Enhancing the effectiveness of medical device incident reporting: final report of the EU pilot on the manufacturer incident reporting form (MIR form)

Aim of the report This report provides a final assessment by DG JRC of the 'EU MIR form pilot' project, concerning the use of nomenclature for manufacturer incident reporting. The purpose of this analysis is to exploit the submitted data in view of addressing the following key questions: 1. Is reporting of adverse events using nomenclature feasible and helpful? 2. Are existing nomenclatures relating to device problems and evaluations of causes adequate? 3. Is there a need for introducing new terms, e.g. to cover novel technologies? 4. What are the lessons learned from the pilot study in terms of international harmonisation of nomenclatures (IMDRF) and development of future reporting tools (e.g. EUDAMED)? Key findings This report focuses on the use of adverse 'event-type' and 'evaluation' terms which relate to problems with the medical device. The device-related terms were used in a 'Manufacturer Incident Report' form, which was designed for the pilot study, and was called the MIR pilot form. 786 forms, which were submitted by 13 manufacturers reporting from 15 European countries, were analysed. Concerning nomenclature usage, the report analyses whether incidents were reported adequately using (1) existing nomenclature (ISO/TS 19218), (2) newly introduced nomenclature (EDMA's IVD-related terms), and (3) newly proposed terms (by the participating manufacturers of the pilot study). The analysis has shown a number of important issues which concern five main topics: 1. Pilot data relate to approx. 50% of device categories on the market Due to voluntary participation, the submitted MIR pilot forms reflect only a certain proportion of medical devices on the market. This needs to be considered when interpreting and using the pilot data. 2. No participation of SMEs in the pilot project Additional bias may be due to (1) the absence of SME participation; and (2) a single manufacturer submitting >60% of the total number of forms (bias towards a particular device category). 3. Adequacy of term selection by manufacturers We assessed the adequacy of term use by comparing textual incident descriptions with the categorised terms chosen by reporters. It was based on a set of 100 randomly selected pilot forms representative of the pilot's overall device portfolio. Both, the event-type and evaluation terms chosen by manufacturers for reporting incidents were largely adequate. Moreover, the analysis shows that three choices per level to describe the incident (event-type terms) or final investigation (evaluation terms) appear sufficient. 4. Available terminology (ISO/TS 19218) is not fully adequate On the basis of the frequency of some proposed terms it appears that the existing ISO/TS 19218 terms are overall not sufficient. This is not surprising given the fact that the terms were derived from FDA's terminology in 2005 and have, since then, not been updated. To resolve the most frequently encountered issues in the analysis, the JRC has proposed several changes to terms used (cf. Fig. 18-24). 5. Proposals for new terms by manufacturers ISO/TS 19218 uses a 2-level hierarchical coding structure for reporting adverse events. Though the pilot study allowed for new proposals at these levels (level 1, 2), it was particularly designed for new proposals at an additional more granular third level. In line with this is the observation that the majority of new terms proposed concern level three terms. The analysis also showed that, although selection of existing terms was overall adequate, many of the new terms proposed by manufacturers are either redundant or do not reflect device problems but are, in fact, patient outcome terms. This clearly shows a need for reporters to have a better understanding of the terms and the reporting form used. Some of the confusion may stem from the simple fact that ISO's medical device problem terminology is called "Adverse Event Terms", i.e. seemingly suggesting that this nomenclature should be used to report adversity, i.e. clinical phenomena at patient / user level. In cases where level one event-type terms have been proposed, these related mainly (>80%) to the orthopaedic device category (cf. Fig. 13). It therefore appears that there is a need for a more elaborate nomenclature in this device category. Proposed terms that were deemed valid when compared with ISO/TS 19218 were subsequently compared with FDA's terms for device problems. This led to the identification of a number of proposed terms that could be proposed for incorporation into ongoing efforts in the development of a globally used nomenclature in the context of the work of the Adverse Event Terminology Working Group of IMDRF. EDMA has proposed new terms to cover specific needs of reporting incidents with in vitro diagnostic medical devices (IVDs). These were meant to complement the ISO/TS 19218 terms, and several of them have been used in the submissions. A closer look at the definitions of some of EDMA's terms does, however, show that they would need to be revised, for example four terms (corresponding to level 2) have identical definitions adding unnecessary ambiguity to their use. The report also provides in Annex I a summary of agreements reached during the workshop and topics that remain to be addressed when developing future tools for incident reporting including concerns voiced by stakeholders. Annex I also considers additional reflections made after the workshop and provides, as a synthesis, key recommendations for a way forward. In summary, this report shows that the outcome of the 'EU MIR form pilot' project has proven to be extremely useful for three reasons. 1. It confirmed the general feasibility of categorised reporting of incidents by manufacturers. 2. It identified inadequacies of the existing ISO/TS 19218 nomenclature suggesting the need for increased efforts into the development of freely available, scientifically and technically satisfying and, from a regulatory and end-user point of view, adequate nomenclature for adverse event reporting of incidents and events also in the pre-market space. 3. It led to the proposal of several potentially useful terms in view of future developments of nomenclature for incident / adverse event reporting.JRC.F.2-Consumer Products Safet

The effects of obesity and polycystic ovary syndrome on serum lipocalin-2 levels: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Lipocalin-2 is a novel adipokine that appears to play a role in the development of insulin resistance. Serum lipocalin-2 levels are elevated in obese patients. Obesity and insulin resistance are cardinal characteristics of the polycystic ovary syndrome (PCOS). However, there are limited data on serum lipocalin-2 levels in patients with PCOS. The aim of the present study was to assess serum lipocalin-2 levels in PCOS.</p> <p>Methods</p> <p>We studied 200 patients with PCOS and 50 healthy female volunteers.</p> <p>Results</p> <p>Serum lipocalin-2 levels were slightly higher in women with PCOS compared with controls (65.4 +/- 34.3 vs. 60.3 +/- 26.0 ng/ml, respectively) but this difference did not reach statistical significance. In contrast, lipocalin-2 levels were higher in overweight/obese women with PCOS than in normal weight women with the syndrome (76.2 +/- 37.3 vs. 54.5 +/- 27.2 ng/ml, respectively; p < 0.001). Serum lipocalin-2 levels were also higher in overweight/obese controls compared with normal weight controls (70.1 +/- 24.9 vs. 50.5 +/- 23.7 ng/ml, respectively; p = 0.004). In the total study population (patients with PCOS and controls), lipocalin-2 levels were independently correlated with the body mass index (p < 0.001). In women with PCOS, lipocalin-2 levels were independently correlated with the waist (p < 0.001).</p> <p>Conclusions</p> <p>Obesity is associated with elevated serum lipocalin-2 levels. In contrast, PCOS does not appear to affect lipocalin-2 levels.</p

Vaspin: a novel adipokine, member of the family of serine protease inhibitors

In 2000, the novel adipokine vaspin, which belongs to the superfamily of serpins, was isolated from visceral adipose tissue. Vaspin is mainly produced in the visceral adipose tissue and is related to insulin resistance, blood glucose levels, sex hormones (women have higher levels compared to men) and nutritional status. Moreover, vaspin levels are modulated by weight loss and several agents, and it possibly constitutes a connecting link between obesity and its associated metabolic disorders. Many patients with polycystic ovary syndrome have insulin resistance, obesity (mostly visceral) and glucose intolerance, conditions associated with abnormalities in the production of vaspin. The role of vaspin in the regulation of human metabolism is unclear at present, but it appears that vaspin might represent a novel marker of obesity and insulin resistance. However, the controversial findings of existing studies on vaspin stress the need for further research in women with obesity and metabolic disorders in order to elucidate the role of this adipokine in these diseases and particularly in the polycystic ovary syndrome

Plasma visfatin levels in normal weight women with polycystic ovary syndrome

Background: The present study was designed to measure plasma visfatin levels in normal weight with polycystic ovary syndrome (PCOS) and to assess possible correlations between visfatin and the hormonal or metabolic parameters of the syndrome. Methods: Twenty-five normal weight [body mass index (BMI) &lt; 25 kg/m(2)] women with PCOS, 24 obese and overweight (BMI &gt; 25 kg/m(2)) controls (ovulating women without clinical or biochemical hyeperandrogenism), and 24 normal weight controls were studied. Blood samples were collected between the 3rd and the 7th days of menstrual cycle in the control groups and during a spontaneous bleeding episode in the PCOS groups at 9:00 A.M., after an overnight fast. Circulating levels of LH, FSH, prolactin (PRL), testosterone (T), Delta 4-androstenedione (Delta 4-A), dehydroepiandrosterone sulfate (DHEA-S), 17 alpha-OH-progestrone (17OH), sex hormone-binding globulin (SHBG), insulin, glucose, and visfatin were measured. Results: Plasma visfatin levels and the visfatin-to-insulin ratio were significantly lower in normal weight controls than in both normal weight women with PCOS and overweight or obese controls. Plasma visfatin levels were found to be positively correlated with LH and Delta(4)A levels, as well as with free androgen index (FAI) values, and negatively correlated with SHBG, LH and SHBG levels were found to be the only independent significant determinants of circulating visfatin. In the control groups, plasma visfatin levels were significantly correlated with BMI, waist (W) measurement, and waist-to-hip ratio (WHR). Conclusions: Visfatin levels are positively associated with obesity in healthy women of reproductive age. Moreover, the present study indicates, for the first time, a possible involvement of increased visfatin levels in PCOS-associated metabolic and hormonal disturbances. (c) 2007 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved

Prognostic Indices of Poor Nutritional Status and Their Impact on Prolonged Hospital Stay in a Greek University Hospital

Background. To ascertain the potential contributors to nutritional risk manifestation and to disclose the factors exerting a negative impact on hospital length of stay (LOS), by means of poor nutritional status, in a nonselected hospitalized population. Materials and Methods. NutritionDay project questionnaires were applied to 295 adult patients. Study parameters included anthropometric data, demographics, medical history, dietary-related factors, and self-perception of health status. Body Mass Index (BMI) and Malnutrition Universal Screening Tool (MUST) were calculated for each participant. MUST score was applied for malnutrition assessment, while hospital LOS constituted the outcome of interest. Results. Of the total cohort, 42.3% were at nutritional risk and 21.4% malnourished. Age, gender, BMI, MUST score, autonomy, health quality, appetite, quantity of food intake, weight loss, arm or calf perimeter (P<0.001, for all), and dietary type (P<0.01) affected nutritional status. Poor nutrition status (P=0.000), deteriorated appetite (P=0.000) or food intake (P=0.025), limited autonomy (P=0.013), artificial nutrition (P=0.012), weight loss (P=0.010), and arm circumference <21 cm (P=0.007) were the most powerful predictors of hospital LOS >7 days. Conclusion. Nutritional status and nutrition-related parameters such as weight loss, quantity of food intake, appetite, arm circumference, dietary type, and extent of dependence confer considerable prognostic value regarding hospital LOS in acute care setting

Plasma metastin levels are negatively correlated with insulin resistance and free androgens in women with polycystic ovary syndrome

Objective: This study was designed to: [1] measure, for the first time, metastin (kisspeptin) levels in women with polycystic ovary syndrome (PCOS), a condition associated with hypersecretion of LH and hyperandrogenemia; and [2] investigate the possible correlations between metastin and PCOS-related reproductive and metabolic disturbances. Design: Clinical study. Setting: University hospital. Patient(s): Twenty-eight obese and overweight (body mass index [BMI] &gt; 25 kg/m(2)) women with the syndrome, and 13 obese and overnight controls (ovulatory women without clinical or biochemical hyperandrogenemia) were selected. Intervention(s): Blood samples were collected between day 3 and day 6 of a sponataneous bleeding episode in the PCOS groups and a menstrual cycle of the controls, at 9:00 AM, after an overnight fast. Main Outcome Measure(s): Circulating levels of LH, FSH, PRL, T, Delta(4)-androstenedione (A), DHEAS, 17 alpha OH-P, sex hormone-binding globulin (SHBG), insulin, glucose, and metastin were measured. Result(s): Both normal weight women with PCOS and obese controls were less insulin resistant and had significantly higher metastin levels, compared to obese and overweight women with the syndrome. Plasma kisspeptin levels were negatively correlated with BMI, free androgen index, and indices of insulin resistance. Conclusion(s): These results indicate that metastin is negatively associated with free androgen levels. The PCOS-associated insulin resistance and consequent hyperinsulinemia probably contribute to this effect by [1] stimulating androgen synthesis by the polycystic ovary (PCO) and [2] suppressing SHBG production in the liver

Mechanisms of infertility in polycystic ovary syndrome

It has been proposed that the follicular problem in polycystic ovary syndrome is 2-fold. First, the intra-ovarian hyperandrogenism may promote early follicular growth, leading to a 2-5mm follicle excess. Second, the ensuing excessive number of selectable follicles would inhibit the selection process, presumably through follicle to follicle interaction involving granulosa cell products such as the anti-Mϋllerian hormone. These factors would induce a reversible refractoriness to the FSH-induced differentiation of granulosa cells. This explanation challenges but does not exclude other hypotheses about the follicular arrest, such as the premature LH action on the granulosa cells of selectable follicles. Hyperinsulinism or insulin resistance would act as a second hit, worsening the follicular arrest either through amplification of the intra-ovarian hyperandrogenism or through dysregulation of the granulosa cells. The loss of cyclic rhythm would prevent the inter-cycle elevation of FSH, thus perpetuating of the ovulation process