Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines.

UNLABELLED: The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. CONCLUSION: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.

Perspectives on allergen-specific immunotherapy in childhood: an EAACI position statement.

This article is the result of consensus reached by a working group of clinical experts in paediatric allergology as well as representatives from an ethical committee and the European Medicine Agency (EMA). The manuscript covers clinical, scientific, regulatory and ethical perspectives on allergen-specific immunotherapy in childhood. Unmet needs are identified. To fill the gaps and to bridge the different points of view, recommendations are made to researchers, to scientific and patient organizations and to regulators and ethical committees. Working together for the benefit of the community is essential. The European Academy of Allergy and Clinical Immunology (EAACI) serves as the platform of such cooperation.

Close collaboration between academia, industry and drug regulators is required in the development of allergen products for specific immunotherapy in children.

Modification of the response to allergens at an early stage and thereby of the natural history of a respiratory allergic disease by preventing disease progression would constitute the key benefit of specific immunotherapy (SIT) in children. However, although allergen products for SIT have been on the market on a named-patient basis for many years, long-term efficacy, the optimal duration of the treatment and the optimal dosage have not been sufficiently elaborated until now. The enactment of the Therapy Allergen Ordinance in Germany mandates that allergen products for SIT of the most prevalent allergies must submit an application for marketing authorization to the German authorities. In line with the European Paediatric Regulation, decisions by the European Medicines Agency on agreed paediatric investigation plans must be included in these applications. These regulatory requirements provide a unique opportunity to fill the gap in knowledge concerning the benefits of SIT for children and to obtain the data needed to support evidence-based authorization of allergen products for immunotherapy. This goal can only be achieved through close cooperation between academia, drug regulators and industry as well as parent/patient organizations.

Respiratory viral infections within one year after pediatric lung transplant.

To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric lung transplant recipients within the first post-transplant year, a retrospective multicenter study of pediatric lung transplant recipients from 1988 to 2005 was conducted at 14 centers in the United States and Europe. Data were recorded for 1 year post transplant. Associations between RVI and continuous and categorical risk factors were assessed using Wilcoxon's rank-sum and chi(2) tests, respectively. Associations between time to RVI and risk factors or survival were assessed by multivariable Cox proportional hazards models. Of 576 subjects, 79 subjects (14%) had 101 RVI in the first year post transplant. Subjects with RVI were younger than those without RVI (median ages 9.7, 13; P<0.01). Viruses detected included adenovirus (n=25), influenza (n=9), respiratory syncytial virus (n=21), parainfluenza virus (n=19), enterovirus (n=4), and rhinovirus (n=22). In a multivariable model for time to first RVI, etiology other than cystic fibrosis (CF), younger age, and no induction therapy were independently associated with risk of RVI. Cytomegalovirus serostatus and acute rejection were not associated with RVI. RVI was independently associated with decreased 12-month survival (hazard ratio 2.6, 95% confidence interval 1.6-4.4). RVI commonly occurs after pediatric lung transplantation with risk factors including younger age and non-CF diagnosis. RVI is associated with decreased 1-year survival.

Nonopsonic antibodies in cystic fibrosis. Pseudomonas aeruginosa lipopolysaccharide-specific immunoglobulin G antibodies from infected patient sera inhibit neutrophil oxidative responses.

Antibody opsonins from cystic fibrosis (CF) patients were investigated using nonmucoid and mucoid lipopolysaccharide (LPS) immunotype 1 Pseudomonas aeruginosa as bacterial ligands and PMN phagocytes. CF sera were compared to normal sera, polyvalent PA LPS hyperimmune globulin, and isotype switch variant monoclonal antibodies (MAbs) specific for type 1 PA LPS. Sera from PA-infected CF patients (CF PA+) had elevated levels of PA LPS and alginate IgG antibodies and promoted significantly greater antibody-dependent PMN chemiluminescence responses than sera from uninfected CF patients (CF PA-) or normal human sera (NHS). After adjustment for autologous IgG PA LPS antibody content, however, CF PA+ sera had less antibody-dependent opsonic activity than sera from CF PA- patients (P less than 0.025) or NHS (P less than 0.0025), suggesting qualitative opsonic defects of IgG PA LPS antibodies in CF PA+ sera. Antigen-specific immunoprecipitation of PA LPS antibodies enhanced opsonization by 40% of CF PA+ sera while uniformly reducing that from CF PA- sera (P less than 0.01), indicating LPS-specific nonopsonic antibodies in some CF PA+ sera. Alginate antibodies were not critical opsonins in most uninfected CF patient sera. PA LPS IgG antibodies isolated by immunoaffinity chromatography from NHS, hyperimmune globulin, and CF PA- sources were opsonic and had greater activity at equal antigen-binding concentration than identical antibodies isolated from infected CF patients (P less than 0.01-0.05); the majority of isolates from CF PA+ sera did not promote PMN oxidative responses above nonopsonic baseline. A potential isotypic basis for these findings was supported by differences in PMN responses to PA opsonized with MAbs of identical specificity but differing isotypes. PA LPS-specific IgG antibodies inhibiting PMN oxidative responses in infected patient sera demonstrate antigen-specific immunomodulation of host responses by chronic bacterial parasitism in CF, which may play a role in the pathophysiology of lung disease.

Longitudinal monitoring of pediatric cystic fibrosis lung disease using nitrite in exhaled breath condensate.

Cystic fibrosis (CF) lung disease is characterized by airway inflammation and airway infection. Nitrites in exhaled breath condensate (EBC-NO(2)(-)) have been shown to be increased in children and adults with CF compared to healthy controls suggesting its use as a measure of airway inflammation. This longitudinal study aimed to evaluate if repeated measurements of EBC-NO(2)(-) are helpful in monitoring CF lung disease activity in children. Thirty-two children with mild CF lung disease (age 10.6 +/- 3.3 years) were recruited in two study centers. Follow-up visits occurred every 3 months over a period of 1 year with a total of five visits. Each visit included a clinical assessment incorporating a modified Shwachman-Kulczycki (SK) score, spirometry, an oropharyngeal swab, or sputum sample for bacterial analysis and an EBC sample analyzed for NO(2)(-) using a spectrophotometric assay. Furthermore at the first and the last visit a chest radiograph was done and scored (Chrispin-Norman (CN) score). There was no correlation of EBC-NO(2)(-) and parameters of spirometry, SK-score, or CN-score. Furthermore, increased EBC-NO(2)(-) levels did not predict subsequent pulmonary exacerbations. We conclude that repeated measurements of EBC-NO(2)(-) are not helpful in the longitudinal monitoring of mild CF lung disease in children.

Health-independent lung transplantation information of parents of children with cystic fibrosis.

BACKGROUND: Twenty-one to 63% of patients with cystic fibrosis (CF) accepted for lung and heart-lung transplantation die on the waiting list. A significant delay between referral and assessment may present an unrecognized hazard toward mortality. METHODS: All parents of children with CF aged 3 to 15 years enrolled in the Vienna CF center were sent questionnaires to investigate their attitudes toward provision of information on lung transplantation (LT). RESULTS: Complete questionnaires were obtained from 59 mothers and 47 fathers of 60 children. Thinking of LT evoked anxiety among 88% of parents, yet 54% wanted to get information at the present time. Parents younger than 30 years and older than 40 years were most interested in obtaining information. Recommendations for the clinicians showed preference for early over health deterioration-induced information (58% vs. 42%). The predominant fears associated with LT were the risk of dying (91%), physical pain (90%), and graft rejection (80%). First information on LT should be presented by the usual CF physician (96%) in the form of a face-to-face conversation (97%) and in the absence of the child (77%). Among the desired content areas, information about the chances LT offers had highest priority (86%). Thorough explanation of the rationale behind the transplant proposal (81%) and details of the whole procedure were requested. If their child were to actually need a transplant, many parents would rely on the doctor's assistance in jointly talking to the child (64%). The most helpful interventions for decision-making included meetings with successfully transplanted individuals (84%) and repeated discussions with experts. CONCLUSIONS: Information may be implemented in medical care as a preventive strategy to avoid dangerous delays in case of unexpected turns toward the need for LT. A policy of recognition and acceptance of parental reluctance is mandatory.

Utilization of prenatal diagnosis for cystic fibrosis over the past seven years.

OBJECTIVE: First trimester prenatal diagnosis (PD) by DNA analysis for cystic fibrosis (CF) has been available for parents of affected children since May 1986. METHODS: In a prospective study 37 couples with a single child affected by CF were investigated. Fathers and mothers were interviewed simultaneously, and their attitudes towards further childbearing and potential utilization of PD ascertained. Parental answers were treated as one. A 7-year follow-up allowed comparison between intended and actual behavior. RESULTS: At the time of the interview, 16 parents (43%) were determined to have further children. Nineteen parents (51%) said they would certainly or probably utilize PD in case of pregnancy. Their predominant reason for favoring PD was the strong desire to have a healthy child (47%). Among the 18 rejectors (49%) the fear of an unsolvable conflict in case of an affected fetus prevailed (39%). Twenty-four pregnancies actually occurred in 18 families. Utilization of PD was arranged in five (21%) and finally performed in four (17%) cases. CONCLUSION: Availability of PD does not substantially change the reproductive behavior of parents of children with CF. Reasons for this were multifactorial, with anticipated difficulty in deciding to continue or terminate pregnancy being predominant.

Parents' recollection of the initial communication of the diagnosis of cystic fibrosis.

BACKGROUND: The diagnosis of a chronic disease in children challenges parents' emotional coping abilities and cognitive capacities. OBJECTIVE: To study parents' emotional and cognitive reactions to the diagnosis of cystic fibrosis (CF) in their children. METHODS: Postal survey by means of a written questionnaire. PARTICIPANTS: Forty-six parents of 29 children with a median age of 2 months at diagnosis. RESULTS: Most parents initially lacked knowledge of CF (76%) and were provided only oral information (96%). Parental estimates of how much of the information given they had understood and retained were 77% and 76%, respectively, with 15 parents (33%) having understood and remembered less than 50% of what the physicians had told them. The most frequent stressing feelings were fear (83%) and despair (56%). Fifty-four percent of parents had initial shocklike reactions. In this group, a significant decrease in the understanding and recall of information was noted compared with parents who had less-emotional responses. CONCLUSIONS: Parents learning the diagnosis are, in effect, receiving a kind of lecture, which contains more information than they can possibly assimilate. Because of the incompatibility of emotional distress and optimum learning, impairment of early comprehension and retention of information about CF is unavoidable. Repeated interviews with both parents and the provision of written and audiovisual materials should be mandatory.

Distilled water challenges in asthmatic children. Comparison of different protocols.

Inhalation of ultrasonically nebulized distilled water (UNDW) appears a promising candidate for routine challenge testing in bronchial asthma. We have compared two different methods of application of UNDW in 12 asthmatic children with a positive response to methacholine provocation (MCh), in an attempt to increase UNDW sensitivity and to establish standard testing protocols. In addition, results from UNDW challenges were compared to responses to inhalation of jet-nebulized distilled water (JNDW) and cold air (CACh). Compared to MCh, the sensitivity of continuously or intermittently (iUNDW) inhaled UNDW was 67 percent or 75 percent, respectively, when a positive response was defined by a greater than or equal to 20 percent fall in FEV1, but was higher when definition of a positive response was based on results from flow volume curves. Sensitivity of continuous or intermittent inhalation of JNDW was lower than for UNDW. The UNDW inhalations were better tolerated than CACh. Following stepwise iUNDW challenge, there was a clear reaction plateau for all variables measured. Results indicate that testing protocols with iUNDW inhalations over 6 to 10 min (corresponding to 7 to 11 ml water inhalation) yield the maximum sensitivity attainable with UNDW challenges, and require a minimum of patient and investigator effort.

Diabetes mellitus and cystic fibrosis: comparison of clinical parameters in patients treated with insulin versus oral glucose-lowering agents.

The prevalence of cystic fibrosis-related diabetes melltitus (CFRD) is increasing as patients with cystic fibrosis (CF) live longer. Because patients with CFRD are insulin-deficient, the standard medical treatment is exogenous insulin. Sulfonylureas enhance insulin secretion by acting on a specific islet beta cell receptor. No data are available about the outcome of sulfonylurea treatment vs. insulin treatment. In this retrospective study, data from 45 patients with CFRD were analyzed regarding their clinical outcome as it related to the treatment protocol. The duration of DM treatment was 7.6 +/- 4.6 years in the insulin-treated group and 3.5 +/- 2.0 years in the sulfonylurea group (n.s.). The age of CFRD diagnosis was significantly earlier in patients treated with insulin (n = 34) than in the patients treated with sulfonylurea (n = 11) (16.4 +/- 3.6 vs. 24.2 +/- 4.8 years, P < 0.001). No statistical differences were found between the two groups in the time of CF diagnosis, the most recent forced expired volume in 1 sec, forced vital capacity, Shwachman score, hemoglobin A(1C) levels, or weight for height index at the end of the study. Our data suggest that a subgroup of CFRD patients can be managed for a number of years with sulfonylurea, and that the clinical outcome was not different in this group compared with the insulin-treated patients.

Dent's disease: identification of a novel mutation in the renal chloride channel CLCN5.

Dent's disease is an inherited tubulopathy caused by a mutation in the CLCN5 chloride channel gene. It is characterized by low-molecular weight proteinuria, hypercalciuria, nephrolithiasis or nephrocalcinosis, rickets and eventual-progressive renal failure. Onset of clinical symptoms show a great variability, making a diagnosis at an early stage of the disease often difficult. Given the variably clinical picture, genetic analysis can provide a reliable method to confirm the diagnosis. Here, we report on the case of a patient with progressive renal failure showing signs of a tubular lesion and symptoms of Dent's disease. Although this rare disease was suspected by means of the clinical features, it was genetic analysis that confirmed the diagnosis and revealed a novel mutation in the CLCN5 gene.

Diabetes mellitus in patients with cystic fibrosis: the impact of diabetes mellitus on pulmonary function and clinical outcome.

In this multicenter study, the impact of CF-related diabetes mellitus (CFRD) on pulmonary function and clinical outcome has been investigated. To better characterize the relationship between insulin deficiency and clinical outcome we prospectively followed a group of 56 CF patients, 28 with CFRD (group 1) and 28 without diabetes (group 2) for 5 years. The clinical course of the patients was registered at each center. Data included were mortality, pulmonary function, body mass index, in-patient treatment, and CF-typical and diabetes typical complications. At the end of the study nearly twice the number of patients had died in group 1 as compared to group 2, however due to the low patient number this did not reach statistical significance. In patients with diabetes FEV1 and FVC declined significantly over the five year study period, whereas patients without diabetes did not show a significant decline during the study period. Retinopathy, nephropathy, and neuropathy were only observed in diabetic patients. In conclusion, the data presented in this prospective, multicenter study give evidence that insulin deficiency leads to a direct decline in pulmonary function suggesting a cause and effect relationship between insulin deficiency and lung disease.

Effects of long-term oral beta-carotene supplementation on lipid peroxidation in patients with cystic fibrosis.

The aim of this study was to determine the efficacy of oral beta-carotene supplementation for the correction of an oxidant-antioxidant imbalance in cystic fibrosis (CF). We studied 24-patients with cystic fibrosis and 14 healthy controls. 13 CF-patients were allocated to a CF-supplementation group, which received 1 mg beta-carotene/kg BW/d up to a body weight (BW) of 50 kg, patients with a BW greater 50 kg received 50 mg beta-carotene/d for 12 weeks. For the following 12 weeks all patients of the CF-supplementation group were treated with 10 mg beta-carotene/d. Placebos with starch were applied to 11 CF-patients. Baseline plasma beta-carotene concentrations of CF patients (mean +/- SD, 0.08 +/- 0.04 mumol/l) were significantly lower than those of age-matched controls (o.3 +/- 0.1 mumol/l) (p < 0.001). beta-carotene concentrations of the CF-supplementation group increased rapidly and reached a value of 0.6 mumol/l after 12 weeks of supplementation. Normal values were measured for plasma ascorbate and alpha-tocopherol. Plasma retinol concentrations were in the lower normal range and did not increase during supplementation. Total antioxidative capacity in plasma of the CF-supplementation group increased after 12 weeks of supplementation at an extent of 12%. Positive influence was indicated by a decrease of plasma malondialdehyde. Thus oral beta-carotene supplementation is effective in normalizing status of beta-carotene and malondialdehyde in CF patients.

[The bismuth-encephalopathy - a new pathological syndrome (author's transl)]. / Die Wismutenzephalopathie - ein neuartiges Krankheitsbild?

The publications concerning cases of bismuthencephalopathy seen in Australia, France, Switzerland and the Federal Republic of Germany are reported. The potential mechanisms of the development of this "new disease" are discussed.

[Effect and effectiveness of iodine brine baths in a spa]. / Zur Wirkung und Wirksamkeit von Jodsodsolewässern im Kurbad.

On the occasion of closing the research department of the Paracelsus Institute in the iodine salt spa, Bad Hall, the results of more than 30 years' research work in this institute are summarized. This work concerned the therapeutic effects of iodine on circulatory illnesses, especially hypertension, bronchitis and degenerative eye diseases. Controlled studies in patients showed significant cure effects of the iodine springs. Other studies demonstrated an influence of iodine on peripheral blood vessels, blood viscosity, connective tissue and vision and demonstrated the scavenger function of iodine, too. The different therapeutic forms of iodine administration (baths, sprays, iontophoresis, drinking cures) are described and the potential side effects of a cure in an iodine spa, notably temporary hypothyroidism, are mentioned.

Blockade of T-lymphocyte KCa3.1 and Kv1.3 channels as novel immunosuppression strategy to prevent kidney allograft rejection.

Currently, there is an unmet clinical need for novel immunosuppressive agents for long-term prevention of kidney transplant rejection as alternatives to the nephrotoxic calcineurin inhibitor cyclosporine (CsA). Recent studies have shown that K(+) channels have a crucial role in T-lymphocyte activity. We investigated whether combined blockade of the T-cell K(+) channels K(Ca)3.1 and K(v)1.3, both of which regulate calcium signaling during lymphocyte activation, is effective in prevention of rejection of kidney allografts from Fisher rats to Lewis rats. All recipients were initially treated with CsA (5 mg/kg d) for 7 days. In rats with intact allograft function, treatment was continued for 10 days with either CsA (5 mg/kg d), or a combination of TRAM-34 (K(Ca)3.1 inhibitor; 120 mg/kg d) plus Stichodactyla helianthus toxin (ShK, K(v)1.3 inhibitor; 80 microg/kg 3 times daily), or vehicle alone. Kidney sections were stained with periodic acid-Schiff or hematoxylin-eosin and histochemically for markers of macrophages (CD68), T-lymphocytes (CD43), or cytotoxic T-cells (CD8). Our results showed that treatment with TRAM-34 and ShK reduced total interstitial mononuclear cell infiltration (-42%) and the number of CD43+ T-cells (-32%), cytotoxic CD8+ T-cells (-32%), and CD68+ macrophages (-26%) in allografts when compared to vehicle treatment alone. Efficacy of TRAM-34/ShK treatment was comparable with that of CsA. In addition, no visible organ damage or other discernible adverse effects were observed with this treatment. Thus, selective blockade of T-lymphocyte K(Ca)3.1 and K(v)1.3 channels may represent a novel alternative therapy for prevention of kidney allograft rejection.