nine samples. Strains of C. botulinum type A were isolated from 14 and type B from 2 of the 20 PCR-positive samples. This is the first report of type A spores of C. botulinum being detected and isolated in Fennoscandia.