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The development of medicines for children
Pharmacological Research 64 (2011) 169–175
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Review
The development of medicines for children Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni Francesca Rocchi a,∗ , Paolo Tomasi b a b
European Assessment Unit – Agenzia Italiana del Farmaco (AIFA), via del Tritone 181, 00187 Rome, Italy Head of Paediatric Medicines, European Medicines Agency, 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom
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Article history: Received 26 January 2011 Accepted 27 January 2011 Keywords: Child Drug approval Clinical trial Europe Drug legislation
a b s t r a c t The lack of availability of appropriate medicines for children is an extensive and well known problem. As a consequence off label or unlicensed administration of medicinal products in every day paediatric practice is frequent. A variety of obstacles hinder the development of paediatric indications for drugs primarily intended for the adult market. The barriers to proper research on children’s drug development include several complex factors, such as the limited commercial interest, lack of suitable infrastructure and competence for conducting paediatric clinical trials, difficulties in trial design, ethical worries and many others. Medicinal products used to treat children should be subjected to ethical research of high quality and be explicitly authorised for use in children as it happens in adults. Conducting adequate clinical trials in children is challenging and demanding. Identification of paediatric medical needs, extrapolation from adult data, modelling and simulation, specific clinical trial methodology are important features in the development of drugs intended for children. Market forces alone have proven insufficient to stimulate adequate research aimed at specific authorisation of medicinal products for the paediatric population, and for that reason, following the US experience, the European Paediatric Regulation has been amended in January 2007 by the European Commission. The objective of the Paediatric Regulation is to improve the development of high quality and ethically researched medicines for children aged 0 to 17 years, to facilitate the availability of information on the use of medicines for children, without subjecting children to unnecessary trials, or delaying the authorisation of medicines for use in adults. The impact of the Paediatric Regulation reflects in an increase in the number of paediatric studies to be performed, even if a significant number of these studies have not started yet. The objective of this review is to describe the main regulatory and scientific features which play a role in the complex issue of paediatric drug development. © 2011 Elsevier Ltd. All rights reserved.
Contents 1.
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. The European regulatory environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Few data are available on the safety and efficacy of medicines in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Harm is associated with off-label use in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Barriers to the development of medicines for children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. The problem of paediatric pharmaceutical forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6. Ethical issues of conducting research in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7. Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author. Tel.: +39 06 59784140. E-mail addresses: [email protected] (F. Rocchi), [email protected] (P. Tomasi). 1043-6618/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2011.01.016
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Conducting clinical trials in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Identification of paediatric needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The role of extrapolation, modelling and simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Clinical trial methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The EU Paediatric Regulation and paediatric drug development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The need for legislative intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Impact of the EU Paediatric Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. The Paediatric Investigation Plan (PIP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Applications for a PIP need to be submitted early . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Deferrals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Waivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Paediatric development is in principle obligatory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. The Paediatric Committee (PDCO) of the European Medicines Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Globalization of the development of paediatric medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Financial incentives to the development of paediatric medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. ENPREMA: the European Network of paediatric research at the European Medicines Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclaimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Background Drug development is a very complex process, that revolves around a balancing of requirements of several stakeholders, including those of science, pharmaceutical industry, regulatory authorities, ethics, politics and, not least, patients. The main goal is to guarantee that high quality medicines with a favourable benefit/risk profile are made available to the individuals who need them. 1.1. The European regulatory environment Prior to marketing a medicinal product in the European Union (EU), a marketing authorisation (product licence) must be obtained. This means that the products have to undergo specific “regulatory” studies to ensure its quality, safety and efficacy for use in the target population. These studies are often not published in peer-reviewed journals, as this is not a requirement for registration; nevertheless, the quality of these regulatory studies is very often higher than that of published studies, as the limitations of the peer review system are well known [1,2]. Furthermore, regulatory agencies that decide on marketing authorisation have the possibility to conduct inspections of trial sites and original data, something usually impossible for academic journals and peer reviewers. In the EU, there are four types of marketing authorisation: 1. National marketing authorisations: issued by the competent authorities of individual EU member states; the medicinal product may be put on the market in all Member States that have granted an authorisation for it. 2. Community marketing authorisation: this is a single authorisation that allows the medicinal product to be put on the market in all Member States. It is granted by the European Commission, following a positive opinion from the European Medicines Agency (EMA). 3. Mutual Recognition Procedure: that means that European countries may approve the decision made about a medicinal product by another European country. 4. Decentralised procedure: used for products that have not yet received authorisation in an European country. In both cases, the conditions of use are laid down in the summary of product characteristics (prescribing information for health professionals), the labelling, and the package leaflet (for users/patients).
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A summary review of the regulatory processes for the authorisation of medicinal products in the EU is contained in the guide for small and medium enterprises published by the EMA [3].
1.2. Few data are available on the safety and efficacy of medicines in children Until now, a lack of information on the paediatric uses of most medicinal products has continued to affect the paediatric population (in the European Union, this refers to children from birth to less than 18 years old). Even if children represent more than 20% of the European population, with about 100 million people aged less than 18 years, children have often been denied proper access to new medications, or they are treated with medications which have not been subjected to a scientific assessment in the same age groups. The lack of specific labelling recommendations for the paediatric population is a long-standing worldwide problem: it is estimated that 50–75% of medicines used in children have not been studied adequately in the paediatric population [4–7], and many have not been tested at all [8]. When special paediatric populations are considered, the situation is even worse: more than 80% of medicines for children with cancer and about 90% of prescriptions for neonates are for products which have not been licensed for that use [9–11]. Often, an assumption that safety and efficacy will be the same as in adults is implicitly accepted, but this is very often not based on any evidence. Using medicines that have not been approved by the appropriate regulatory authorities in the specific age groups makes children, particularly the younger ones, constant participants in uncontrolled N-of-1 trials.
1.3. Harm is associated with off-label use in children The consequence of the above is frequent off-label administration of medicinal products in everyday paediatric practice. Off-label use (which means outside the terms of the marketing authorisation) may be supported by limited evidence in the form of published reports in the scientific literature, not followed by explicit regulatory approval. However, in some cases no evidence at all is available to support the use in a given indication/condition. This last occurrence, which may put children at increased risk, is considered tantamount to unauthorised clinical experimentation by some national legislations, with possible serious consequences to the practitioners (in addition to the risk for the patients).
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Lack of suitably adapted medicinal products for children means inadequate dosage information, which may lead to an increased risk of adverse reactions, including death, or to ineffective treatment through under-dosage. Other consequences are non-availability to the paediatric population of therapeutic advances, suitable formulations and routes of administration, non compliance, and use of magistral or extemporaneous formulations (which may be of poor quality). There is sufficient evidence that harm from off-label or unlicensed use of medicinal products in children does occur, and is underreported [12]. 1.4. Barriers to the development of medicines for children A variety of obstacles hinder the development of paediatric indications for drugs primarily intended for the adult market. The barriers to proper research on children’s drug development are long-lasting and include several complex factors. The main determinant is probably the limited commercial interest, as the paediatric population is smaller and healthier than the adult population, and therefore diseases are rarer and often of shorter duration, implying a limited market for paediatric medicinal products. In addition, several other factors play a role: lack of suitable infrastructure and competence for conducting paediatric clinical trials, difficulties in trial design (including ethical difficulties), potential risks of affecting health, in particular growth or sexual development, long after the administration of the drug, difficulties in determining or predicting the paediatric dose–response or concentration–response relationship, and the additional time required to complete studies in children as compared in adults. Paediatric clinical trials of new products are often started many years after initiation or even completion of studies in adults, and involve testing at arbitrary doses and schedules on the basis of scaled down versions of those used in adults. By this time often the drugs are already off-patent, and the financial incentive for the pharmaceutical company to be involved in this phase of development will have lapsed [13]. 1.5. The problem of paediatric pharmaceutical forms For oral drugs, a formulation suitable for very young children (who are generally unable to swallow tablets or capsules) is often unavailable. As a consequence, clinicians have had to improvise, to administer such drugs to these children, with often unknown pharmacokinetic consequences. The magnitude of doses required through childhood can vary up to 100-fold, and the ability to cope with different dosage forms can also vary considerably. Thus, if a medicinal product is to be used in all age groups, a range of different dosage forms should be available providing different strengths or concentrations to allow simple, accurate and safe dosing. A detailed concept paper on the formulations of choice for the paediatric population has been adopted by the European Medicines Agency, and is available on its website [14]. 1.6. Ethical issues of conducting research in children Even though there could be some theoretical concerns in conducting trials in the paediatric population, this has to be balanced by the ethical issues correlated to giving medicines to a population in which they have not been tested, and therefore their effects, positive or negative, are unknown. The ethics of using child research to guide risk assessment in balance with the potential benefit to the single child, and children in general, is constantly evolving.
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Today, the balance of scientific and ethical consensus has swung away from emphasizing the need to protect children against research, to the need of having reasonable evidence of both safety and efficacy of paediatric medicines. Children will always need protection in research; however, research to improve child health is now perceived as an ethical obligation and delays in passing benefits from pharmaceutical progress is considered unethical. Nevertheless, in everyday practice paediatricians very often face the dilemma of whether to prescribe a drug that has not been studied for children, or to deny a potential useful treatment to a sick child. It is exactly to reduce the instances of such dilemmas that clinical data on the paediatric use of medicines are needed. Children of different ages are vulnerable groups with specific developmental, physiological and psychological differences from adults, which make age and development related research of medicines particularly important. In terms of both public health and ethics, it is clearly preferable to test medicines in children, in a safe and controlled paediatric clinical trial environment, where the individual child is protected. 1.7. Objective Optimizing the health outcomes of children has the potential for a big impact on public health because children are at an early stage in the life trajectory. The under-investment in paediatric clinical trials is a good example of how our resource allocation may be insufficient. Over the last few decades, the drug development specifically designed for children has passed from the tight attention of few to the attention of a wide group of stakeholders, especially government and regulatory authorities. 2. Conducting clinical trials in children 2.1. Identification of paediatric needs When developing a medicinal product, the first step is to identify if there is a potential need for the product in children. This is now required because of the legislative obligations introduced by the Paediatric Regulation. Importantly, children are not a single homogeneous group, as preterm neonates as well as post-pubertal adolescents are both paediatric age groups, but with clearly different size, development, maturation of biochemical pathways, response to therapy. 2.2. The role of extrapolation, modelling and simulation The design and implementation of paediatric clinical trials remains a challenging problem. Ethical, practical and economic considerations have caused the use of medicinal products in children to be based on empirical extrapolations from clinical trials in adults. Once the paediatric needs and the study question have been clarified, the possibility of replacing some studies, or reducing the number of patients involved, through extrapolation, modelling and simulation should be discussed. Unnecessary clinical trials in children should be avoided, and the use of extrapolation for efficacy is encouraged by current guidelines [15]. Extrapolation of efficacy, from adults to children (or from older to younger children or vice versa) is allowable under certain circumstances. If the pathophysiology of the disease, its progression, and its response to therapy are known to be similar, then a specific demonstration of efficacy may not be required (e.g. in some infectious diseases). However, dose-finding/PK studies and safety studies are usually necessary, as these aspects cannot usually be extrapolated.
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Since conducting unnecessary studies in children is unethical, the possibility of extrapolation should be considered in all cases of development of paediatric medicinal products; however in most cases at least some studies will be required to support the use in children. Modelling and simulation is a methodology widely used in the exploratory context with great acceptance from both industry and regulators. It is one way to circumvent some difficulties in developing medicinal products in children. This approach allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/pharmacodynamics, extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. However, its pivotal use is controversial but in the case of paediatrics, where ethical and practical constrains necessitate smaller trials, this methodology could have a more important role in the regulatory assessment [16].
2.3. Clinical trial methodology Because children are not small adults, the methodology used to design trials involving children needs to be adapted from that used to design trials in adult patients. A paediatric trial must be conceived and developed in its own right. This may involve particular attention to the exploration of alternative designs [17]. In some cases, a feasibility study may be required, to determine whether it is possible to complete a significant clinical trial. The analysis of feasibility should always be justified with available evidence. A properly conducted feasibility study may constitute the basis to request regulatory agencies to grant a waiver from conducting clinical trials in one or more subsets of the paediatric population. The process of selecting the outcomes to include in paediatric trials needs to take into account the differences between adults and children, in terms of choice of the outcomes and timing for the assessment. Outcomes should be meaningful and measurable, with adequate control or normative data for comparison and there should be appropriate power analysis to ensure enrolment of an adequate number of subjects to answer the research question and strategies for dealing with potential problems with recruitment and retention. Paediatric studies may need very different primary endpoints from those of adult studies: the causes for this include for example different expected effect sizes, a better spontaneous outcome in the control group, the inability of the child to perform a particular test, etcetera. Should a primary endpoint which is suitable for adult trials not be useful for children, it should usually be included as a secondary endpoint, to allow comparison among different trials. In addition, the time of assessment of a primary or secondary endpoint could be shorter or longer in children and adolescents, compared to adults. One of the burdens in paediatric clinical trials is patient recruitment. Sufficient statistical power is sometimes difficult to achieve, due to the limitations of the primary endpoint, effect size, variation of the outcome measure, number of available patients, or, more often, a combination of these factors. This does not represent per se an adequate justification to declare the study unfeasible, especially considering that in some situations an underpowered study may still be preferable to no data. Children are an especially vulnerable population, and respect for children is a critical guide for research in this population. Proposals for clinical investigation of drugs in children must include measures to protect the interests of children and must be scientifically sound and significant, with value to children in general and, in most cases, to the individual child.
This situation imposes special considerations when inviting participation in studies, assessing risks and benefits, and ensuring equitable participation in and benefits of clinical research. According to the declaration of Ottawa, every effort should be made “to ensure that children share in the benefits from scientific research relevant to their individual age-related health needs”. Minimisation of pain and distress should be a central part of paediatric protocols, particularly in younger children who may express pain and distress in different ways, difficult to detect and quantify. 3. The EU Paediatric Regulation and paediatric drug development 3.1. The need for legislative intervention As discussed above, market forces alone have proven insufficient to stimulate adequate research aimed at specific development and authorisation of medicinal products for the paediatric population. In 1997 paediatric legislation was introduced in the USA to reduce the off label use in children of medications primarily developed for adults; this was confirmed in the Best Pharmaceuticals for Children Act (BPCA) of 2002, which was followed by a second legislation in 2003, the Paediatric Research Equity Act (PREA), and both were confirmed (with some additional measures) by the Food and Drug Administration Amendments Act (FDAAA) of 2007.1 Discussion on paediatric legislation began at the European level in 1997 as well, and it took 10 years of development until the Paediatric Regulation (Regulation [EC] 1901/2006) was published in the Official Journal of the European Communities (on 27th December 2006) and entered into force (on 27th January 2007) [18]. As this is a regulation, it is the strongest type of legislation in the EU since it is directly applicable in each European Union member state without any need for implementation/conversion into national laws. Even more so than the US laws, the Paediatric Regulation emphasizes the need for the inclusion of children at an early stage of the drug development process, and sets clear obligations as well as a system of incentives to ensure that medicinal products are also studied in children. 3.2. Impact of the EU Paediatric Regulation Almost four years have elapsed since the entry into force of the Paediatric Regulation, whose objectives are: to increase the availability of medicines intended for children, to make information on those medicines widely available and to stimulate high quality paediatric research. This European law has begun to impact significantly access to new drugs for children. By considerably changing the landscape of drug development for children, the law is going to provide an opportunity to make further progress in the treatment and quality of treatment for children. However, there are some risks and pitfalls that need to be controlled in order to ensure that children will ultimately benefit from the European initiative in the broadest possible way. The Regulation sets up a system of requirements, rewards, incentives, and obligations for pharmaceutical companies, together with horizontal measures to ensure that medicinal products are researched, developed and authorised to meet the therapeutic needs of children. The objectives are to improve the health of children in Europe (1) without subjecting children to unnecessary trials, and (2) without delaying the authorisation of medicinal products for use in adults.
1 These US laws are adopted with a sunset clause, i.e. they expire after 5 years and require confirmation (unless explicitly prolonged indefinitely). The current sunset date for FDAAA (including BPCA and PREA) is 2012.
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In the regulation, the paediatric population consists of all children from birth (term or preterm) to the day of the 18th birthday. 3.3. The Paediatric Investigation Plan (PIP) The new key element of the Paediatric Regulation is the early involvement of pharmaceutical companies/developers in the research and development programme of a medicinal product, through the requirement to reach an agreement with the Paediatric Committee (PDCO) of the European Medicines Agency (EMA) on the proposed studies and measures to be undertaken for a new medicinal product, the so-called Paediatric Investigation Plan (PIP). This is to ensure that the necessary data are generated determining the conditions in which a drug may be authorised to treat the paediatric population; in other words, a PIP should provide the data to enable the assessment of the quality, safety and efficacy in children, and consequently the benefit/risk profile in the paediatric population. The EMA decision on the PIP contains the timelines and the measures proposed to assess quality, safety and efficacy in all subsets of the paediatric population. Furthermore, any measures to adapt the formulation of the medicinal product for its use in the paediatric population need to be included. If an agreed PIP becomes no longer feasible, or inappropriate due to new scientific knowledge, applicants can always request one or more modifications to the agreed PIP. 3.4. Applications for a PIP need to be submitted early For new active substances, pharmaceutical companies are asked to prepare and submit a PIP application no later than the completion of the “basic” pharmacokinetic studies in adults, i.e. at the end of the so-called phase I studies. At the end of phase I, the available data in humans are preliminary data on tolerability and pharmacokinetics. With the exception of some products (anti-tumour agents), usually very little or no evidence of clinical efficacy will have been collected at this stage in the development process. However, the development plan of most drugs is often linked more to the condition being targeted and on the pharmacodynamic action of the product than to a demonstration of efficacy, and therefore an early submission of the PIP is advisable, to avoid the risk of delaying of delaying the marketing authorisation in adults. At the end of phase I development, it is possible to assess the incidence/prevalence of the targeted disease in the different paediatric age groups, and to discuss possible existing alternative treatments. Recent data show that this requirement is not satisfied by current applicants: of 463 applications for a PIP or waiver (see below) that contained a date of completion of pharmacokinetic studies in adults, most were submitted late, i.e. after the completion of the studies (293/463 = 63%). The median delay was 22 months (range: 0–221) for PIP applications, and 12 months (0–148) for applications for a product-specific waiver. These delays may adversely affect the procedure and the outcome, and cause a delay in the marketing authorisation of the product in adults. 3.5. Deferrals Deferrals are the instrument to avoid a delay in marketing authorisation in adults. In many cases (albeit not always) paediatric studies can or should be performed after studies in adults have confirmed the activity and the safety of the product; a deferral to initiate or complete one or more studies in children may therefore be requested and agreed by the PDCO.
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3.6. Waivers Some conditions do not occur in children, or in some subsets of the paediatric population. Therefore, a waiver from the obligation to do studies can be granted by the PDCO. In addition, waivers can be granted when the medicinal product is expected to be unsafe or ineffective in children (or in some subsets of the paediatric population), and finally when the product appears to have no significant benefit over existing treatments for the same condition. When a waiver is granted for all subsets of the paediatric population, for one or more predefined condition, it is called a “full” product-specific waiver. However, so far no waiver has been granted for a given medicinal product in all possible conditions, as the risk/benefit balance clearly varies across different conditions. 3.7. Paediatric development is in principle obligatory In practice, paediatric development of medicinal products in Europe is now obligatory, unless a waiver is granted by the European Medicines Agency. Marketing authorisation applications for new products (not authorised in the EU) have to include the results of studies conducted in the paediatric population, in compliance with an agreed PIP. This obligation however may be delayed (if a deferral is granted) or waived (see above). This obligation also applies to already authorised medicinal products, but only if: (a) the product is still patented; and (b) the applicant is seeking approval for a new indication, or a new pharmaceutical form, or a new route of administration (but not for a new strength, for example). 3.8. The Paediatric Committee (PDCO) of the European Medicines Agency One of the pillars of the Regulation is the Paediatric Committee, which is primarily responsible for reviewing and agreeing applications for PIPs (including deferrals and/or waivers). The assessment of the safety, quality and efficacy of medicinal products, in children as in adults, still lies with another Committee of the European Medicines Agency, the CHMP (Committee on Human Medicinal Products). Since its first meeting on 4 July 2007 to December 2010, the PDCO has evaluated a very high number of applications: 953 in total, with 214 for a full product-specific waiver and 739 requesting a PIP. Of these applications, 696 (73%) were for new medicinal products. This high productivity has been possible thanks to the Committee members, supported in many cases by staff in the National Competent Authorities, as well as to the scientific and administrative staff of the European Medicines Agency secretariat, who share the workload of the Committee. The PDCO has several other tasks, particularly regarding other aspects of paediatric drug development such as guidance and reflection on of innovative methods of development. 3.9. Globalization of the development of paediatric medicinal products To avoid unnecessary and unethically repetition of trials in children, paediatric development is addressed globally, through a close cooperation with the US Food and Drug Administration (FDA) and other regions (particularly Japan, Canada, China and India). Monthly teleconferences take place between the EMA and the FDA, to which the regulators in Canada and Japan participate as observers, during which the paediatric development of specific products is discussed, and information is shared between the agencies.
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3.10. Financial incentives to the development of paediatric medicinal products The main incentive provided by the Paediatric Regulation is that, once authorisation is obtained in all EU Member States and the results of all the studies in the PIP are included in the product information the medicine is eligible for a six-month patent extension (which protects the product from competition from generic medicines). This applies also if the results of the studies are “negative”, i.e. they do not support an indication in children, provided that the studies have been conducted in compliance with the agreed PIP. A medicinal product is usually patented for a variable period, during which no other manufacturer can market the active substance, and therefore the “innovator” (the pharmaceutical company holding the patent) can enjoy returns on its investments. The 6 month extension provided by the regulation is a substantial reward for at least some products, since the extended protection represents a significant monetary benefit when the product is sold throughout Europe in sufficient quantities. However, the interest of this incentive is usually linked to the magnitude of the sales in adults, rather than to those in children; therefore, products with a limited market will reap a smaller benefit from the extension than the so-called blockbusters. The Paediatric Regulation however also includes provisions for funding of research into off-patent medicines. Public funding is necessary as off-patent medicines are of little commercial interest for pharmaceutical companies. The PDCO has recently updated a list of priorities [19] that indicates the areas and products that require paediatric development and should have potential for funding by the European Commission in the Framework Programme 7 for Research and Technological Development [20]. 3.11. ENPREMA: the European Network of paediatric research at the European Medicines Agency Another fundamental aim of the Paediatric Regulation is to increase research in paediatric pharmacology and paediatric medicines. Clinical trials in the paediatric population require specific expertise, in some cases specific methodology and specific facilities, and should be carried out by appropriately trained investigators. The European Medicines Agency is responsible for establishing a network of existing networks, centres and investigators of paediatric research. The strategy for the establishment of the European Network has been adopted and published [21]. The network’s objectives are to coordinate studies relating to paediatric medicinal products, to build up the necessary scientific and administrative competences at European level, in order to avoid duplication of studies and testing in children. The European Medicines Agency is supporting the development of this strategy through free paediatric scientific advice for paediatric development, information tools (i.e. an inventory of therapeutic needs, information on new product labelling requirements, a public database of clinical trials), enhanced safety monitoring for marketed products concerning the obligation to include long-term follow-up of adverse drug reactions (ADRs), and the requirement for post marketing data for pharmacovigilance. The benefits of a European Network of paediatric research include technical and/or administrative competences in the performance of paediatric clinical trials through effective collaboration. They also include avoiding duplication of work and efforts, making the use of facilities more efficient and profitable, developing common methods of working with special attention to quality assurance. Additional benefits are the facilitation of recruitment of patients, and avoiding unnecessary studies in children.
The EU network should serve as a tool for industry to perform trials with children in keeping with the PIP.
4. Conclusion Paediatric drug development is a complex issue that revolves around the gravitational centres of science, regulatory authorities, business, politics and public opinion, to name but a few factors. There is no doubt that there is an urgent need for high-quality and ethical clinical research in children, to ensure that the medications we use in this vulnerable population are both safe and effective. The impact of the legislative and regulatory changes discussed here certainly reflects in an increase in the number of paediatric studies to be performed; however, a significant number of these studies have not started yet. An overall examination of the paediatric studies performed under this new legislation has shown that the types of drugs studied have tended to mirror those most commonly used by the adult market rather than drugs commonly used by children, as expected [22]. The Paediatric Regulation requires the pharmaceutical industry to include children in their planning from an early stage of drug development. Development teams need a basic understanding of the differences between adults and children, including disparities in: physiological factors, organ maturation, maturation of metabolic pathways, maturation of excretion pathways, psychological challenges towards parents, children and study personnel; an early interaction between all the stakeholders (to include patients, parents, industry, researchers, clinicians and regulators) will ensure success and the development of safe and effective medicines for children.
Disclaimer The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties.
References [1] Mahoney MJ. Publication prejudices: an experimental study of confirmatory bias in the peer review system. Cognit Ther Res 1977;1(2):161–75. [2] Resnik DB, Gutierrez-Ford C, Peddada S. Perceptions of ethical problems with scientific journal peer review: an exploratory study. Sci Eng Ethics 2008;14(3):305–10. [3] User guide for micro, small and medium-sized enterprises (SMEs). http://www.ema.europa.eu/docs/en GB/document library/Regulatory and procedural guideline/2009/10/WC500004134.pdf [EMA website accessed 18.12.10]. [4] Hoppu K. Paediatric clinical pharmacology: at the beginning of a new era. Eur J Clin Pharmacol 2008;64:201–5. [5] Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European network for drug investigation in children. BMJ 2000;320:79–82. [6] Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr 2005;164:552–8. [7] Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labelling improving the safety and efficacy of pediatric therapies. JAMA 2003;290(7):905–11. [8] Campbell H, Surry S, Royle E. A review of randomised controlled trials published in Archives of Disease in Childhood from 1982–1996. Arch Dis Child 1997;79:192–7. [9] Stephenson T. How children’s responses to drugs differ from adults. Br J Clin Pharmacol 2005;59:670–3. [10] Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off label drug use in paediatric wards: prospective study. BMJ 1998;316:343–5. [11] McIntyre J, Conroy S, Avery A, Corns H, Choonara I. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child 2000;83:498–501. [12] Evidence of harm from off-label or unlicensed medicines in children. http://www.ema.europa.eu/docs/en GB/document library/Other/2009/10/ WC500004021.pdf [EMA website accessed 18.12.10].
F. Rocchi, P. Tomasi / Pharmacological Research 64 (2011) 169–175 [13] Paolucci P, Jones KP, Cano Garcinuno MC, Catapano M, Iolascon A, Ceci A. Challenges in prescribing drugs for children with cancer. Lancet Oncol 2008;9(2):176–83. [14] Reflection Paper: Formulations of choice for the Paediatric Population. http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline /2009/09/WC500003782.pdf [EMA website accessed 18.12.10]. [15] ICH E11. http://www.ich.org/LOB/media/MEDIA487.pdf [EMA website accessed 18.12.10]. [16] Manolis E, Pons G. Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. Br J Clin Pharmacol 2009;68:493–501. [17] Tomasi P. Paediatric population: in search of safe and effective medicines. http://www.samedanltd.com/magazine/11 [last access verified 18.12.10]. [18] Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12/12/2006. http://ec.europa.eu/health/files/eudralex/vol1/reg 2006 1901/reg 2006 1901 en.pdf [last access verified 18.12.10].
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[19] Revised priority list for studies into off-patent paediatric medicinal products for the 5th Call 2011 of the 7th Framework Programme of the Commission. http://www.ema.europa.eu/ema/index.jsp?curl European =pages/regulation/document listing/document listing 000092.jsp&murl [EMA =menus/regulations/regulations.jsp&mid=WC0b01ac05800260a4# website accessed on 18.12.10]. [20] Seventh Framework programme (FP7). http://cordis.europa.eu/fp7/dc/index. cfm?fuseaction=UserSite.CooperationDetailsCallPage&call id=323 [last access verified 18.12.10]. [21] The Network of Paediatric Networks at the EMEA Implementing Strategy http://www.emea.europa.eu/docs/en GB/document library/Regulatory and procedural guideline/2009/12/WC500026679.pdf [EMA website accessed 18.12.10]. [22] Klassen TP, Hartling L, Craig JC, Offringa M. Children are not just small adults: the urgent need for high-quality trial evidence in children. PLoS Med 2008;5:e172.
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Review
The development of medicines for children Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni Francesca Rocchi a,∗ , Paolo Tomasi b a b
European Assessment Unit – Agenzia Italiana del Farmaco (AIFA), via del Tritone 181, 00187 Rome, Italy Head of Paediatric Medicines, European Medicines Agency, 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom
a r t i c l e
i n f o
Article history: Received 26 January 2011 Accepted 27 January 2011 Keywords: Child Drug approval Clinical trial Europe Drug legislation
a b s t r a c t The lack of availability of appropriate medicines for children is an extensive and well known problem. As a consequence off label or unlicensed administration of medicinal products in every day paediatric practice is frequent. A variety of obstacles hinder the development of paediatric indications for drugs primarily intended for the adult market. The barriers to proper research on children’s drug development include several complex factors, such as the limited commercial interest, lack of suitable infrastructure and competence for conducting paediatric clinical trials, difficulties in trial design, ethical worries and many others. Medicinal products used to treat children should be subjected to ethical research of high quality and be explicitly authorised for use in children as it happens in adults. Conducting adequate clinical trials in children is challenging and demanding. Identification of paediatric medical needs, extrapolation from adult data, modelling and simulation, specific clinical trial methodology are important features in the development of drugs intended for children. Market forces alone have proven insufficient to stimulate adequate research aimed at specific authorisation of medicinal products for the paediatric population, and for that reason, following the US experience, the European Paediatric Regulation has been amended in January 2007 by the European Commission. The objective of the Paediatric Regulation is to improve the development of high quality and ethically researched medicines for children aged 0 to 17 years, to facilitate the availability of information on the use of medicines for children, without subjecting children to unnecessary trials, or delaying the authorisation of medicines for use in adults. The impact of the Paediatric Regulation reflects in an increase in the number of paediatric studies to be performed, even if a significant number of these studies have not started yet. The objective of this review is to describe the main regulatory and scientific features which play a role in the complex issue of paediatric drug development. © 2011 Elsevier Ltd. All rights reserved.
Contents 1.
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. The European regulatory environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Few data are available on the safety and efficacy of medicines in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Harm is associated with off-label use in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Barriers to the development of medicines for children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. The problem of paediatric pharmaceutical forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6. Ethical issues of conducting research in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7. Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author. Tel.: +39 06 59784140. E-mail addresses: [email protected] (F. Rocchi), [email protected] (P. Tomasi). 1043-6618/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2011.01.016
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Conducting clinical trials in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Identification of paediatric needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The role of extrapolation, modelling and simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Clinical trial methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The EU Paediatric Regulation and paediatric drug development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The need for legislative intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Impact of the EU Paediatric Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. The Paediatric Investigation Plan (PIP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Applications for a PIP need to be submitted early . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Deferrals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Waivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Paediatric development is in principle obligatory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. The Paediatric Committee (PDCO) of the European Medicines Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Globalization of the development of paediatric medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Financial incentives to the development of paediatric medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. ENPREMA: the European Network of paediatric research at the European Medicines Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclaimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Background Drug development is a very complex process, that revolves around a balancing of requirements of several stakeholders, including those of science, pharmaceutical industry, regulatory authorities, ethics, politics and, not least, patients. The main goal is to guarantee that high quality medicines with a favourable benefit/risk profile are made available to the individuals who need them. 1.1. The European regulatory environment Prior to marketing a medicinal product in the European Union (EU), a marketing authorisation (product licence) must be obtained. This means that the products have to undergo specific “regulatory” studies to ensure its quality, safety and efficacy for use in the target population. These studies are often not published in peer-reviewed journals, as this is not a requirement for registration; nevertheless, the quality of these regulatory studies is very often higher than that of published studies, as the limitations of the peer review system are well known [1,2]. Furthermore, regulatory agencies that decide on marketing authorisation have the possibility to conduct inspections of trial sites and original data, something usually impossible for academic journals and peer reviewers. In the EU, there are four types of marketing authorisation: 1. National marketing authorisations: issued by the competent authorities of individual EU member states; the medicinal product may be put on the market in all Member States that have granted an authorisation for it. 2. Community marketing authorisation: this is a single authorisation that allows the medicinal product to be put on the market in all Member States. It is granted by the European Commission, following a positive opinion from the European Medicines Agency (EMA). 3. Mutual Recognition Procedure: that means that European countries may approve the decision made about a medicinal product by another European country. 4. Decentralised procedure: used for products that have not yet received authorisation in an European country. In both cases, the conditions of use are laid down in the summary of product characteristics (prescribing information for health professionals), the labelling, and the package leaflet (for users/patients).
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A summary review of the regulatory processes for the authorisation of medicinal products in the EU is contained in the guide for small and medium enterprises published by the EMA [3].
1.2. Few data are available on the safety and efficacy of medicines in children Until now, a lack of information on the paediatric uses of most medicinal products has continued to affect the paediatric population (in the European Union, this refers to children from birth to less than 18 years old). Even if children represent more than 20% of the European population, with about 100 million people aged less than 18 years, children have often been denied proper access to new medications, or they are treated with medications which have not been subjected to a scientific assessment in the same age groups. The lack of specific labelling recommendations for the paediatric population is a long-standing worldwide problem: it is estimated that 50–75% of medicines used in children have not been studied adequately in the paediatric population [4–7], and many have not been tested at all [8]. When special paediatric populations are considered, the situation is even worse: more than 80% of medicines for children with cancer and about 90% of prescriptions for neonates are for products which have not been licensed for that use [9–11]. Often, an assumption that safety and efficacy will be the same as in adults is implicitly accepted, but this is very often not based on any evidence. Using medicines that have not been approved by the appropriate regulatory authorities in the specific age groups makes children, particularly the younger ones, constant participants in uncontrolled N-of-1 trials.
1.3. Harm is associated with off-label use in children The consequence of the above is frequent off-label administration of medicinal products in everyday paediatric practice. Off-label use (which means outside the terms of the marketing authorisation) may be supported by limited evidence in the form of published reports in the scientific literature, not followed by explicit regulatory approval. However, in some cases no evidence at all is available to support the use in a given indication/condition. This last occurrence, which may put children at increased risk, is considered tantamount to unauthorised clinical experimentation by some national legislations, with possible serious consequences to the practitioners (in addition to the risk for the patients).
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Lack of suitably adapted medicinal products for children means inadequate dosage information, which may lead to an increased risk of adverse reactions, including death, or to ineffective treatment through under-dosage. Other consequences are non-availability to the paediatric population of therapeutic advances, suitable formulations and routes of administration, non compliance, and use of magistral or extemporaneous formulations (which may be of poor quality). There is sufficient evidence that harm from off-label or unlicensed use of medicinal products in children does occur, and is underreported [12]. 1.4. Barriers to the development of medicines for children A variety of obstacles hinder the development of paediatric indications for drugs primarily intended for the adult market. The barriers to proper research on children’s drug development are long-lasting and include several complex factors. The main determinant is probably the limited commercial interest, as the paediatric population is smaller and healthier than the adult population, and therefore diseases are rarer and often of shorter duration, implying a limited market for paediatric medicinal products. In addition, several other factors play a role: lack of suitable infrastructure and competence for conducting paediatric clinical trials, difficulties in trial design (including ethical difficulties), potential risks of affecting health, in particular growth or sexual development, long after the administration of the drug, difficulties in determining or predicting the paediatric dose–response or concentration–response relationship, and the additional time required to complete studies in children as compared in adults. Paediatric clinical trials of new products are often started many years after initiation or even completion of studies in adults, and involve testing at arbitrary doses and schedules on the basis of scaled down versions of those used in adults. By this time often the drugs are already off-patent, and the financial incentive for the pharmaceutical company to be involved in this phase of development will have lapsed [13]. 1.5. The problem of paediatric pharmaceutical forms For oral drugs, a formulation suitable for very young children (who are generally unable to swallow tablets or capsules) is often unavailable. As a consequence, clinicians have had to improvise, to administer such drugs to these children, with often unknown pharmacokinetic consequences. The magnitude of doses required through childhood can vary up to 100-fold, and the ability to cope with different dosage forms can also vary considerably. Thus, if a medicinal product is to be used in all age groups, a range of different dosage forms should be available providing different strengths or concentrations to allow simple, accurate and safe dosing. A detailed concept paper on the formulations of choice for the paediatric population has been adopted by the European Medicines Agency, and is available on its website [14]. 1.6. Ethical issues of conducting research in children Even though there could be some theoretical concerns in conducting trials in the paediatric population, this has to be balanced by the ethical issues correlated to giving medicines to a population in which they have not been tested, and therefore their effects, positive or negative, are unknown. The ethics of using child research to guide risk assessment in balance with the potential benefit to the single child, and children in general, is constantly evolving.
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Today, the balance of scientific and ethical consensus has swung away from emphasizing the need to protect children against research, to the need of having reasonable evidence of both safety and efficacy of paediatric medicines. Children will always need protection in research; however, research to improve child health is now perceived as an ethical obligation and delays in passing benefits from pharmaceutical progress is considered unethical. Nevertheless, in everyday practice paediatricians very often face the dilemma of whether to prescribe a drug that has not been studied for children, or to deny a potential useful treatment to a sick child. It is exactly to reduce the instances of such dilemmas that clinical data on the paediatric use of medicines are needed. Children of different ages are vulnerable groups with specific developmental, physiological and psychological differences from adults, which make age and development related research of medicines particularly important. In terms of both public health and ethics, it is clearly preferable to test medicines in children, in a safe and controlled paediatric clinical trial environment, where the individual child is protected. 1.7. Objective Optimizing the health outcomes of children has the potential for a big impact on public health because children are at an early stage in the life trajectory. The under-investment in paediatric clinical trials is a good example of how our resource allocation may be insufficient. Over the last few decades, the drug development specifically designed for children has passed from the tight attention of few to the attention of a wide group of stakeholders, especially government and regulatory authorities. 2. Conducting clinical trials in children 2.1. Identification of paediatric needs When developing a medicinal product, the first step is to identify if there is a potential need for the product in children. This is now required because of the legislative obligations introduced by the Paediatric Regulation. Importantly, children are not a single homogeneous group, as preterm neonates as well as post-pubertal adolescents are both paediatric age groups, but with clearly different size, development, maturation of biochemical pathways, response to therapy. 2.2. The role of extrapolation, modelling and simulation The design and implementation of paediatric clinical trials remains a challenging problem. Ethical, practical and economic considerations have caused the use of medicinal products in children to be based on empirical extrapolations from clinical trials in adults. Once the paediatric needs and the study question have been clarified, the possibility of replacing some studies, or reducing the number of patients involved, through extrapolation, modelling and simulation should be discussed. Unnecessary clinical trials in children should be avoided, and the use of extrapolation for efficacy is encouraged by current guidelines [15]. Extrapolation of efficacy, from adults to children (or from older to younger children or vice versa) is allowable under certain circumstances. If the pathophysiology of the disease, its progression, and its response to therapy are known to be similar, then a specific demonstration of efficacy may not be required (e.g. in some infectious diseases). However, dose-finding/PK studies and safety studies are usually necessary, as these aspects cannot usually be extrapolated.
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Since conducting unnecessary studies in children is unethical, the possibility of extrapolation should be considered in all cases of development of paediatric medicinal products; however in most cases at least some studies will be required to support the use in children. Modelling and simulation is a methodology widely used in the exploratory context with great acceptance from both industry and regulators. It is one way to circumvent some difficulties in developing medicinal products in children. This approach allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/pharmacodynamics, extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. However, its pivotal use is controversial but in the case of paediatrics, where ethical and practical constrains necessitate smaller trials, this methodology could have a more important role in the regulatory assessment [16].
2.3. Clinical trial methodology Because children are not small adults, the methodology used to design trials involving children needs to be adapted from that used to design trials in adult patients. A paediatric trial must be conceived and developed in its own right. This may involve particular attention to the exploration of alternative designs [17]. In some cases, a feasibility study may be required, to determine whether it is possible to complete a significant clinical trial. The analysis of feasibility should always be justified with available evidence. A properly conducted feasibility study may constitute the basis to request regulatory agencies to grant a waiver from conducting clinical trials in one or more subsets of the paediatric population. The process of selecting the outcomes to include in paediatric trials needs to take into account the differences between adults and children, in terms of choice of the outcomes and timing for the assessment. Outcomes should be meaningful and measurable, with adequate control or normative data for comparison and there should be appropriate power analysis to ensure enrolment of an adequate number of subjects to answer the research question and strategies for dealing with potential problems with recruitment and retention. Paediatric studies may need very different primary endpoints from those of adult studies: the causes for this include for example different expected effect sizes, a better spontaneous outcome in the control group, the inability of the child to perform a particular test, etcetera. Should a primary endpoint which is suitable for adult trials not be useful for children, it should usually be included as a secondary endpoint, to allow comparison among different trials. In addition, the time of assessment of a primary or secondary endpoint could be shorter or longer in children and adolescents, compared to adults. One of the burdens in paediatric clinical trials is patient recruitment. Sufficient statistical power is sometimes difficult to achieve, due to the limitations of the primary endpoint, effect size, variation of the outcome measure, number of available patients, or, more often, a combination of these factors. This does not represent per se an adequate justification to declare the study unfeasible, especially considering that in some situations an underpowered study may still be preferable to no data. Children are an especially vulnerable population, and respect for children is a critical guide for research in this population. Proposals for clinical investigation of drugs in children must include measures to protect the interests of children and must be scientifically sound and significant, with value to children in general and, in most cases, to the individual child.
This situation imposes special considerations when inviting participation in studies, assessing risks and benefits, and ensuring equitable participation in and benefits of clinical research. According to the declaration of Ottawa, every effort should be made “to ensure that children share in the benefits from scientific research relevant to their individual age-related health needs”. Minimisation of pain and distress should be a central part of paediatric protocols, particularly in younger children who may express pain and distress in different ways, difficult to detect and quantify. 3. The EU Paediatric Regulation and paediatric drug development 3.1. The need for legislative intervention As discussed above, market forces alone have proven insufficient to stimulate adequate research aimed at specific development and authorisation of medicinal products for the paediatric population. In 1997 paediatric legislation was introduced in the USA to reduce the off label use in children of medications primarily developed for adults; this was confirmed in the Best Pharmaceuticals for Children Act (BPCA) of 2002, which was followed by a second legislation in 2003, the Paediatric Research Equity Act (PREA), and both were confirmed (with some additional measures) by the Food and Drug Administration Amendments Act (FDAAA) of 2007.1 Discussion on paediatric legislation began at the European level in 1997 as well, and it took 10 years of development until the Paediatric Regulation (Regulation [EC] 1901/2006) was published in the Official Journal of the European Communities (on 27th December 2006) and entered into force (on 27th January 2007) [18]. As this is a regulation, it is the strongest type of legislation in the EU since it is directly applicable in each European Union member state without any need for implementation/conversion into national laws. Even more so than the US laws, the Paediatric Regulation emphasizes the need for the inclusion of children at an early stage of the drug development process, and sets clear obligations as well as a system of incentives to ensure that medicinal products are also studied in children. 3.2. Impact of the EU Paediatric Regulation Almost four years have elapsed since the entry into force of the Paediatric Regulation, whose objectives are: to increase the availability of medicines intended for children, to make information on those medicines widely available and to stimulate high quality paediatric research. This European law has begun to impact significantly access to new drugs for children. By considerably changing the landscape of drug development for children, the law is going to provide an opportunity to make further progress in the treatment and quality of treatment for children. However, there are some risks and pitfalls that need to be controlled in order to ensure that children will ultimately benefit from the European initiative in the broadest possible way. The Regulation sets up a system of requirements, rewards, incentives, and obligations for pharmaceutical companies, together with horizontal measures to ensure that medicinal products are researched, developed and authorised to meet the therapeutic needs of children. The objectives are to improve the health of children in Europe (1) without subjecting children to unnecessary trials, and (2) without delaying the authorisation of medicinal products for use in adults.
1 These US laws are adopted with a sunset clause, i.e. they expire after 5 years and require confirmation (unless explicitly prolonged indefinitely). The current sunset date for FDAAA (including BPCA and PREA) is 2012.
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In the regulation, the paediatric population consists of all children from birth (term or preterm) to the day of the 18th birthday. 3.3. The Paediatric Investigation Plan (PIP) The new key element of the Paediatric Regulation is the early involvement of pharmaceutical companies/developers in the research and development programme of a medicinal product, through the requirement to reach an agreement with the Paediatric Committee (PDCO) of the European Medicines Agency (EMA) on the proposed studies and measures to be undertaken for a new medicinal product, the so-called Paediatric Investigation Plan (PIP). This is to ensure that the necessary data are generated determining the conditions in which a drug may be authorised to treat the paediatric population; in other words, a PIP should provide the data to enable the assessment of the quality, safety and efficacy in children, and consequently the benefit/risk profile in the paediatric population. The EMA decision on the PIP contains the timelines and the measures proposed to assess quality, safety and efficacy in all subsets of the paediatric population. Furthermore, any measures to adapt the formulation of the medicinal product for its use in the paediatric population need to be included. If an agreed PIP becomes no longer feasible, or inappropriate due to new scientific knowledge, applicants can always request one or more modifications to the agreed PIP. 3.4. Applications for a PIP need to be submitted early For new active substances, pharmaceutical companies are asked to prepare and submit a PIP application no later than the completion of the “basic” pharmacokinetic studies in adults, i.e. at the end of the so-called phase I studies. At the end of phase I, the available data in humans are preliminary data on tolerability and pharmacokinetics. With the exception of some products (anti-tumour agents), usually very little or no evidence of clinical efficacy will have been collected at this stage in the development process. However, the development plan of most drugs is often linked more to the condition being targeted and on the pharmacodynamic action of the product than to a demonstration of efficacy, and therefore an early submission of the PIP is advisable, to avoid the risk of delaying of delaying the marketing authorisation in adults. At the end of phase I development, it is possible to assess the incidence/prevalence of the targeted disease in the different paediatric age groups, and to discuss possible existing alternative treatments. Recent data show that this requirement is not satisfied by current applicants: of 463 applications for a PIP or waiver (see below) that contained a date of completion of pharmacokinetic studies in adults, most were submitted late, i.e. after the completion of the studies (293/463 = 63%). The median delay was 22 months (range: 0–221) for PIP applications, and 12 months (0–148) for applications for a product-specific waiver. These delays may adversely affect the procedure and the outcome, and cause a delay in the marketing authorisation of the product in adults. 3.5. Deferrals Deferrals are the instrument to avoid a delay in marketing authorisation in adults. In many cases (albeit not always) paediatric studies can or should be performed after studies in adults have confirmed the activity and the safety of the product; a deferral to initiate or complete one or more studies in children may therefore be requested and agreed by the PDCO.
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3.6. Waivers Some conditions do not occur in children, or in some subsets of the paediatric population. Therefore, a waiver from the obligation to do studies can be granted by the PDCO. In addition, waivers can be granted when the medicinal product is expected to be unsafe or ineffective in children (or in some subsets of the paediatric population), and finally when the product appears to have no significant benefit over existing treatments for the same condition. When a waiver is granted for all subsets of the paediatric population, for one or more predefined condition, it is called a “full” product-specific waiver. However, so far no waiver has been granted for a given medicinal product in all possible conditions, as the risk/benefit balance clearly varies across different conditions. 3.7. Paediatric development is in principle obligatory In practice, paediatric development of medicinal products in Europe is now obligatory, unless a waiver is granted by the European Medicines Agency. Marketing authorisation applications for new products (not authorised in the EU) have to include the results of studies conducted in the paediatric population, in compliance with an agreed PIP. This obligation however may be delayed (if a deferral is granted) or waived (see above). This obligation also applies to already authorised medicinal products, but only if: (a) the product is still patented; and (b) the applicant is seeking approval for a new indication, or a new pharmaceutical form, or a new route of administration (but not for a new strength, for example). 3.8. The Paediatric Committee (PDCO) of the European Medicines Agency One of the pillars of the Regulation is the Paediatric Committee, which is primarily responsible for reviewing and agreeing applications for PIPs (including deferrals and/or waivers). The assessment of the safety, quality and efficacy of medicinal products, in children as in adults, still lies with another Committee of the European Medicines Agency, the CHMP (Committee on Human Medicinal Products). Since its first meeting on 4 July 2007 to December 2010, the PDCO has evaluated a very high number of applications: 953 in total, with 214 for a full product-specific waiver and 739 requesting a PIP. Of these applications, 696 (73%) were for new medicinal products. This high productivity has been possible thanks to the Committee members, supported in many cases by staff in the National Competent Authorities, as well as to the scientific and administrative staff of the European Medicines Agency secretariat, who share the workload of the Committee. The PDCO has several other tasks, particularly regarding other aspects of paediatric drug development such as guidance and reflection on of innovative methods of development. 3.9. Globalization of the development of paediatric medicinal products To avoid unnecessary and unethically repetition of trials in children, paediatric development is addressed globally, through a close cooperation with the US Food and Drug Administration (FDA) and other regions (particularly Japan, Canada, China and India). Monthly teleconferences take place between the EMA and the FDA, to which the regulators in Canada and Japan participate as observers, during which the paediatric development of specific products is discussed, and information is shared between the agencies.
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3.10. Financial incentives to the development of paediatric medicinal products The main incentive provided by the Paediatric Regulation is that, once authorisation is obtained in all EU Member States and the results of all the studies in the PIP are included in the product information the medicine is eligible for a six-month patent extension (which protects the product from competition from generic medicines). This applies also if the results of the studies are “negative”, i.e. they do not support an indication in children, provided that the studies have been conducted in compliance with the agreed PIP. A medicinal product is usually patented for a variable period, during which no other manufacturer can market the active substance, and therefore the “innovator” (the pharmaceutical company holding the patent) can enjoy returns on its investments. The 6 month extension provided by the regulation is a substantial reward for at least some products, since the extended protection represents a significant monetary benefit when the product is sold throughout Europe in sufficient quantities. However, the interest of this incentive is usually linked to the magnitude of the sales in adults, rather than to those in children; therefore, products with a limited market will reap a smaller benefit from the extension than the so-called blockbusters. The Paediatric Regulation however also includes provisions for funding of research into off-patent medicines. Public funding is necessary as off-patent medicines are of little commercial interest for pharmaceutical companies. The PDCO has recently updated a list of priorities [19] that indicates the areas and products that require paediatric development and should have potential for funding by the European Commission in the Framework Programme 7 for Research and Technological Development [20]. 3.11. ENPREMA: the European Network of paediatric research at the European Medicines Agency Another fundamental aim of the Paediatric Regulation is to increase research in paediatric pharmacology and paediatric medicines. Clinical trials in the paediatric population require specific expertise, in some cases specific methodology and specific facilities, and should be carried out by appropriately trained investigators. The European Medicines Agency is responsible for establishing a network of existing networks, centres and investigators of paediatric research. The strategy for the establishment of the European Network has been adopted and published [21]. The network’s objectives are to coordinate studies relating to paediatric medicinal products, to build up the necessary scientific and administrative competences at European level, in order to avoid duplication of studies and testing in children. The European Medicines Agency is supporting the development of this strategy through free paediatric scientific advice for paediatric development, information tools (i.e. an inventory of therapeutic needs, information on new product labelling requirements, a public database of clinical trials), enhanced safety monitoring for marketed products concerning the obligation to include long-term follow-up of adverse drug reactions (ADRs), and the requirement for post marketing data for pharmacovigilance. The benefits of a European Network of paediatric research include technical and/or administrative competences in the performance of paediatric clinical trials through effective collaboration. They also include avoiding duplication of work and efforts, making the use of facilities more efficient and profitable, developing common methods of working with special attention to quality assurance. Additional benefits are the facilitation of recruitment of patients, and avoiding unnecessary studies in children.
The EU network should serve as a tool for industry to perform trials with children in keeping with the PIP.
4. Conclusion Paediatric drug development is a complex issue that revolves around the gravitational centres of science, regulatory authorities, business, politics and public opinion, to name but a few factors. There is no doubt that there is an urgent need for high-quality and ethical clinical research in children, to ensure that the medications we use in this vulnerable population are both safe and effective. The impact of the legislative and regulatory changes discussed here certainly reflects in an increase in the number of paediatric studies to be performed; however, a significant number of these studies have not started yet. An overall examination of the paediatric studies performed under this new legislation has shown that the types of drugs studied have tended to mirror those most commonly used by the adult market rather than drugs commonly used by children, as expected [22]. The Paediatric Regulation requires the pharmaceutical industry to include children in their planning from an early stage of drug development. Development teams need a basic understanding of the differences between adults and children, including disparities in: physiological factors, organ maturation, maturation of metabolic pathways, maturation of excretion pathways, psychological challenges towards parents, children and study personnel; an early interaction between all the stakeholders (to include patients, parents, industry, researchers, clinicians and regulators) will ensure success and the development of safe and effective medicines for children.
Disclaimer The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties.
References [1] Mahoney MJ. Publication prejudices: an experimental study of confirmatory bias in the peer review system. Cognit Ther Res 1977;1(2):161–75. [2] Resnik DB, Gutierrez-Ford C, Peddada S. Perceptions of ethical problems with scientific journal peer review: an exploratory study. Sci Eng Ethics 2008;14(3):305–10. [3] User guide for micro, small and medium-sized enterprises (SMEs). http://www.ema.europa.eu/docs/en GB/document library/Regulatory and procedural guideline/2009/10/WC500004134.pdf [EMA website accessed 18.12.10]. [4] Hoppu K. Paediatric clinical pharmacology: at the beginning of a new era. Eur J Clin Pharmacol 2008;64:201–5. [5] Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European network for drug investigation in children. BMJ 2000;320:79–82. [6] Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr 2005;164:552–8. [7] Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labelling improving the safety and efficacy of pediatric therapies. JAMA 2003;290(7):905–11. [8] Campbell H, Surry S, Royle E. A review of randomised controlled trials published in Archives of Disease in Childhood from 1982–1996. Arch Dis Child 1997;79:192–7. [9] Stephenson T. How children’s responses to drugs differ from adults. Br J Clin Pharmacol 2005;59:670–3. [10] Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off label drug use in paediatric wards: prospective study. BMJ 1998;316:343–5. [11] McIntyre J, Conroy S, Avery A, Corns H, Choonara I. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child 2000;83:498–501. [12] Evidence of harm from off-label or unlicensed medicines in children. http://www.ema.europa.eu/docs/en GB/document library/Other/2009/10/ WC500004021.pdf [EMA website accessed 18.12.10].
F. Rocchi, P. Tomasi / Pharmacological Research 64 (2011) 169–175 [13] Paolucci P, Jones KP, Cano Garcinuno MC, Catapano M, Iolascon A, Ceci A. Challenges in prescribing drugs for children with cancer. Lancet Oncol 2008;9(2):176–83. [14] Reflection Paper: Formulations of choice for the Paediatric Population. http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline /2009/09/WC500003782.pdf [EMA website accessed 18.12.10]. [15] ICH E11. http://www.ich.org/LOB/media/MEDIA487.pdf [EMA website accessed 18.12.10]. [16] Manolis E, Pons G. Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. Br J Clin Pharmacol 2009;68:493–501. [17] Tomasi P. Paediatric population: in search of safe and effective medicines. http://www.samedanltd.com/magazine/11 [last access verified 18.12.10]. [18] Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12/12/2006. http://ec.europa.eu/health/files/eudralex/vol1/reg 2006 1901/reg 2006 1901 en.pdf [last access verified 18.12.10].
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[19] Revised priority list for studies into off-patent paediatric medicinal products for the 5th Call 2011 of the 7th Framework Programme of the Commission. http://www.ema.europa.eu/ema/index.jsp?curl European =pages/regulation/document listing/document listing 000092.jsp&murl [EMA =menus/regulations/regulations.jsp&mid=WC0b01ac05800260a4# website accessed on 18.12.10]. [20] Seventh Framework programme (FP7). http://cordis.europa.eu/fp7/dc/index. cfm?fuseaction=UserSite.CooperationDetailsCallPage&call id=323 [last access verified 18.12.10]. [21] The Network of Paediatric Networks at the EMEA Implementing Strategy http://www.emea.europa.eu/docs/en GB/document library/Regulatory and procedural guideline/2009/12/WC500026679.pdf [EMA website accessed 18.12.10]. [22] Klassen TP, Hartling L, Craig JC, Offringa M. Children are not just small adults: the urgent need for high-quality trial evidence in children. PLoS Med 2008;5:e172.