Allergen Immunotherapy (AIT) in children: a vulnerable population with its own rights and legislation - summary of EMA-initiated multi-stakeholder meeting on Allergen Immunotherapy (AIT) for children, held at Paul-Ehrlich-Institut, Langen, Germany, 16.1.2019.

Concerning development of medicinal products, children belong to a so-called "special population" for which additional legislation applies: Regulation (EC) No 1901/2006 on medicinal products for paediatric use sets up a system of requirements, rewards and incentives to ensure that medicinal products are researched, developed and authorized to meet the therapeutic needs of children. Allergen Immunotherapy (AIT) is believed to contain a strong potential for immunomodulatory effects inducing sustained clinical efficacy after cessation of treatment (disease modifying effect) and thereby may prevent the progression of the atopic march towards asthma manifestation. However, to this day only few data on long-term effects in general exist and even fewer in children. These are predominantly data from open studies, which are strongly influenced in their validity by the known placebo effect of AIT. Furthermore, there are no studies allowing for the conclusion that efficacy in adults are mirrored by a similar efficacy in children and thus, up to now, it is not possible to extrapolate data from adults to children. The Paediatric Committee (PDCO)-European Medicines Agency's (EMA) scientific committee responsible for activities on medicines for children-initiated a Multi-Stakeholder Meeting on AIT for Children held at the Paul-Ehrlich-Institut in Langen, Germany, to provide a platform for discussion and exchange of thoughts to this topic between allergy experts from academia, regulators and AIT-manufacturers. The consented meeting minutes, conclusions and participants are presented.

User preferences for a mobile application to report adverse events following vaccination.

The passive surveillance system is an important tool in pharmacovigilance of vaccines. However, reporting of adverse events following immunization (AEFI) post-marketing has limitations regarding under-reporting, biased reports and lack of exposure data resulting in imprecise estimates. New mobile application technology may provide an opportunity for an enhanced surveillance. A pre-requisite for the use of new app-based technology is to identify practical challenges and end users' preferences for design of app-features. The objectives were (i) to investigate the recruitment and feasibility of an app-based study in Germany, (ii) to assess individuals' motivation to participate in such a study and (iii) to identify app-features for reporting AEFI. We conducted a cross-sectional study among employees of a financial institution who attended the occupational health office during the seasonal influenza vaccination in November 2017. Participants tested feasibility and assessed an app prototype for AEFI reporting by using a case vignette and a questionnaire. Of the 153 attending employees, 65 (42%) agreed to participate and returned the questionnaire. Twenty-three (63%) rated the experience of reporting AEFI with the app prototype to be positive. Among three features offered for gamification, collecting points was most frequently chosen (n=22, 34%). The main reason for declining participation was the apprehension about data protection (n=28, 43%). Results suggest that the app-based technology was well accepted and is a suitable supplement for AEFI reporting and in our study. A convincing data protection concept is likely to enhance acceptability of such a system.

Rotavirus vaccination: a risk factor for intussusception?

Recently published pharmacoepidemiological studies associate the currently authorized Rotavirus (RV) vaccines with intussusception (IS). We aimed at investigating whether, in Germany, there are excess IS cases in RV vaccinees compared with the background incidence before market authorization in 2006. Suspected cases of IS following receipt of RV vaccines reported to the Paul-Ehrlich-Institut (PEI) from 2006 to 2010 were reviewed and validated against the criteria of the Brighton Collaboration's definition for IS. An observed-versus-expected analysis was conducted using standardized morbidity ratio (SMR) methods based on age-specific incidence rates for IS ranging from 19.2 to 98.5 per 100,000 person-years. A total of 27 cases of suspected IS in RV vaccinees were reported to the PEI. No excess of IS cases could be detected 1-7 days after receipt of either RV vaccine after any dose in the first year of life; however, in infants aged 3-5 months, a significantly increased SMR for IS was found in a risk window of 1-7 days after the first dose of either RV vaccine [SMRs: Rotarix® 4.6 (95% CI 1.5-10.7); RotaTeq® 5.8 (95% CI 1.2-17.1)]. A significantly increased risk of IS in a risk window of 1-7 days after RV vaccination was not found when the first dose was administered earlier. Therefore, it is recommended to start the vaccination course at 6-12 weeks of age.

[Safety and tolerability of monovalent measles and combined measles, mumps, rubella, and varicella vaccines]. / Sicherheit und Verträglichkeit von monovalenten Masern- und kombinierten Masern-, Mumps-, Röteln- und Varizellenimpfstoffen.

Although effective monovalent and combined measles vaccines have been available for several decades in Germany, measles outbreaks continue to occur leading to severe cases of measles and even death. Possible reasons for the low acceptance of the measles vaccination are concerns about adverse events and serious complications following vaccination. In this report, we have summarized and assessed all adverse events reported in Germany from 2001 to 2012 after vaccination with monovalent- and combined measles-containing vaccines. A total of 1,696 suspected adverse reaction reports describing 5,297 adverse events were sent to the Paul Ehrlich Institute (PEI) between 1 January 2001 and 31 December 2012. The calculated mean reporting rate was 5.7 reports per 100,000 vaccine doses released by the PEI. Analysis of the reports indicates that measles-containing vaccines are well tolerated with a constantly low rate of adverse events reported. Compared to the high rate of serious complications following wild-type measles infection, the benefit of measles-containing vaccines clearly outweighs the anticipated risks of adverse events.

[Clinical trials in children--between the expectations of scientific requirements, the assurance of proven treatment and ethical demands]. / Klinische Prüfung an Kindern im Spannungsfeld zwischen wissenschaftlichen Anforderungen, der Sicherstellung der korrekten Behandlung und ethischen Aspekten.

Regulation (EC) No. 1901/2006 of the European Parliament and the Council dated 12 December 2008 on medicinal products for paediatric use is the result of a survey by the European Commission, concluding that children in the European Union are inadequately treated with medicinal products. The Regulation is addressed to the pharmaceutical industry with the intention to place medicinal products on the market and to the Member States to register all information on medicinal products for the treatment of children. The pharmaceutical industry will be obliged to conduct clinical trials in children for new medicinal products and medicinal products still under patent. This will be supported by incentives and rewards. As a consequence of the requirement to conduct clinical trials in children the framework and conditions have to be defined and ethical considerations have to be respected.

[Adverse drug reactions following immunization in Germany pursuant to the German Infection Protection Act and the German Medicinal Products Act from January 1, 2004 to December 31, 2005]. / Verdachtsfälle von Impfkomplikationen nach dem Infektionsschutzgesetz und Verdachtsfälle von Nebenwirkungen (von Impfstoffen) nach dem Arzneimittelgesetz vom 1. 1. 2004 bis zum 31. 12. 2005.

Sufficient post-marketing surveillance is necessary for safety monitoring of vaccines. In this respect the spontaneous reporting system of reporting suspected adverse drug reactions (ADR) following vaccination is an essential tool for safety monitoring. The marketing authorization holder and/or pharmaceutical manufacturer has the legal obligation to report suspected adverse drug reactions (German Drug Law and European Regulation). In addition physicians and traditional healers have to report suspected cases of complications after immunizations pursuant to the German Infection Protection Act (Infektionsschutzgesetz, IfSG). The reports are medically assessed and stored in a database at the Paul Ehrlich Institute. For the publication referenced here, all reported suspected cases of adverse drug reactions after immunizations were evaluated for the period from January 1, 2004-December 31, 2005 according to different criteria. In 2004 (2005) a total of 1237 (1393) suspected cases of adverse drug reactions or suspected complications after immunizations were notified. 858 (919) of these adverse drug reactions (ADR) were serious (69 % and 66 %, respectively). 414 (517) of the ADRs (i.e. 33 % and 37 %, respectively) were reported by physicians according to the IfSG; the other reports were from industry and other reporting sources. 251 (229) i.e. 61 % (44 %) of these reactions were serious. The total number of reports divided by the total number of vaccine doses launched on the German market during the observation period (according to the data provided by the pharmaceutical industry) revealed an overall "reporting rate" of approx. 3 reports per 100,000 vaccine doses. The age groups with the highest absolute number of reported cases were infants and young children (0-2 years), and adults (18-59 years) accounting for approx. one third each of the reports. The age distribution of the suspected cases was comparable with that of previous years. In both years, approx. half of all suspected adverse drug reactions following immunization were of transient nature, i.e. there was a complete recovery (restitution ad integrum). In both years, a very small proportion of cases were reported as permanent damage (30 and 34 cases respectively; 2.4 % of all cases) or resulted in death (35 or 23 cases, respectively; 2.8 % or 1.7 %, respectively). With a few exceptions these adverse events were considered to be related to other diseases and unlikely related to vaccination. Overall, the association between vaccination and adverse events was assessed by the PEI as "possible" in 58 % (62 %) of all cases, respectively, as "likely" in 6 % (8 %) of all cases, and as "certain" in 0.4 % (0.6 %) of all cases. In 14 % (13 %) of the cases, the causal relation was stated as "unlikely". In 17 % (15 %) of all cases, a scientific evaluation was not possible on the basis of the data provided. A separate analysis of reports was conducted for all suspected adverse drug reactions following varicella immunization. According to these data varicella vaccination is considered to be well tolerated. With the exception of an increase in local reactions following pneumococcal polysaccharide vaccination no new safety signal has been recognised during the observation period.

[Nervous system manifestations in HIV infected children]. / Affektionen des Nervensystems bei perinatal HIV-infizierten Kindern.

In 34 perinatally HIV infected children time of manifestation, type and treatability of neurologic disorders were investigated for a period of 7 years (1987-1994). Neurological investigations were done every 6 months; EEG and MRI/CT were examined initially in the asymptomatic stage and were repeated when neurologic Symptoms occurred. Zidovudine therapy was started after onset of symptoms, dosage was raised, when treatment with Zidovudine had already begun (600-720 mg/m2/day). Various neurological manifestations were seen in 4 of 12 patients in stage B (33%) and in 11 of 14 children in AIDS (80%). 7 of the 14 AIDS-patients (50%) developed a subacute progressive course or progressive plateau course and 4 of 14 (30%) a static course of encephalopathy. Pathological changes in EEG were seen in 54% of investigated patients with neurological deficits. Neuroimaging revealed pathological findings in all symptomatic subjects, 6 of 11 patients in AIDS (55%) has a severe general cerebral atrophy and multifocal white matter lesions. Zidovudine had a positive temporary effect from 6 to 12 months in 5 of 11 treated patients (45%). At present a thorough neurological examination is the most sensitive method to detect neurological impairment in HIV infected children. In most cases CT/MRI scan provides information about the course of the encephalopathy. Antiretroviral therapy has a limited benefit, if neurologic symptoms start after the second year of life.

Immune tolerance therapy in paediatric haemophiliacs with factor VIII inhibitors: 14 years follow-up.

We report our clinical experience in the immune tolerance (IT) therapy of 21 paediatric haemophiliacs with FVIII inhibitor: high responders (16HR) received initially FVIII twice daily at a dosage of 50-300 U/kg/day, 11/16 received a concomitant treatment with activated prothrombin complex concentrate (100-200 U/kg/day). Low responders (five LR) received 20-100 FVIII U/kg every second or third day. Inhibitor elimination was achieved in 19/21 patients in a median time of 4 months in HR and 1.5 months in LR. The outcome and length of time needed to induce IT was significantly correlated with FVIII exposure between the first inhibitor detection and onset of IT therapy and to interruption of IT therapy. For a rapid elimination of FVIII inhibitors it is important to start continuous administration of high-dose FVIII (≥ 100 FVIII U/kg/day) before repeated exposure to FVIII, in order to prevent rebooster effects, prolongation of elimination time, and to reduce expense.

Haemate P in children with von Willebrand's disease.

In our center, 289 children with von Willebrand's disease (vWD) have been diagnosed since 1982. The majority of cases (n = 198) were congenital vWD whereas 91 patients suffered from vWD induced by valproate (VPA). We overview bleeding episodes in 45 children and 64 operative procedures requiring therapeutic intervention. The aim of therapeutic and prophylactic procedures in vWD is correcting the hemostatic disorder and normalization of bleeding time. This can be achieved by application of Haemate P leading to an elevation of plasma levels of von Willebrand parameters together with normalization of bleeding time. In patients with vWD type I, DDAVP will be preferred if contraindications can be excluded and efficacy has been shown. Severe bleeding complications could be prevented in a total of 50 surgical procedures in children with vWD type I by prophylactic treatment with DDAVP or Haemate P. Two children initially treated with DDAVP had to be substituted with Haemate P in the follow-up because of continuous bleeding. In type IIa and type III vWD as well as in VPA-induced vWD, the use of Haemate P was essential for sufficient hemostasis in all bleeding and operations. We conclude that Haemate P provides effective bleeding prophylaxis and treatment in all types of vWD except platelet-type.