Challenges in conducting paediatric trials with off-patent drugs.

INTRODUCTION: For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge. AIM: This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement. DISCUSSION: Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug. CONCLUSION: Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life.

Asthma mortality in Danish children and young adults, 1973-1994: epidemiology and validity of death certificates.

Several reports indicate that asthma mortality has increased during the last few decades. International comparisons reveal some striking differences in the pattern of asthma mortality. The authors investigated the asthma mortality rate in the Danish child and youth population 1973-1994 and studied the validity of death certificates. The authors reviewed all death certificates coded as asthma death in the International Classification of Diseases (ICD 8-ICD 10 (1994)) and adjacent respiratory code numbers for the age group 1-19 yrs. Hospital records and autopsy reports were assessed to validate the cause of death. Age-standardized and age-specific mortality rates were calculated. From 1973 to 1987 there was a significant upward trend in the mortality. On subdivision, this trend was limited to the age group 15-19 yrs. Generally the mortality rate decreased from 1988 to 1994. Four per cent coded as asthma were false positive. Twelve per cent were false negative asthma deaths, wrongly coded as due to other causes. Only 62% of all true positive death caused by asthma were appropriately coded. The number of false negative certifications increased with increasing autopsy frequency. Asthma mortality rates in Denmark increased in adolescents during 1973-1987 and decreased from 1988 to 1994. A possible explanation may be an increased awareness of asthma symptoms combined with a steadily improved treatment of asthma. Even in children and young adults under the age of 20 yrs, validity problems still make comparisons between countries difficult; even interpretation of national trends requires caution.

[Latex allergy]. / Latexallergi.

Latex allergy has been described with increasing frequency throughout the last years. The prevalence in Denmark is not yet known. The growing frequency is partly explained by the extensive use of latex-containing products (especially gloves), which has followed the appearance of the HIV-epidemic. The symptoms of latex allergy are usually those produced by type-I hypersensitivity. Type-IV allergy (contact dermatitis) to rubber chemicals is well described but is not directly associated with the latex proteins. The allergens in latex have nearly been identified; diagnostic tools are known but are not yet satisfactory. Cross-reacting antigens are found in banana, kiwi, avocado, chestnut and other plants. It is concluded, that attention to latex allergy has to be intensified and the risk factors reduced, especially concerning the health care units.

[Latex allergy in children]. / Latexallergi hos børn.

More than a thousand cases of type-1 latex allergy have been presented. In children the condition is most often described in patients with spina bifida. Six cases of latex allergy in atopic children are presented. Five of these had food allergies, especially to banana. The allergy was verified with prick-test, LHR-test and measurement of specific IgE. It is concluded that attention to latex allergy in atopic children has to be intensified. Prick-test with standardised latex extracts is the preferred method for diagnosis of the allergy. Latex dummies, latex toys, balloons etc, have to be avoided.

Fatal unintentional child injuries in Denmark.

The purpose of this study was to estimate the risk of death from unintentional injury among children living in Danish counties and to identify high-risk counties of residence for different categories of external causes of injuries. All Danish children aged 0-14 who died from unintentional injuries (1202) between January 1, 1976 and December 31, 1985 were registered. The study was designed as a historical follow-up study in a dynamic population with particular emphasis on mortality rate (MR), cumulative mortality proportion (CMP) and standardized rate ratio (SRR). Considerable variation in mortality was observed. The analyses showed that, for boys, the risk of unintentional injury death was 32-48% greater in three of the rural counties than in Denmark as a whole. For girls the risk was 40% higher in one of the rural counties. For both sexes the risk in the area around the capital was around 50% lower than the national average. The mortality for the different categories of external causes varied according to county. In the vast majority of counties traffic injuries were the most common category. Pedestrian injuries and bicycle injuries predominated. With the purpose of identifying serious local problems as a basis for injury control/accident prevention, the distribution of the external causes of injuries within each county was stated. The method seems to be an effective tool in mapping county health conditions. One of the prime objectives in injury stategy is the collection of locally relevant information.

The epidemiology of fatal unintentional child injuries in Denmark.

The main object of this historical follow-up study in a dynamic population was to examine the extent of fatal unintentional child injuries in Denmark. Particular attention was paid to identifying risks and risk groups as targets for prophylactic measures. All 1,202 fatal injuries which occurred during 1976-85 and were reported to the police were included in the study. Death certificate information was supplemented by data from medical files, post-mortem medical examinations and police reports. The average mortality rate (MR) was 14.43 per 100,000 person-years in the group of boys, and 8.21 per 100,000 person years among girls. The cumulative mortality proportion was 2.18 per thousand for boys and 1.25 per thousand for girls. The mortality for boys fell during the period, but remained constant for girls. In the last years of the study the mortality rate for both sexes approached the same level. Boys had an overall mortality rate twice that of girls (RR 1.75 (CI 1.56-1.97)). Mortality was highest in the first five years of children's lives, i.e. the period of motor development and increasing curiosity regarding their surroundings. An overmortality in the rural areas as compared with the urban areas was identified (RR 1.47 (CI 1.31-1.64)). One reason for this may be that children living in rural areas are exposed to greater risks in everyday life and that they must venture into the traffic for purposes of social contact. Traffic-related deaths comprised 58% of all unintentional injury deaths. In around 50% of all cases the cause of death was head injury.(ABSTRACT TRUNCATED AT 250 WORDS)

[Sudden death in children with gastrointestinal diseases. 24 forensic cases]. / Uventet død hos børn med gastrointestinal sygdom. 24 mediko-legale tilfaelde.

During the period 1963-1986, 24 fatal cases of gastrointestinal disease in children aged 0-14 years were referred to the Institute of Forensic Medicine, Aarhus, Denmark, for autopsy. We have retrospectively, reviewed the cases and asked the medical officers of health, whether complaints against doctors or hospitals for negligence had been raised. The material consists of 19 boys and 5 girls with 9 different gastrointestinal diagnoses, predominantly small intestinal obstructive diseases such as intussuception, volvolus and adhesions. Five children with gastroenteritis were included who were treated and died at home. Reported prodromal symptoms were present in 23 of 24 cases. Nineteen had contacted a doctor in the week preceding death. The number of consultations ranged from 1 to 3 and involved general practitioners predominantly. Among 14 of 19 cases where death occurred at home, a doctor had been called prior to the death of the child. In 12 cases the clinical diagnoses were different from the autopsy results. The most frequent wrong clinical diagnosis was gastroenteritis. After the autopsies, five cases were reported to the National Board of Health for further consideration. In four cases the National Board of Health stated that negligence had existed. From our investigations and research from elsewhere it appeared that the National Board of Health defines negligence as considerable error of judgement, or where examination or history raking, had been insufficient. The main purpose is to prevent these gastrointestinal deaths. Attention has been drawn, in particular, to the small intestinal obstructive diseases and dehydration following gastroenteritis.

Methods and validity of dietary assessments in four Scandinavian populations.

Average intakes of nonstarch polysaccharides (dietary fiber), foods, and nutrients were measured in representative samples of 30 men aged 50-59 in 4 Scandinavian populations with a 3-4 fold difference in risk for large bowel cancer. The assessment technique, a 4-day weighed record of food consumed and duplicate collections of all food eaten, was validated by chemical analysis of the duplicates, by measuring 24-hour urine and fecal nitrogen excretion, and by comparing the constituents of the urine samples collected during the survey with similar collections 1-2 weeks later. There were good agreements between estimates of fat and protein intake obtained by food-table calculations of the 4-day weighed record and the chemically analyzed duplicates. Urinary plus fecal nitrogen excretion was equal to estimated nitrogen intake during the survey, and no discernable changes in urinary output occurred after the survey, thereby implying that dietary habits had not changed as a result of the investigative technique. It is concluded that the dietary data are indicative of current patterns of food consumption and are sufficiently valid for comparison with data on cancer risk in the 4 areas.

Dietary patterns in Them and Copenhagen, Denmark.

Four-day weighing and 24-hour recall were used to record food consumption in groups of 30 men, aged 50-59 years, in 2 areas of Denmark: Them, a rural Danish community, and Copenhagen. Fat consumption was found to be higher in Them, whereas alcohol consumption was higher in Copenhagen. The absolute daily intake of dietary fiber was higher in Them than in Copenhagen. These observations document changes due to industrialization of food production, modern distribution, and marketing methods.