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Von Jeinsen B.K.J.G.,University of Bonn | Sudhop T.,Federal Institute for Drugs and Medical Devices BfArM
European Journal of Clinical Pharmacology | Year: 2013

Purpose: The aim of non-interventional studies (NIS) with medicinal products is to investigate the use of authorized medicinal products in daily routine. In the past, this type of study has been subject to frequent criticism, and many recommendations have been published. The aim of our study was to assess the quality of NIS study protocols. Methods: Nearly all NIS study protocols submitted to the German Federal Institute for Drugs and Medical Devices (BfArM) within a period of one year could be analyzed. The protocols were evaluated in terms of objectives, methods and included patients, as well as with regard to their compliance with quality recommendations for NIS by federal authorities and pharmaceutical industry associations. Results: The 136 NIS available for study were scheduled to enroll approximately 330,000 patients (2,500 patients per study) and 43,000 healthcare professionals. Of these NIS, 58 % were performed with medicinal products that had been authorized within the past 5 years; however, 68 % of the investigated active pharmaceutical ingredients were older than 5 years, and 19 % were even older than 19 years. Only 56 % of the protocols provided information on publication policy, and 65 % required the involvement of ethic committees. The adherence to current quality recommendations was average, but the compliance of NIS performed by member companies of the Association of Research-Based Pharmaceutical Companies was significantly higher than that of other sponsors. Conclusions: Current quality recommendations are still not fully implemented in most NIS protocols. Therefore, the scientific value of many NIS is still questionable, and the criticism that NIS are mainly conducted for marketing reasons could not be refuted by the data analyzed here. © 2013 The Author(s). Source


Siekmeier R.,Federal Institute for Drugs and Medical Devices | Wetzel D.,Federal Institute for Drugs and Medical Devices BfArM
Advances in Experimental Medicine and Biology | Year: 2013

The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) regulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of incidents and field corrective actions, the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD. In this study all notifications regarding IVD for therapeutic drug monitoring (TDM) between begin 1999 until end of 2010 were analysed. A total of 2,851 notifications were received, of which 65 were related to IVD for TDM included in this study (54 tests vs. 11 analysers). Reports were received from manufacturers (58), CAs (5 cases) and users (2 cases). Most frequently IVD used for TDM of toxicologically relevant substances, antibiotics, antiepileptics and immunosuppressives were affected. Investigations of the manufacturers were able to identify the underlying root causes of product failures in 50 cases (76.9%), 40 (74.1%) of which were tests and 10 (90.9%) analysers. In 11 cases (16.9%, all tests), the root cause remained unclear and in 4 cases (6.2%, 3 tests, 1 analyser) a product failure was excluded. Product failures in tests were most commonly material defects (12 cases), interferences (7 cases) and manufacturing errors (7 cases), whereas in the analyser group software errors (5 cases) were most common. Corrective actions were performed in 56 cases (86.2%); 46 (85.2%) in tests, and 10 (90.9%) in analysers. In the group of tests these were predominantly (multiple entries) customer information (46 cases, mandatory in case of a recall), recall (29 cases), modifications in production or quality management (29 cases) and modifications of the instructions for use (9 cases). However, in the analyser group corrective actions were typically customer information (10 cases), recall (5 cases) and software-update (4 cases). The obtained data demonstrate that there are differences in the type of product failures between analysers and tests, which are followed by different corrective actions depending on the root causes of product failure accordingly. The results and the experience since 1999 suggest that the system for post marketing surveillance of IVD is an established tool to enhance product safety even though further optimisation is possible. © Springer Science+Business Media Dordrecht 2013. Source


Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide. The present Cochrane Review compares tandem autologous stem cell transplantation (TASCT) with single autologous stem cell transplantation (SASCT) as first-line treatment in patients with symptomatic MM with respect to overall survival (OS), event-free survival (EFS), quality of life (QoL) and treatment- or transplantation-related mortality. We systematically identified controlled trials published between January 1995 and May 2011 in two bibliographic databases (MEDLINE and CENTRAL) and in clinical trial registries. One researcher screened references for controlled trials to determine eligibility for the systematic review (SR) according to pre-specified inclusion and exclusion criteria, reflecting characteristics of disease and the interventions. We required a minimal set of details to be reported for observational studies for the studies to be included. We critically evaluated eligible trials with respect to quality of design and actual performance. One researcher extracted individual trial results, which were checked by another researcher. We recapitulated the results of the individual trials in a standardised way for the SR in order to allow a systematic assessment of potential sources of bias. Overall, we identified 14 controlled studies. One registered randomised controlled trial (RCT) is still recruiting patients at the time of this review and no clinical results have been published. Two registered RCTs have remained unpublished despite their termination. Publications on one RCT had been retracted. We excluded five observational studies since neither patients nor treatment regimens were sufficiently characterised to allow an assessment of potential confounding by indication. We conducted a SR of study designs, definition of endpoints, treatment regimens and baseline characteristics of patients in the five included RCTs (two full-text publications, three conference presentations) enrolling1506 patients in total. Because we identified substantial clinical and methodological heterogeneity, we refrained from conducting a formal meta-analysis.While we included only previously untreated, symptomatic patients with MM the treatment regimens differed notably with respect to acute toxicity, between trials and also between study arms. Compared to state of the art treatment standards, the treatment regimens applied in all trials have to be considered as below standard from a contemporary perspective in at least one component.Three trials were likely to have the potential of being highly biased while two RCTs had a moderate potential for bias. The observed treatment effects in the set of included trials may have been influenced by a steep decrease in compliance with the second ASCT and the concomitant selection of patients. In addition, OS data were confounded by the treatment subsequent to first-line therapy.OS was statistically significantly improved in one trial only. While EFS was prolonged in four of the five trials, the median prolongation ranged between three to 12 months, with an uncertain direction of bias in the individual trials. QoL was not reported in any study. Results concerning treatment- or transplantation-related mortality could not be adequately assessed due to substantial differences in definitions between trials and low reporting quality. We did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question single versus tandem ASCT in view of inherent biases. In addition, none of the trials integrated the so-called "novel agents" which are now considered standard treatment for MM. To improve the quality of future studies, sample size calculations should consider the potentially steep decrease in compliance with the second ASCT. Reporting of results of treatment- or transplantation-related mortality should clearly specify the type and number of events (the numerator) in a well-defined population (the denominator). Source


Ehrt U.,University of Stavanger | Broich K.,Federal Institute for Drugs and Medical Devices BfArM | Larsen J.P.,University of Stavanger | Ballard C.,Kings College London | And 2 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2010

Background: Cognitive decline is common in Parkinson's disease (PD). Although some of the aetiological factors are known, it is not yet known whether drugs with anticholinergic activity (AA) contribute to this cognitive decline. Such knowledge would provide opportunities to prevent acceleration of cognitive decline in PD. Objective: To study whether the use of agents with anticholinergic properties is an independent risk factor for cognitive decline in patients with PD. Methods: A community-based cohort of patients with PD (n=235) were included and assessed at baseline. They were reassessed 4 and 8 years later. Cognition was assessed using the Mini-Mental State Examination (MMSE). A detailed assessment of the AA of all drugs prescribed was made, and AA was classified according to a standardised scale. Relationships between cognitive decline and AA load and duration of treatment were assessed using bivariate and multivariate statistical analyses. Results: More than 40% used drugs with AA at baseline. During the 8-year follow-up, the cognitive decline was higher in those who had been taking AA drugs (median decline on MMSE 6.5 points) compared with those who had not taken such drugs (median decline 1 point; p=0.025). In linear regression analyses adjusting for age, baseline cognition and depression, significant associations with decline on MMSE were found for total AA load (standardised β=0.229, p=0.04) as well as the duration of using AA drugs (standardised β 0.231, p=0.032). Conclusion: Our findings suggest that there is an association between anticholinergic drug use and cognitive decline in PD. This may provide an important opportunity for clinicians to avoid increasing progression of cognitive decline by avoiding drugs with AA. Increased awareness by clinicians is required about the classes of drugs that have anticholinergic properties. Source


Chinou I.,National and Kapodistrian University of Athens | Knoess W.,Federal Institute for Drugs and Medical Devices BfArM | Calapai G.,Messina University
Phytochemistry Reviews | Year: 2014

A new European legislation on herbal medicinal products (HMPs) was developed, in order to harmonise the use of HMPs in the 28 member states of the European Union, according to Directive 2004/24/EC which amended the basic legislation laid down in Directive 2001/83/EC. The objective of this legislation was to ensure the future existence of such products and to consider particular characteristics during the assessment of their quality, efficacy and safety, having defined two categories for herbal medicines: (a) well-established use HMPs, which can be granted a marketing authorisation; and (b) traditional herbal medicinal products which can be granted a registration based on their long-standing safe and efficient use. The Committee on Herbal Medicinal Products was established at the European Medicines Agency in 2004, in order mainly to provide community monographs and list entries on herbal substances and preparations. 120 monographs have been published since then, which offer a scientific and regulatory standard for their safety and efficacy, during their use as medicinal products. The HMPs can be placed in the market after quality, efficacy, and safety have been assessed according to the provisions of the legislation (Directive 2004/24/EC and Directive 2001/83/EC), with adequate labeling information to patients and health care professionals, distinguishing them from other product categories containing herbs like: foods, food supplements, medical devices and cosmetics. © 2014 Springer Science+Business Media. Source

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