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Published on 1 March 2007

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ESCP special paediatrics report: moving on with legislation and information

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Laurence A Goldberg
FRPharmS
Editorial Consultant
HPE
E: lag@salt.u-net.com

Children account for 20% (100 million people below the age of 18 years) of the European Union population, and they can be divided into five different subpopulations according to their developmental, physical and psychological differences, Annic Weyersberg (European Medicines Evaluation Agency, Medicines for Paediatric Use Project, London, UK) told the audience.

Up to 90% of paediatric medicines have not been tested in children. Part of the reason for this is that trials in children are complex, involve higher costs than adult trials, require special formulations and are still sometimes regarded as being unethical. In general, medicines for paediatric indications are not profitable and the pharmaceutical industry is reluctant to undertake studies in children. Some studies are conducted in the USA, but the data are not necessarily submitted to competent authorities in Europe, she noted.

Conducting clinical trials in children is particularly challenging because appropriate doses and formulations are often not available and there may be a greater risk of adverse events. The type of information that has to be provided with paediatric products is also more complex. Details of indication and age limits need to be included, along with posology for different subpopulations,with details of dosing by weight or surface area if appropriate. If justified, there should be instructions for the preparation of extemporaneous products. Specific information should be provided about interactions, especially if the previous studies have involved only adults.

Reviewing progress so far, Dr Weyersberg said that data on paediatric products throughout Europe had been gathered with a view to harmonising the available information, and the Paediatric Expert Group (PEG) had been established to identify paediatric needs in different therapeutic areas. The PEG is also concerned with scientific and regulatory guidelines, for example those relating to the investigation of medicinal products in neonates.

The Paediatric Regulation is designed to improve the health of children by increasing the amount of high-quality, ethical research on medicines in paediatrics. One of its provisions is the introduction of paediatric investigation plans (PIPs) that specify the research and development work that will be done in regard to paediatric formulations when a marketing authorisation application is made. The incentive for following the PIP is a six-month extension in the patent life of the product.

Some of the key changes in information about paediatric medicines will be:

  • The introduction of a paediatric symbol that will be used on all products that have paediatric indications.
  • The inclusion of all study results in the summary of product characteristics and package leaflets.
  • The establishment of an inventory of use by EU Member States and a register listing all the medicines used in paediatrics in EU Member States.
  • The introduction of a database of clinical trials.
  • The publication by the EMEA of all clinical trials involving paediatric medicines, including those that have to be discontinued early.
  • The establishment of community funding for studies of “off-patent” medicinal products where this is linked to identified needs.

The net result of all these measures is that the development of paediatric medicines will become an integral part of the development of adult medicines.

Medicines information
More research is still needed into children’s requirements for information about medicines, according to Theo Raynor (Professor of Pharmacy Practice, University of Leeds, UK). Children are interested in health and medicines – as was shown by the success of websites such as Teenage Health Freak (see Resources) – and they have a right to be informed about their medicines. In developing information for children, we should first consider what is known from research in adults, he said.

Medicines information for consumers is often very poor. A focus group of patients with asthma had told researchers that the printing on drug information leaflets was always too small, the information that they wanted did not come first and, in general, they were “uninspiring”. Most people do not value written information highly and do not want it as a substitute for spoken information. Furthermore, written information does not influence compliance if given in isolation. Research shows that most patients want as much information as possible about side-effects. People would also like more information to help them with the decision about whether to start to take a medicine. This shows that information can play an important part in concordance, he pointed out. However, some healthcare professionals thought that information should be kept short and to the point and not give details about side-effects. Research in children had tended to focus on the use and perception of medicines, and children reported feeling excluded from discussions with adults.

It is important to make information appealing. The comic-strip format is not necessarily attractive to children, and pictograms are good for concrete information but can be culturally sensitive, said Professor Raynor. Some new approaches might be explored with children, for example web-based information.

Many package insert leaflets say “Not recommended for use in children”, and this causes major problems for paediatric practitioners because often when patients or parents read them they decide that it might be better not to use the treatment at all, explained Steve Tomlin (Principal Paediatric Pharmacist, Guy’s and St Thomas’ NHS Foundation Trust, London, UK). Up to 90% of patients in a paediatric hospital could be receiving medicines for off-label or unlicensed indications, and providing information of suitable quality is a problem. When explanations about unlicensed use of medicines had been tested in children they had reported that they did not understand it and also that it was boring. One solution was to produce their own information, but this raised numerous concerns such as accountability, who should undertake the writing, whether the information should be written for toddlers, older children, teenagers or adults, and what should be included. The priority given to some pieces of information was critical; for example, for adolescent patients, weight gain was a more important consideration than liver or renal damage. Another issue was helping people to interpret instructions such as “Tell your doctor if this happens”. It was helpful to clarify whether this meant that patients should contact the doctor immediately or wait until the next appointment. Generic leaflets might also lead to problems; in the UK two different strengths of phenytoin suspension are available, one with 30mg in 5ml and one with 90mg in 5ml – parents tend to remember dose volumes rather than the doses in milligrams and, at present, this leads to several adverse events each year,
he said.

Work is now ongoing at Guy’s and St Thomas’ Hospital to develop an interesting and readily comprehensible way to convey the key pieces of information to help parents and children to manage their treatment effectively.

Oncology
Pharmacists face considerable challenges when treating children with cancer, but the work is professionally satisfying, Judith Delaney (Lead Pharmacist for Haematology/Oncology, Great Ormond Street Hospital, London, UK) told the audience.

Childhood cancer is relatively rare – 1,700 cases are diagnosed annually in the UK, compared with about 300,000 adult cases. Leukaemia accounts for approximately one-third of all childhood cancers, and brain tumours represent the next most common category. The overall five-year survival is about 75%.

Children develop different cancers from adults and in general the cure rates are good. However, medicines are often used “off-label”, suitable formulations may be lacking, and information about short- and long-term effects is often not available. One illustration of this point was the treatment of standard-risk hepatoblastoma, a condition that affects about eight children per year in the UK. Although there is a 91% overall three-year survival rate, recent studies have shown that 59% of children who have received cisplatin develop hearing impairment. The SIOPEL-6 study (see Resources) was designed to investigate the otoprotective effects of sodium thiosulphate in patients receiving cisplatin chemotherapy for standard-risk hepatoblastoma. This presented numerous challenges because sodium thiosulphate is an unlicensed product, with very few data in children and no standardised formulation. A paediatric datasheet was needed because the dose required was greater than that normally used for cyanide poisoning.

Ms Delaney described her role as a member of a multidisciplinary team (MDT) (see Box). In future, her job would involve more direct contact with patients and their families, a greater role in palliative care and more time on the daycare unit for preclinic meetings and screening of prescriptions for oral medication.

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The benefits of nutritional support in children with cancer are now well established. Jean-Baptiste Rey (Pharmacy Department, Reims University Hospital, France) described the factors that determine nutritional requirements of children with cancer and how treatment should be managed. Adequate nutrition in these children is particularly important because they have both maintenance and growth requirements. In addition, they often undergo aggressive chemotherapy, and nutritional support is known to improve the prognosis. Poor nutrition can be related to the presence of the tumour; 30% of patients suffer from anorexia, tumours increase energy requirements, and in some cases digestive function is compromised by compression or tumour infiltration.

Other factors that contribute to poor nutrition include anorexia due to mucositis or chemotherapy-induced nausea and vomiting, catabolism associated with infections and malabsorption due to multiple courses of chemotherapy. Nutritional support has to be regarded as part the overall care offered by the oncology clinical pharmacist. Aspects such as pain control and the management of side-effects should also be considered.

Resources
Teenage Health Freak
W: www.teenagehealthfreak.org
Childhood Liver Tumours Strategy Group
W: www.siopel.org



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