Licensing Status Research Articles

Reactor pressure vessel embrittlement of NPP borssele: Design lifetime and lifetime extension

Embrittlement of the reactor pressure vessel of the Borssele nuclear power plant has been investigated taking account of the design lifetime of 40 years and considering 20 years subsequent lifetime extension. The paper presents the current licensing status based on considerations of material test data and of US nuclear regulatory standards. Embrittlement status is also evaluated against German and French nuclear safety standards. Results from previous fracture toughness and Charpy tests are investigated by means of the Master curve toughness transition approach. Finally, state of the art insights are investigated by means of literature research. Regarding the embrittlement status of the reactor pressure vessel of Borssele nuclear power plant it is concluded that there is a profound basis for the current license up to the original end of the design life in 2013. The embrittlement temperature changes only slightly with respect to the acceptance criterion adopted postulating further operation up to 2033. Continued safe operation and further lifetime extension are therefore not restricted by reactor pressure vessel embrittlement.

Status of International Technology Transfer and Patent Licensing in the Medical and Pharmaceutical Field

Status of International Technology Transfer and Patent Licensing in the Medical and Pharmaceutical Field

Unlicensed and off-label use of medicines at a neonatology clinic in Italy

Many drugs used for children are not licensed or are used off-label. An increased risk of medication errors and unexpected adverse drug reactions (ADR) associated with off-label and unlicensed drug prescription has been reported. This risk increases in the newborn, who are more likely to be predisposed to an ADR due to their physiological immaturity. The objective of this study was to describe the use of unlicensed or off-label drugs in a Neonatal Intensive Care Unit (NICU). All drugs prescribed to newborn admitted to the Neonatology Unit of Bari University Hospital, from July 1st to August 31st in 2004 were recorded. All the drugs prescribed were analysed with regard to their license status, then the licensed drugs were compared to the indications, dose, route of administration, duration of treatment, contraindications and warnings specified in the summary of product characteristics of the marketing authorization. Data were collected on 176 prescriptions for 61 different drugs given to 34 newborns. Drugs were licensed in 88% and unlicensed in 12% of cases. About the licensed drugs, in 37.5% medicines were used following the terms of the marketing authorization, in 22.7% of cases medicines were used in an off-label manner as they contained no information for paediatric use in the marketing authorization and in 27.8% of cases medicines were licensed for paediatric use, but they were used off-label with regard to age, dose, route of administration and duration of treatment. Despite European and American initiatives aiming to promote greater awareness and research in the paediatric population, these data demonstrate that there is still a high percentage of unlicensed or off-label drugs use in neonatology, underlining the need to stimulate scientific data collection by means of experimental studies or outcome research.

Alcohol and other drug use and the transition from riding to driving

Poulin, Boudreau and Ashbridge [Addiction 2007;102(1):51-61.] provide an intriguing analysis of the problem of adolescents riding with drunk drivers. Their analysis, based on a survey of 13 000 students in grades 7-12 in the four Maritime Provinces of Canada, includes individual, school and province variables. Highlighted are the factors not within the student's direct control that determine the extent of riding with a drunk driver (RDD). They found that rural residence, single parent or no parents, socio-economic status (SES), prevalence of driving under the influence (DUI), lower licensure rate and lower educational attainment in the community were associated with RDD. Of particular interest was their finding that, once the impact of those factors was controlled, being licensed reduced the probability of RDD. Presumably, this is because youths with licenses have less need to ride with others and thus are less likely to ride with a drunk driver. The Poulin et al. results highlight the need to pay more attention to the risk that unlicensed youths will become riders in alcohol-related crashes. Sixteen-year-old drivers have crash rates that are three times greater than 17-year-olds and five times greater than 18-year-olds. The current official response to this problem is GDL, which extends the period of adult-supervised driving and provides for an intermediate period when the novice driver may not carry teenage passengers or drive late at night. This should reduce the opportunity for teenage passengers to be injured in crashes involving drinking novice drivers. There is substantial evidence that GDL programs are effective in reducing the crashes of novice drivers. However, there have been no studies of the impact of GDL on teenage passengers. Although imposing night-time restrictions on teenage driversand teenage passengers appears to effectively reduce novice-driver injuries, there is evidence that GDL laws achieve their primary impact through a delay in the licensing of 16- and 17-year-olds. If GDL laws are achieving their impact primarily by limiting the number of licensed 16- and 17-year-olds, then more teenagers in that age group will need rides. It is therefore important to study the limits on mobility (a potential economic burden on some families) and safety (if lack of a license increases RDD) if a teenager is unlicensed. The Poulin et al. paper challenges us to increase our knowledge about RDD as a signal for alcohol problems. It suggests a need to examine more closely the trade-off between discouraging early licensing versus reducing RDD by making licensing more available. It also suggests more research on programs that discourage RDD that go beyond current educational efforts. Language: en

California’s Graduated Driver License Law

Many traffic safety researchers believe Graduated Driver Licensing (GDL) laws save lives by imposing restrictions, stronger licensing requirements, and delayed licensure status on drivers under age 18. To determine the effects of California’s GDL law on traffic fatalities among older (age 18-19) and younger (age 16-17) teens by age, sex, accident characteristics, and license status, mortality data from California’s Center for Health Statistics, driver and accident data from the Fatality Analysis Reporting System, and population data from the California Department of Finance were analyzed for the 1995-2004 period. Compared to California who began driving before the GDL law took effect and to corresponding trends among Californians ages 20 through 44, 16- and 17-year-olds subject the GDL law experienced net decreases of 13% in motor vehicle fatality rates and 14% in driver involvements in fatal accidents. However, 18- and 19-year-olds subjected to GDL programs experienced net increases of 11% in traffic fatalities and 10% in involvements of drivers in fatal accidents, more than offsetting the declines among younger teenagers. These results support reassessment of the effects of the GDL law, including its specific requirements, on older teenagers.

Pediatric Licensing Status and the Availability of Suitable Formulations for New Medical Entities Approved in the United States Between 1998 and 2002

The availability of new medical entities for children in the United States was examined at the time of marketing approval and 3 years later. New medical entities approved in the United States in each of the years 1998 to 2002 were identified using the Center for Drug Evaluation and Research Web site. Each Physicians' Desk Reference published in the years 1998 to 2005 was examined to determine formulations and licensing information. For the 133 new medical entities licensed to be marketed in the period 1998 to 2002, the number licensed for children increased from 5 (4%) to 39 (29%) in the 3 years after registration. After 3 years' marketing, 79 (59%) drugs were in formulations suitable for children, and 27 (20%) of the new medical entities were licensed and had a suitable formulation for children. Incentives to improve access for children to medicines should focus more on demonstration of improved access.

Is the Driving Experience of Older Women Changing?

Older women currently have travel patterns substantially different from those of older men even when they are licensed to drive. These differences have different safety and mobility implications for older women in the future—if they persist—but equally important consequences if they do not. This paper shows that women drivers at all ages drive less often and for fewer miles than men of comparable ages; as a result, in the next three decades most women will enter their retirement years with substantially less driving experience than their licensing status might indicate. The differences in travel patterns and driving experiences between women and men are likely to persist, and policy makers must address both their safety and mobility consequences. There is a significant need to conduct the kind of safety and mobility research that will inform intelligent policy development and planning strategies for what has been called the feminization of aging.

Is the Driving Experience of Older Women Changing? Safety and Mobility Consequences over Time

Older women currently have travel patterns substantially different from those of older men even when they are licensed to drive. These differences have different safety and mobility implications for older women in the future—if they persist—but equally important consequences if they do not. This paper shows that women drivers at all ages drive less often and for fewer miles than men of comparable ages; as a result, in the next three decades most women will enter their retirement years with substantially less driving experience than their licensing status might indicate. The differences in travel patterns and driving experiences between women and men are likely to persist, and policy makers must address both their safety and mobility consequences. There is a significant need to conduct the kind of safety and mobility research that will inform intelligent policy development and planning strategies for what has been called the feminization of aging.

Doctors without Borders? Relicensing Requirements and Negative Selection in the Market for Physicians

Relicensing requirements for professionals who move across borders are widespread. In this article, we measure the effects of occupational licensing by exploiting an immigrant physician retraining assignment rule. Instrumental variables and quantile treatment effects estimates indicate large returns to acquiring an occupational license and negative selection into licensing status. We also develop a model of optimal license acquisition that, together with the empirical results, suggests that stricter relicensing requirements may lead not only to practitioner rents but also to lower average quality of service in the market for physicians.

05/01034 Potentials of hydrogen and nuclear towards global warming mitigation-expansion of an integrated assessment model MARIA and simulations

Embrittlement of the reactor pressure vessel of the Borssele nuclear power plant has been investigated taking account of the design lifetime of 40 years and considering 20 years subsequent lifetime extension. The paper presents the current licensing status based on considerations of material test data and of US nuclear regulatory standards. Embrittlement status is also evaluated against German and French nuclear safety standards. Results from previous fracture toughness and Charpy tests are investigated by means of the Master curve toughness transition approach. Finally, state of the art insights are investigated by means of literature research. Regarding the embrittlement status of the reactor pressure vessel of Borssele nuclear power plant it is concluded that there is a profound basis for the current license up to the original end of the design life in 2013. The embrittlement temperature changes only slightly with respect to the acceptance criterion adopted postulating further operation up to 2033. Continued safe operation and further lifetime extension are therefore not restricted by reactor pressure vessel embrittlement.

Subcutaneous administration of drugs in the elderly: survey of practice and systematic literature review

Survey of subcutaneous drug use and hypodermoclysis with a standardized questionnaire to 27 nursing teams and 52 physicians in a geriatric hospital department (404 beds). Evaluation of license status (CH, F, D and UK) and systematic literature review of 34 drugs used in the geriatric setting. Subcutaneous route is used daily with drugs and fluids mostly for patients in palliative care (83%) or who are dehydrated (54%) when oral or IV administration is impossible (73%, 68% respectively). Morphine (98%), haloperidol (90%), furosemide (69%) and hydromorphone (56%) by bolus (36%) or slow injection over 5 min (82%) are the main drugs used and NaCI 0.9% (95%), and glucose 5%/NaCI 0.9% (31 %) are commonly used for rehydration. Among the 34 drugs reviewed, only 13 (38%) are licensed for subcutaneous use in CH, UK, F or D, and only, morphine (14 articles of 68) and rehydration (six articles) are evaluated in high level studies. Haloperidol and furosemide are used off-label and there are no well-designed studies supporting their subcutaneous use. There is a lack of information on drugs widely used by subcutaneous route in the elderly. In that context, physicians carry responsibility for the prescription.

Effect of the pediatric exclusivity provision on children's access to medicines.

To determine the paediatric licensing status in the USA, UK, Australia and New Zealand of the 79 medicines granted paediatric exclusivity in the USA, and to assess the importance of those medicines to paediatric practice. The medicines granted a patent extension in the USA as of 10 November 2003 were identified from the FDA website. Data on paediatric licensing were obtained from the Physicians Desk Reference (USA), the Electronic Medicines Compendium (UK), the Australian Prescription Products Guide (Australia) and the MedSafe website (New Zealand). A questionnaire was administered to seven paediatric consultants to assess the importance of the 79 PEMs for use in children. The questionnaire sought opinions on each drug, by age grouping, regarding: usefulness in patients with the condition, number of patients likely to be treated with each drug in a year, and acceptable therapeutic alternatives. Fifty-eight (73%) of the medicines had attained paediatric licensing in the USA. Sixty were licensed for adults in all four countries and of these 45 (75%) were licensed for children under 12 years in the USA compared with 31 (52%) to 33 (55%) for the other three countries. The proportion of these medicines licensed for children under 1 month, under 2 years and under 6 years of age ranged from 10% to 58% and there were no significant differences between the countries. For all four countries perceived usefulness and predicted numbers of patients both had some influence on the odds of a medicine having paediatric licensing. Improvements in licensing of some medicines for children have occurred in the USA, relative to the UK, Australia and New Zealand, subsequent to the Paediatric Exclusivity Provision. Improvements occurred for children over the age of six, but not for younger children.

Predicting gas production from future gas discoveries in the Netherlands: quantity, location, timing, quality

Recent policy and market developments have raised the question not only as to how much gas remains to be discovered in the Netherlands but also where and when it will be produced and of what quality. These questions are addressed by compiling a ‘firm futures’ database, estimating the ‘potential futures in proven plays’ and simulating the exploration process using the prospect portfolio. The firm futures are assessed using an integrated play evaluation method in a combined database/GIS environment. The database includes a prospect portfolio of firm futures, well data and maps. Volumetric estimates (low, mean and high success volumes) are assigned to the prospects. The risk of each prospect is estimated using play maps and the historical success ratio for that play. Using standard GIS functionality, the distance to production nodes, the gas quality, licence status and operator are determined for each prospect. The prospect portfolio is not static but dynamic. Using the creaming curve, fractal distribution analysis and the average POS (Possibility of Success) of the play, the gas volume and the amount of structures in the potential futures category are estimated. Again, GIS functionality is used to determine possible new locations and the gas quality of the prospects. The prospect portfolio is the input for a computer program that stochastically simulates the exploration process. Assumptions about future drilling efforts, economic screening scenarios and time delays from discovery to production are made explicit. The program simulates annual drilling campaigns. A number of prospects are drilled according to an assumed exploration efficiency and the POS is used to determine the result: a discovery or a dry well. The discovered volume is economically assessed and, if economic, transformed into a production and gas-quality profile.

Alcohol and road safety behaviour among New Zealand tertiary students

In New Zealand, as in most developed countries, rates of injury mortality and morbidity peak in late adolescence (15-19 years), when they account for around three quarters of fatalities and a third of hospitalisations. Road traffic crashes account for over half of fatal injuries in New Zealand as in most developed countries. Individuals engaged in post-secondary education, i.e., tertiary students, are a large and important subgroup of young people exposed to the risk of road traffic injury. The aims of this study were to estimate the prevalence of unsafe road behaviours and to examine the role of demographic variables, alcohol use, driver licence status, and transport needs. Participants were 1,480 students (899 women) from 12 residential halls in Dunedin, New Zealand. They anonymously completed a questionnaire on alcohol use and road safety at the start of the 2000 academic year. A sub-sample of 967 students completed a follow-up survey six months later. The mean age of the sample was 18.3 years (SD=1.6), and 88% had a driver licence. Male gender and drinking status were independently associated with speeding, drink-driving and drink-riding, but not seatbelt use. Drinking levels showed a strong dose-response relationship with the prevalence of unsafe behaviours with the exception of seatbelt use. In marked contrast to drinking levels, which increased from baseline to follow-up, drink-driving and drink-riding levels decreased, probably reflecting the reduced motor vehicle transport needs of students in residential halls, relative to their out-of-term living environments. In addition to various existing, evidence-based countermeasures, application of interventions for reducing hazardous drinking may be required to help reduce road traffic injury rates in this population.

P0808 ADMINISTRATION OF UNLICENSED/OFF-LABEL DRUGS VIA ENTERAL TUBE

Introduction: Drug absorption is dependant upon drug properties–solubility, permeability and formulation as well as physiological variables like pH, lumenal and mucosal enzymology and regional permeability differences. Little data is available on the effect of route of administration on drug efficacy. Over 50% of prescriptions for children with GI diseases are either un-licensed or off-label (1). Methods: Prospective review of prescribed medications in paediatric in-patients who required nasogastric (NG), nasojejunal (NJ) or gastrostomy drug administration. Dose, indication and license status were recorded over a 9 month period. Manufacturers were contacted for pharmacokinetic/dynamic data pertinent to tube administration, and literature was reviewed to establish guidelines on commonly used medications. Results: 35 children (M=15) were given a total of 10,660 dose medications via enteral tube (PEG 20, NGT 13, NJT 2). 96% (10,238) of drug administrations were off-label. Most drugs were given as liquid formulations (49/74), although capsules, powder, injectables and tablets were also modified for tube administration. The most commonly administered drugs included Domperidone, Gaviscon, Ranitidine, Senna and Omeprazole. Omeprazole, pancreatic enzymes, ursodeoxycholic acid and picosulphate all required specialist knowledge and formulation to ensure sustained efficacy when administered via enteral tubes. Conclusion: The vast majority of drugs used via enteral feeding tubes are given without knowledge of their absorption when given other then by the oral route. Caution is advisable before assuming equal efficacy. Many of the above drugs require reformulation in ways that make their use off-label and therapeutic efficacy less predictable. Manipulation of dosage forms into easily administerable formulations may alter osmolality of the final product. Increased osmolality, as well as concentrations of excipient (e.g. sorbitol) can exacerbate diarrhoea.Lack of passage through an acid medium with direct instillation into an alkali medium, can significantly alter bioavailability of drugs formulated for oral consumption.Further work needs to be carried out to provide licensed formulations that may be given intra-gastrically or intra-jejunally.

Changes in alcohol involvement, cognitions and drinking and driving behavior for youth after they obtain a driver's license.

This study tested whether obtaining a driver's license was associated with increases in alcohol and other drug involvement and changes in alcohol-related cognitions for youth, and whether drinking and driving behavior increased with driving experience. Confidential, anonymous surveys were conducted at two time points (fall, spring) with students at four high schools in San Diego county (N = 2,865, 51% female). Data were collected on alcohol, cigarette and marijuana use, license status, alcohol use by peers, attitudes towards drinking and driving and drinking and driving behaviors. Nondrivers (60%), new drivers (obtained a license between Time 1 and Time 2) and experienced drivers (26%) were compared on study variables at both time points and over time. Initially obtaining a driver's license was associated with increased frequency of substance use. Results were not significant for quantity of alcohol use, frequency of heavy drinking or perceived alcohol use norms. Attitudes towards drinking and driving reflected an increase in the perceived dangerousness of this behavior for new drivers. Drinking and driving behavior during the last 30 days increased with increased driving experience. The results indicate a number of changes in substance involvement after obtaining a driver's license. However, initially this transition may also indicate a period of protection against drinking and driving. These results may have implications for the target and content of drinking and driving interventions.

Off-label prescribing in oncology.

Off-label prescribing occurs when a practitioner prescribes a drug for a use, or in a manner, not listed in the 'approved product information' (API) for that drug. The literature suggests that this is a frequent occurrence in many areas of medicine, but data are limited in the hospitalized oncology setting. The aim of this study was to quantify the extent of off-label prescribing in a hospitalized oncology population in Australia. The study was conducted at Peter MacCallum Cancer Centre, Australia. On a single day the medication charts of all hospitalized patients were prospectively reviewed. Drug prescribing was assessed for licensing status by comparison with the API as approved by the Therapeutic Goods Administration of Australia. Prescriptions were classified as licensed, off-label or unlicensed. Medication charts of 130 patients were assessed. There were 1351 prescriptions. In 293 (22%) of the prescriptions the drug was either off-label (242, 18%) or unlicensed (51, 4%). Among the 130 patients, 110 (85%) received at least one drug that was prescribed off-label or that was unlicensed. Off-label dosing was the most frequent reason for a drug being off-label (139, 10% of all prescriptions). Off-label due to use for an unapproved indication was found in 118 prescriptions (9%), and off-label due to an unapproved route of administration was found in 38 prescriptions (3%). Off-label prescribing is widespread in the acute hospitalized oncology population, with approximately 22% of all prescriptions being for off-label or unlicensed medication. Such prescribing affects a significant proportion of patients.

Unlicensed and off-label prescription of respiratory drugs to children.

Many respiratory drugs are not available in formulations suitable for infants and toddlers. Efficacy and safety research is mostly restricted to older children. However, respiratory drugs are frequently used in children for common diseases like asthma, upper and lower respiratory tract infections, rhinitis and sinusitis. The unlicensed and off-label use of respiratory drugs in children were studied. A population-based cohort study was conducted by using the computerised medical records in the Integrated Primary Care Information project. The study population comprised a random sample from all children aged 0-16 yrs who were registered with a general practitioner in 1998. All prescriptions for respiratory drugs during the study period were classified according to their licensing and off-label status. The study population comprised 13,426 patients (51.7% male, median age 8.7 yrs), of whom 2,502 (19%) received 5,253 prescriptions for respiratory drugs in 1998. A total of 3,306 (62.9%) prescriptions concerned licensed drugs. Of the remaining 1,947 prescriptions (37.1%), 882 (16.8%) were unlicensed for use in children, and 1,065 (20.3%) were prescribed off-label. The 1-yr cumulative risk of receiving an unlicensed or off-label prescription was 45% among children with at least one prescription for a respiratory drug. This population-based study showed that a large proportion of respiratory drugs prescribed by the general practitioner are unlicensed for use in children, or licensed but prescribed in an off-label manner. Results have to be interpreted with caution because they may unjustly suggest inaccurate prescribing, whereas it may be difficult to treat children with respiratory symptoms and diseases, because for many respiratory drugs paediatric data on safety and efficacy are insufficient. These findings underline the importance of research on suitable formulations, dosages and efficacy of respiratory drugs in children.

Lack of appropriate formulations of medicines for children in the community

Aim: Appropriate formulations are essential in pharmacotherapy. This study surveyed the use of different formulations by children in the community, and examined the reported lack of appropriate formulations (oral solutions) in relation to the licensing status of drugs. Methods: A crosssectional study based on 68 019 pharmacy dispensing records was performed in The Netherlands. For each prescription the formulation was assessed, and all prescriptions were categorized: unlicensed (no product licence), off‐label (licensed drugs used outside the licence terms) and authorized (licensed drugs used according to the licence). The types of formulation used were assessed in relation to age and licensing status. Results: In all age groups, approximately half of all prescriptions were for oral drugs. The only major age‐related trend was within oral drugs: younger children were more likely to be prescribed oral solutions. For authorized drugs the proportion of tablet/capsules exceeded oral solutions at the age of 7 y, whereas for off‐label drugs this occurred at 3 y of age. For those medicines prepared by the pharmacy, tablets and capsules were more likely to be prescribed from the age of 9 y. Conclusion: Many children in the community receive inappropriate oral formulations. Regulatory authorities and the pharmaceutical industry need to ensure that children have access to medicines with appropriate formulations.

Factors associated with young drivers’ car crash injury: comparisons among learner, provisional, and full licensees

This exploratory study aimed to investigate factors associated with car crash injury among young drivers aged <25 years with different license status. Of special interest were the differences in risk patterns among different license holders of different age groups. Data utilised in this study were obtained from the New South Wales (NSW) police. The results indicated that female young drivers were more at risk of being killed or injured in a crash than males. Some risk factors, in particular environment-related factors, were identified as license-status-and-age specific. On the contrary, disregarding their driving experiences and ages, young drivers were more influenced by their own behaviours and driving conditions. Young drivers of 16–17 years with learner and provisional licenses tended to have increased risk of crash injury due to special road features. Night-time driving seemed to be a problem for older and more experienced drivers only. Fully licensed drivers of 18–19 and 20–24 years were more susceptible to the influence of alcohol. Risk-taking, speeding, fatigue, and carrying many passengers increased the risk of crash injury to car occupants for nearly all young drivers disregarding their ages and driving experiences. The results obtained provided indicative information on areas where the graduated licensing systems in NSW might be effective, and on other areas that might be lacking. A population-based case-control study was proposed to overcome the limitations of this study.