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The European Regulation on medicines for paediatric use
PAEDIATRIC RESPIRATORY REVIEWS (2007) 8, 177–183
REVIEW
The European Regulation on medicines for paediatric use Julia Dunne* Medicines and Healthcare Products Regulatory Agency, 1 Nine Elms Lane, London SW8 9NQ UK KEYWORDS european paediatric use regulation; requirements and incentives; paediatric committee; paediatric investigation plan; paediatric clinical trials database; paediatric use marketing authorisation; extension of supplementary protection certificate; paediatric research network, paediatric study programme
Summary The European Regulation on medicines for paediatric use entered into force on 26 January 2007. It marks a radical change in the European Union in terms of encouraging the development of medicines for paediatric age groups and improving the availability of information on the use of medicines in children. How will the new Paediatric Regulation achieve this? For the first time, companies will be required to study medicines in the paediatric population and develop age-appropriate formulations. As a reward or incentive for conducting these studies, companies will be entitled to extensions of patent protection and market exclusivity. The Regulation establishes a European paediatric clinical trials network and a paediatric study programme for off-patent medicines, the latter to be funded through the Community Framework Programmes. A Paediatric Committee, based at the European Medicines Agency, will be responsible for agreeing the paediatric investigation plan (PIP) with companies. This will describe the clinical trials and other measures necessary to investigate a particular medicine in the paediatric population. A European paediatric clinical trials database, partly accessible to the public, will hold the details and the results of all paediatric trials conducted in line with these PIPs. All medicines authorised for a paediatric use will be identified by a new symbol on the package label. After 5 years, there will be a stocktake with a view to making changes to the Regulation if necessary. ß 2007 Elsevier Ltd. All rights reserved.
The lack of appropriately authorised and formulated medicines for use in the paediatric population is a longstanding problem and cause for concern. As a result, most medicines are prescribed to children on an off-label or an unlicensed basis. (For the purposes of this article the word ‘children’ is synonymous with ‘paediatric population’ and describes the age group between 0 and 18 years.) Dosing regimens approved for adults are extrapolated to paediatric age groups, for example on the basis of proportionality of weight, without paediatric pharmacokinetic or pharmacodynamic data. Safety and efficacy are presumed to be the same as in adults, but this may not be the case. Evidence* Tel.: +44 207 084 2115. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2007.04.004
based information in children is often not readily available, and prescribing decisions may have to be based on accepted practice presented in formularies such as the British National Formulary for Children (BNF-C). There are a number of reasons why medicines are not properly tested for use in children. These include concerns about conducting clinical trials in this vulnerable population and commercial considerations on the part of the pharmaceutical industry. More recently, however, concerns about the ethics of studying medicines in children have been outweighed by concerns about denying children access to properly tested, formulated and authorised medicines. What now remains as the principal barrier is the reluctance of the pharmaceutical industry to develop medicines when there is an insufficient commercial return on investment. In
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October 2004, the European Commission launched a legislative proposal for a European regulation to overcome this barrier. Following intensive negotiations with the Member States and the European Parliament, the Regulation on medicines for paediatric use, which is based on a system of requirements and incentives, entered into force on US Food and Drug Administration, Center for Drug Evaluation and Research, Paediatric Drug Development 26 January 2007.
REGULATORY BACKGROUND Regulators began to take action to stimulate the pharmaceutical industry to develop more medicines for children in the early 1980s. By the mid 1990s, it was clear that exhortations and guidance alone were not having the necessary effect and that legislation was needed. In the late 1990s, the first pieces of legislation relating to paediatric medicines were adopted in the USA. These established a framework of incentives and requirements for the conduct of studies on medicines in the paediatric population. The US incentive, an additional 6 months’ market exclusivity in return for the submission of paediatric studies (‘paediatric exclusivity’),1 was highly successful in stimulating paediatric clinical trials, although not necessarily in the areas of greatest therapeutic need, as commercial considerations still seemed to predominate. Although there was resistance to the introduction of requirements in the USA, it was evident that without the Pediatric Rule,2 the industry would not conduct paediatric studies on medicines in less commercially attractive therapeutic areas. The US laws have evolved over the past decade, but the incentives and obligations still remain, refined and enshrined in separate pieces of legislation, The Best Pharmaceuticals for Children Act 20023 and the Pediatric Research Equity Act of 2003.4 In the European Union (EU), regulators and other interested parties agreed as long ago as December 1997 that a strengthening of EU legislation was needed ‘in order to overcome current barriers that prevent the use of new medicinal products in children’.5 In a Council resolution of December 2000, the European Health Ministers called on the European Commission to make proposals for legislation ‘to ensure that new medicinal products for children and medicinal products already on the market are fully adapted to the specific needs of children’.6 In October 2004, after much debate and extensive consultations, the Commission issued a proposal for a Regulation on medicines for paediatric use.7 Although the Commission was criticised for taking nearly 4 years to respond to the Council resolution, the proposal took on board lessons learned from the US experience. When it emerged, therefore, it was a balanced and comprehensive response to the call from the Council. In addition, through the repeated debate and public consultation, the more controversial issues had already been widely rehearsed and the resulting passage of the proposal
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through the co-decision procedure, which involves both the Council (Member States) and the European Parliament, was relatively rapid. Final agreement on the text of the proposal was achieved in June 2006. Due to various administrative delays, however, the Regulation did not enter into force until 6 months later. During the negotiations between the Commission, the Council and the Parliament on the text of the Regulation, surprisingly few key provisions were altered, and some new important provisions were gained. Examples of the latter include public accessibility of the paediatric clinical trials database, funding for a paediatric study programme for off-patent medicines, and a provision to discourage the discontinuation from the market of medicines authorised for paediatric use. Perhaps the most controversial issue during the negotiations was the question of the financial incentives for industry: the addition of 6 months’ extra patent protection through an extension of the duration of the Supplementary Protection Certificate (SPC) for those medicines for which an agreed paediatric investigation plan (PIP) had been completed (and a number of other criteria have been fulfilled), and an additional 2 years market exclusivity for orphan medicines.8 During the Council discussions, amendments were proposed by a number of Member States to moderate the extent of these incentives, the financial burden of which will fall most heavily on those Member States with a high use of generic medicines as the cheaper generic copies will be kept off the market for the additional period of the SPC extension. Proposed amendments included a reduction of the duration of the extension, for example to 3 months, and a variable extension period depending on financial returns. There were parallel proposals to reduce the period of extra market exclusivity for orphan medicines. Similar amendments were proposed in the European Parliament. The wide range in the estimates of both the economic impact of the measures as a whole and the scale of the reward in relation to individual medicines led in part to the difficulties in agreeing a fair way to determine the duration of the extension. Eventually a compromise was reached that retained as financial incentives the Commission proposal of a 6-month extension to the duration of the SPC and a 2-year extension of market exclusivity for orphan medicines, but added a requirement for a detailed assessment of the economic and public health impact of these incentives when sufficient experience had been gained through the operation of the Regulation. The significance of the use of a regulation as a legal instrument is that it is directly applicable in national law and takes immediate effect without any further action on the part of national authorities. It is binding in all its parts. A directive, which would have been the other option, is binding on the Member States in terms of the result to be achieved but leaves to each State the choice of the form and method to achieve the Community objectives within
THE EUROPEAN REGULATION ON MEDICINES FOR PAEDIATRIC USE
the framework of its own internal legal system. By choosing a regulation, the Commission can ensure that the new provisions for paediatric medicines will be applied in exactly the same way throughout the EU and that, as a result, all the children of the EU should benefit equally. Much of the detail on the operation of the Regulation is left to the implementing texts. These texts, mostly in the form of guidelines, will be developed by the European Commission and the European Medicines Agency (EMEA), in consultation with Member States and other stakeholders. Such texts have the advantage of being relatively easy to update in the event of scientific or technical progress, without the need to return to the Council or the European Parliament.
AIMS AND OBJECTIVES OF THE REGULATION The overall aim of the Regulation is to improve the health of children in the EU. More specifically the objectives include: increasing the development of medicines for use in children; o ensuring that medicines used to treat children are: - subject to high quality research; - appropriately authorised for use in children; o improving the information available on the use of medicines in children; o achieving the above objectives without subjecting children to unnecessary clinical trials or delaying the authorisation of medicines in the adult population. The Regulation establishes a number of new provisions, structures and procedures in order to achieve its objectives.
KEY PROVISIONS Requirements and incentives The pharmaceutical industry has previously been free to restrict a particular medicine’s development to the adult population; the development of paediatric medicines has been solely at the industry’s discretion. The new Regulation is the first piece of European legislation that requires the pharmaceutical industry to develop medicines for use in a particular patient population. Perhaps, therefore, the most important requirement of the Regulation is that all applications for marketing authorisation for new medicines, including orphan medicines, must contain the results of all studies and information required in a previously agreed PIP. The PIP will contain a full proposal of all the studies (and their timings) necessary to support the paediatric use of an individual product and will cover all paediatric age groups and all necessary age-appropriate formulations. This is the default position of the Regulation. In some cases, it will be possible to defer the start of some or all of the studies in relation to the development of the product in adults. In this
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case, the paediatric data will be provided after the initial marketing authorisation has been granted. In other cases, the requirement may be waived for part or all of the paediatric population, for example where there is no paediatric therapeutic need or where paediatric use of the product is not appropriate. But the important point is that, unless a deferral or a waiver has been granted, paediatric data must be provided in all applications for the authorisation of new medicinal products. The requirement also applies to applications to add a new indication, new pharmaceutical form or new route of administration for medicines still covered by patent protection. It will start to apply 18 months after the Regulation enters into force. The Regulation also includes incentives for companies to develop medicines for use in children. This is to stimulate paediatric development for products not bound by the requirements discussed above, as well as to reward the industry for conducting the obligatory investigation programmes. When an agreed paediatric plan has been completed and all the information has been submitted to the regulatory authorities, the medicinal product will be granted an extra 6 months’ patent protection (through an extension of the duration of its SPC), provided that the medicinal product is authorised in all Member States and that relevant information (whether negative or positive) from the paediatric studies has been incorporated into the summary of product characteristics. This extension will be granted whether or not the data support a paediatric indication. The incentive only applies if the product has an active SPC; there is no financial incentive in cases where there is no SPC or where the SPC has expired, and there is no mechanism to extend the duration of the period of the patent itself. For orphan medicinal products, the incentive takes the form of an extra 2 years’ market exclusivity in addition to the 10 years’ market exclusivity that is granted on authorisation of an orphan medicine. The financial incentives do not apply retrospectively. Therefore, they do not apply if the contents of an agreed PIP were completed before entry into force of the Regulation, unless the plan contains ‘significant studies’ that were completed after the Regulation’s entry into force. The requirements and the financial incentives are independent of each other. Thus, a marketing authorisation holder may be required to provide a completed PIP for a product but may be ineligible for the incentive (for example, because the SPC has expired before the PIP has been completed). Conversely, a marketing authorisation holder may not be obliged to submit a completed plan but may do so in order to benefit from the financial incentives. The Regulation also establishes a new type of marketing authorisation, called the paediatric use marketing authorisation (PUMA), intended to stimulate the development of
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off-patent products for use in the paediatric population. Only medicines that are intended solely for use in children will be eligible for a PUMA. The incentives associated with a PUMA are relatively weak. Nevertheless, it is hoped that they will encourage the development of new paediatric formulations for these older products. Applications for PUMAs, which must contain the results from an agreed PIP, can refer to third-party data for the same active substance, are able to use the centralised procedure for authorisation and, if authorised, will benefit from 10 years, market protection.
Paediatric investigation plan The PIP is a research and development programme aimed at ensuring that the necessary data are generated to determine the conditions in which a medicinal product may be authorised for the paediatric population. It is necessary to draw up such a plan whenever there is an intention to apply either for a marketing authorisation for a new medicine, or for a new indication, pharmaceutical form or route of administration of an existing authorised medicine that is covered by patent protection, or when applying for a PUMA. The plan must specify the timing and the measures proposed to assess the quality, safety and efficacy of the medicinal product in all relevant subsets of the paediatric population, as defined in ICH E11.9 In addition, it must describe any measures to adapt the formulation of the medicinal product that make its use more acceptable, easier, safer or more effective for the different subsets of the paediatric population. The PIP must be submitted to the Paediatric Committee no later than upon completion of the pharmacokinetic studies in adults. This time point was chosen to ensure that the paediatric development of the product is considered at a very early stage of the overall product development rather than as an afterthought. It is accepted that the initial submission will in many cases be preliminary as it will be too early in the development process to have a complete and detailed plan. The Regulation, therefore, allows the Committee to request further information or initial modifications to the plan. It also allows for modifications of the plan at a later stage as the product development progresses. The plan must, however, be agreed by the Paediatric Committee, both in order to fulfil the requirements for a valid application for marketing authorisation and to fulfil the criteria to qualify for the financial incentives provided by the Regulation. If the Paediatric Committee refuses to agree a plan, the applicant can request the Committee to re-examine its opinion. If following re-examination the Committee remains negative and the applicant disagrees with the opinion, the applicant has recourse to the European Courts of Justice. The Paediatric Committee also has to agree to any requests for deferral of the timing of the studies in the plan or for waivers from the requirement to
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develop the product for use in all or part of the paediatric population.
Paediatric Committee Membership The Regulation establishes a new scientific committee of the EMEA, the Paediatric Committee, which must be set up within 6 months of entry into force of the Regulation. The Committee membership includes five members of the Committee on Human Medicinal Products (CHMP) plus their alternates. The CHMP is the main scientific committee of the EMEA and is responsible, among other things, for giving opinions on applications for centralised marketing authorisations for medicinal products and on scientific advice on medicines development. These five members will provide an important link between the two committees. Member States that are not represented on the Paediatric Committee by a CHMP member will appoint a member and an alternate. In addition, the European Commission will appoint three members plus alternates to represent health professionals, and three members plus alternates to represent patient associations. The European Commission will appoint these six members and alternates following a public call for expressions of interest and after consulting the European Parliament. The EMEA, the Agency and the Commission are expected to cooperate to ensure that the final composition of the Committee, including members and alternates, covers those scientific areas relevant to paediatric medicines. The members, who are appointed for a renewable period of 3 years, may be accompanied by other relevant experts at the Committee meetings. The members, alternates and experts must not have any financial or other interests in the pharmaceutical industry that could affect their impartiality.
Tasks The Paediatric Committee has a number of important responsibilities, and its effective functioning will be pivotal to the success of the Regulation. Its most important task is to assess the content of PIPs for individual medicinal products and to produce opinions on them. In addition, the Committee gives opinions on applications for deferrals and waivers. In this regard, the Committee may itself impose a waiver if it considers that the product may be unsafe or ineffective in the paediatric population or that the product will not provide any significant therapeutic benefit. The Committee will also, on request, give an opinion on the compliance of an application for marketing authorisation with an agreed PIP or on the safety, quality and efficacy of a medicinal product for paediatric use. Other specific tasks include establishing an inventory of specific needs for paediatric medicinal products and giving scientific input
THE EUROPEAN REGULATION ON MEDICINES FOR PAEDIATRIC USE
in the development of any documents related to achieving the Regulation’s objectives. The Committee also has an advisory role to the EMEA and to the Commission. This includes giving advice on the new symbol that is to appear on the labels of all medicines with an authorised paediatric use, on the establishment of the European paediatric clinical trials network, on communication issues relating to conducting research in the paediatric population and on any question relating to the paediatric use of medicines. The Committee is expected to meet monthly for 3–4 days. Members will also need to devote a significant amount of time to preparation prior to meetings, so the workload involved with membership is not to be underestimated.
Paediatric use symbol All products that have an authorised paediatric indication will be required to display a new designated symbol on the package label to ensure that they are readily identifiable. This applies irrespective of when the indication was granted. The meaning of this symbol, which will be selected by the European Commission on the basis of a recommendation from the Paediatric Committee, will be explained in the patient information leaflet. Companies whose products were authorised for paediatric use before the publication of the symbol will have 2 years following publication to change their package labels.
Paediatric study programme Funding for research into the paediatric use of off-patent medicines or active substances will be provided through the Community research programmes. The exact amount of funding is not specified in the Regulation. This will be established by the European Commission following consultation with the European Parliament and the Member States as well as the scientific community, industry and other stakeholders. To obtain Community funding under the rules governing the Framework Programme, the applicants must bid successfully in response to a call for research proposals. The study must take place in more than one Member State of the EU or with a qualifying associated, candidate or third country. An inventory of therapeutic needs for the paediatric population will be compiled by the Paediatric Committee and will help to identify research priorities. It is anticipated that the first calls for proposals will be issued by the European Commission in late 2006/early 2007.
Research network The Regulation also requires the EMEA to develop a European network for paediatric clinical trials. This network will bring together existing national and European networks
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as well as individual investigators and centres with specific expertise in the conduct of studies in the paediatric population. The objectives of the European network include coordinating studies relating to paediatric medicinal products, building up the necessary scientific and administrative competences at European level, and avoiding the unnecessary duplication of studies and testing in the paediatric population. There is no specific funding provided through the Regulation for this European network, although some funds will be made available from the EMEA budget. Constituent individual networks, centres and investigators will still need to obtain funding for their infrastructure and research activities from other sources, such as national governments, the pharmaceutical industry or the Community Framework Programmes. Some Member States, anticipating the increased amount of research that the Regulation will stimulate, have already taken steps to create national networks for paediatric clinical trials. One such example is the UK, where the Medicines for Children Research Network was formally launched in December 2006.
ACHIEVING THE OBJECTIVES Increasing the development of medicines for use in children The regulatory requirements and financial incentives established by the Regulation should go a long way to increasing the development of medicines for paediatric use. As described above, for all new medicines data must be generated covering all the relevant subsets of the paediatric population and age-appropriate formulations, unless the product has been granted a waiver. This also applies to new indications, new pharmaceutical forms and new routes of administration for medicines still covered by patent protection. Furthermore, unless the product has been granted a deferral, these data must be submitted at the time of the application for marketing authorisation. The creation of the PUMA, which has its own associated incentives, should stimulate the development of off-patent medicines for paediatric use. This will also be helped by the provision of Community funding for studies relating to medicines or active substances not covered by patent protection.
Ensuring that medicines used to treat children are subject to high quality research and appropriately authorised for use in children A number of measures contained within the Regulation are aimed at ensuring that the research conducted in children is of high quality. For example, the EMEA and its scientific committees will provide free advice to applicants on the design and conduct of the studies in a PIP and on the design
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and conduct of paediatric pharmacovigilance and risk management systems. In support of the latter, the EMEA/CHMP has already finalised guidance on the conduct of pharmacovigilance in the paediatric population. Further guidance will be developed on the conduct of paediatric clinical trials in different therapeutic areas and in specific paediatric populations. In addition, the European Commission is developing a document on ethical considerations for clinical trials performed in children, which was released for a 4-month consultation period in October 2006.10 The European network established by the Regulation aims to facilitate the coordination of studies relating to paediatric medicines as well as helping to increase the expertise necessary to conduct high-quality research, for example by providing training and developing guidance on best practice. The application process for marketing authorisations can appear complex, especially for smaller companies that may not have much experience in this area. The EMEA, as well as national authorities, will give free regulatory advice on submitting applications for marketing authorisations in paediatric indications. Such applications are also eligible for the centralised procedure, which, in a single process, enables a company to obtain a marketing authorisation that applies throughout the EU. It is particularly frustrating when authorised paediatric medicines are discontinued from the market. The Regulation contains a provision to discourage this. If a company intends to discontinue a paediatric medicine that has benefited from the financial incentives of the Regulation, the company must either transfer the marketing authorisation to a third party or allow a third party to use the scientific documentation relating to the medicine in order to support an application for marketing authorisation.
publishing an inventory of all national incentives and rewards for paediatric medicine development offered by the Member States; the names of all those infringing the terms and provisions of the Regulation; the names of the companies and products that have benefited from the Regulation; and the names of companies that have failed to comply with any of the obligations of the Regulation. The Commission is also charged with writing a general report on the experience acquired as a result of the application of the Regulation. This will include a detailed inventory of all medicinal products authorised for paediatric use since its entry into force. The Commission must also present an analysis of the economic impact of the rewards and incentives, together with an analysis of the estimated public health impact. There are three principal measures that will increase the information publicly available on the paediatric use of medicines. The Regulation establishes a paediatric clinical trials database that will contain information on all clinical trials conducted according to a PIP, including trials conducted solely in countries outside the EU. This will be based on the clinical trials database that was established by the Clinical Trials Directive.11 Parts of this paediatric database, including the trial results, will be publicly accessible. In addition, companies must submit to the regulatory authorities the data from all paediatric trials completed before the entry into force of the Regulation. The regulatory authorities have the power to update the relevant summaries of product characteristics and patient information leaflets with this information, if appropriate. Finally, when the data from PIPs have been submitted, the relevant summaries of product characteristics and patient information leaflets must reflect the results of the studies, whether these are positive or negative.
Increasing the information available
Avoiding unnecessary trials
The Regulation contains a number of measures that are intended to increase transparency as well as the amount of information publicly available on the paediatric use of medicines. The responsibilities for transparency are divided between the EMEA and the European Commission. The EMEA has the responsibility of publishing the following: the names and qualifications of the members of the Paediatric Committee; the list of waivers; all opinions of the Paediatric Committee, after the deletion of commercially confidential information; a register of all medicines with paediatric indications authorised following completion of a PIP and the deadlines for placing the products on the market; the names of any marketing authorisation holder intending to discontinue a paediatric medicine from the market; and the inventory of paediatric therapeutic needs compiled by the Paediatric Committee. The European Commission is responsible for: selecting and publishing the new symbol that must be placed on the label of every medicine with an authorised paediatric use;
The Regulation contains a number of measures aimed at avoiding unnecessary trials in the paediatric population. This is particularly important in view of the heightened ethical concerns about involving children in clinical trials. The Regulation specifies that, whenever carrying out its tasks, the Paediatric Committee must consider whether or not any proposed studies can be expected to be of significant therapeutic benefit to and/or fulfil a therapeutic need of the paediatric population. A principal provision in this respect is the power of the Paediatric Committee to impose a waiver from the requirement to provide data from a PIP, for example if it considers that the product is likely to be ineffective or unsafe in part or all of the paediatric population or that the product does not represent a significant therapeutic benefit over existing treatments. If such a waiver is imposed, the product cannot benefit from the financial incentives of the Regulation, and it is therefore unlikely that a commercial sponsor would proceed with development of the product for children.
THE EUROPEAN REGULATION ON MEDICINES FOR PAEDIATRIC USE
Perhaps of equal importance is public availability of parts of the paediatric clinical trials database. Access to details of trials in progress and the results of completed trials will help investigators, applicants and others to judge whether the proposed trial will contribute to the evidence base for the product. In addition, the free scientific advice on the content of a PIP provided by the EMEA and national authorities should help to avoid errors in design and methodology that may render the trial uninterpretable.
CONCLUSION The entry into force of the Regulation on paediatric medicines will mark the beginning of a new era in the development of medicines for children. It will entail a heavy workload for all of the interested parties and, in some areas at least, a steep leaning curve. But, finally, we have a comprehensive set of tools to achieve the goal of providing children with appropriately tested, authorised and formulated medicines, and can anticipate tangible public health benefits as a result.
REFERENCES 1. Section 111 of Title I of the Food and Drug Administration Modernization Act of 1997 (the Modernization Act). http://www.fda.gov/ cder/guidance/2891fnl.htm#ATTACHMENT%20A 2. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients (‘‘Pediatric Rule’’), 21 C.F.R. §§ 201, 312, 314, 601, 63 Fed. Reg. 66,632 (December 2, 1998).
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3. Best Pharmaceuticals for Children Act. http://www.fda.gov/opacom/ laws/pharmkids/pharmkids.html. 4. Pediatric Research Equity Act of 2003, http://www.fda.gov/cder/ pediatric/S-650-PREA.pdf. 5. Report on the Experts’ Round Table on the Difficulties Related to the Use of New Medicinal Products in Children Held on 18 December 1997. http://www.emea.eu.int/pdfs/human/regaffair/2716498en.pdf 6. Council Resolution on Paediatric Medicinal Products, 14 December 2000, J.O. C-17, 19/01/2001. http://europa.eu.int/eur-lex/en/archive/ 2001/c_01720010119en.html 7. Proposal for a Regulation of the European Parliament and Council on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/ 2004. http://ec.europa.eu/enterprise/pharmaceuticals/paediatrics/ docs/_2004_09/en.pdf. 8. Regulation (EC) No.141/2000 of the European Parliament and of the Council on Orphan Medicinal Products (Official Journal L 18, 22/1/ 2000, pp. 1–5). http://ec.europa.eu/enterprise/pharmaceuticals/ orphanmp/doc/141_2000/141_2000_en.pdf 9. Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population (CPMP/ICH/2711/99). http://www. emea.eu.int/pdfs/human/ich/271199en.pdf 10. Ethical Considerations for Clinical Trials Performed in Children. Recommendations of the Ad Hoc Group for the Development of Implementing Guidelines for Directive 2001/20/EC Relating to Good Clinical Practice in the Cconduct of Clinical Trials on Medicinal Products for Human Use. http://ec.europa.eu/enterprise/pharmaceuticals/ paediatrics/docs/paeds_ethics_consultation20060929.pdf 11. Directive 2001/20/EC OF the European Parliament and of the Council of 4 April 2001 on the Approximation of the Laws, Regulations and Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use (Official Journal L 121, 1/ 5/2001, pp. 34–44). http://ec.europa.eu/enterprise/pharmaceuticals/ eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf
REVIEW
The European Regulation on medicines for paediatric use Julia Dunne* Medicines and Healthcare Products Regulatory Agency, 1 Nine Elms Lane, London SW8 9NQ UK KEYWORDS european paediatric use regulation; requirements and incentives; paediatric committee; paediatric investigation plan; paediatric clinical trials database; paediatric use marketing authorisation; extension of supplementary protection certificate; paediatric research network, paediatric study programme
Summary The European Regulation on medicines for paediatric use entered into force on 26 January 2007. It marks a radical change in the European Union in terms of encouraging the development of medicines for paediatric age groups and improving the availability of information on the use of medicines in children. How will the new Paediatric Regulation achieve this? For the first time, companies will be required to study medicines in the paediatric population and develop age-appropriate formulations. As a reward or incentive for conducting these studies, companies will be entitled to extensions of patent protection and market exclusivity. The Regulation establishes a European paediatric clinical trials network and a paediatric study programme for off-patent medicines, the latter to be funded through the Community Framework Programmes. A Paediatric Committee, based at the European Medicines Agency, will be responsible for agreeing the paediatric investigation plan (PIP) with companies. This will describe the clinical trials and other measures necessary to investigate a particular medicine in the paediatric population. A European paediatric clinical trials database, partly accessible to the public, will hold the details and the results of all paediatric trials conducted in line with these PIPs. All medicines authorised for a paediatric use will be identified by a new symbol on the package label. After 5 years, there will be a stocktake with a view to making changes to the Regulation if necessary. ß 2007 Elsevier Ltd. All rights reserved.
The lack of appropriately authorised and formulated medicines for use in the paediatric population is a longstanding problem and cause for concern. As a result, most medicines are prescribed to children on an off-label or an unlicensed basis. (For the purposes of this article the word ‘children’ is synonymous with ‘paediatric population’ and describes the age group between 0 and 18 years.) Dosing regimens approved for adults are extrapolated to paediatric age groups, for example on the basis of proportionality of weight, without paediatric pharmacokinetic or pharmacodynamic data. Safety and efficacy are presumed to be the same as in adults, but this may not be the case. Evidence* Tel.: +44 207 084 2115. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2007.04.004
based information in children is often not readily available, and prescribing decisions may have to be based on accepted practice presented in formularies such as the British National Formulary for Children (BNF-C). There are a number of reasons why medicines are not properly tested for use in children. These include concerns about conducting clinical trials in this vulnerable population and commercial considerations on the part of the pharmaceutical industry. More recently, however, concerns about the ethics of studying medicines in children have been outweighed by concerns about denying children access to properly tested, formulated and authorised medicines. What now remains as the principal barrier is the reluctance of the pharmaceutical industry to develop medicines when there is an insufficient commercial return on investment. In
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October 2004, the European Commission launched a legislative proposal for a European regulation to overcome this barrier. Following intensive negotiations with the Member States and the European Parliament, the Regulation on medicines for paediatric use, which is based on a system of requirements and incentives, entered into force on US Food and Drug Administration, Center for Drug Evaluation and Research, Paediatric Drug Development 26 January 2007.
REGULATORY BACKGROUND Regulators began to take action to stimulate the pharmaceutical industry to develop more medicines for children in the early 1980s. By the mid 1990s, it was clear that exhortations and guidance alone were not having the necessary effect and that legislation was needed. In the late 1990s, the first pieces of legislation relating to paediatric medicines were adopted in the USA. These established a framework of incentives and requirements for the conduct of studies on medicines in the paediatric population. The US incentive, an additional 6 months’ market exclusivity in return for the submission of paediatric studies (‘paediatric exclusivity’),1 was highly successful in stimulating paediatric clinical trials, although not necessarily in the areas of greatest therapeutic need, as commercial considerations still seemed to predominate. Although there was resistance to the introduction of requirements in the USA, it was evident that without the Pediatric Rule,2 the industry would not conduct paediatric studies on medicines in less commercially attractive therapeutic areas. The US laws have evolved over the past decade, but the incentives and obligations still remain, refined and enshrined in separate pieces of legislation, The Best Pharmaceuticals for Children Act 20023 and the Pediatric Research Equity Act of 2003.4 In the European Union (EU), regulators and other interested parties agreed as long ago as December 1997 that a strengthening of EU legislation was needed ‘in order to overcome current barriers that prevent the use of new medicinal products in children’.5 In a Council resolution of December 2000, the European Health Ministers called on the European Commission to make proposals for legislation ‘to ensure that new medicinal products for children and medicinal products already on the market are fully adapted to the specific needs of children’.6 In October 2004, after much debate and extensive consultations, the Commission issued a proposal for a Regulation on medicines for paediatric use.7 Although the Commission was criticised for taking nearly 4 years to respond to the Council resolution, the proposal took on board lessons learned from the US experience. When it emerged, therefore, it was a balanced and comprehensive response to the call from the Council. In addition, through the repeated debate and public consultation, the more controversial issues had already been widely rehearsed and the resulting passage of the proposal
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through the co-decision procedure, which involves both the Council (Member States) and the European Parliament, was relatively rapid. Final agreement on the text of the proposal was achieved in June 2006. Due to various administrative delays, however, the Regulation did not enter into force until 6 months later. During the negotiations between the Commission, the Council and the Parliament on the text of the Regulation, surprisingly few key provisions were altered, and some new important provisions were gained. Examples of the latter include public accessibility of the paediatric clinical trials database, funding for a paediatric study programme for off-patent medicines, and a provision to discourage the discontinuation from the market of medicines authorised for paediatric use. Perhaps the most controversial issue during the negotiations was the question of the financial incentives for industry: the addition of 6 months’ extra patent protection through an extension of the duration of the Supplementary Protection Certificate (SPC) for those medicines for which an agreed paediatric investigation plan (PIP) had been completed (and a number of other criteria have been fulfilled), and an additional 2 years market exclusivity for orphan medicines.8 During the Council discussions, amendments were proposed by a number of Member States to moderate the extent of these incentives, the financial burden of which will fall most heavily on those Member States with a high use of generic medicines as the cheaper generic copies will be kept off the market for the additional period of the SPC extension. Proposed amendments included a reduction of the duration of the extension, for example to 3 months, and a variable extension period depending on financial returns. There were parallel proposals to reduce the period of extra market exclusivity for orphan medicines. Similar amendments were proposed in the European Parliament. The wide range in the estimates of both the economic impact of the measures as a whole and the scale of the reward in relation to individual medicines led in part to the difficulties in agreeing a fair way to determine the duration of the extension. Eventually a compromise was reached that retained as financial incentives the Commission proposal of a 6-month extension to the duration of the SPC and a 2-year extension of market exclusivity for orphan medicines, but added a requirement for a detailed assessment of the economic and public health impact of these incentives when sufficient experience had been gained through the operation of the Regulation. The significance of the use of a regulation as a legal instrument is that it is directly applicable in national law and takes immediate effect without any further action on the part of national authorities. It is binding in all its parts. A directive, which would have been the other option, is binding on the Member States in terms of the result to be achieved but leaves to each State the choice of the form and method to achieve the Community objectives within
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the framework of its own internal legal system. By choosing a regulation, the Commission can ensure that the new provisions for paediatric medicines will be applied in exactly the same way throughout the EU and that, as a result, all the children of the EU should benefit equally. Much of the detail on the operation of the Regulation is left to the implementing texts. These texts, mostly in the form of guidelines, will be developed by the European Commission and the European Medicines Agency (EMEA), in consultation with Member States and other stakeholders. Such texts have the advantage of being relatively easy to update in the event of scientific or technical progress, without the need to return to the Council or the European Parliament.
AIMS AND OBJECTIVES OF THE REGULATION The overall aim of the Regulation is to improve the health of children in the EU. More specifically the objectives include: increasing the development of medicines for use in children; o ensuring that medicines used to treat children are: - subject to high quality research; - appropriately authorised for use in children; o improving the information available on the use of medicines in children; o achieving the above objectives without subjecting children to unnecessary clinical trials or delaying the authorisation of medicines in the adult population. The Regulation establishes a number of new provisions, structures and procedures in order to achieve its objectives.
KEY PROVISIONS Requirements and incentives The pharmaceutical industry has previously been free to restrict a particular medicine’s development to the adult population; the development of paediatric medicines has been solely at the industry’s discretion. The new Regulation is the first piece of European legislation that requires the pharmaceutical industry to develop medicines for use in a particular patient population. Perhaps, therefore, the most important requirement of the Regulation is that all applications for marketing authorisation for new medicines, including orphan medicines, must contain the results of all studies and information required in a previously agreed PIP. The PIP will contain a full proposal of all the studies (and their timings) necessary to support the paediatric use of an individual product and will cover all paediatric age groups and all necessary age-appropriate formulations. This is the default position of the Regulation. In some cases, it will be possible to defer the start of some or all of the studies in relation to the development of the product in adults. In this
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case, the paediatric data will be provided after the initial marketing authorisation has been granted. In other cases, the requirement may be waived for part or all of the paediatric population, for example where there is no paediatric therapeutic need or where paediatric use of the product is not appropriate. But the important point is that, unless a deferral or a waiver has been granted, paediatric data must be provided in all applications for the authorisation of new medicinal products. The requirement also applies to applications to add a new indication, new pharmaceutical form or new route of administration for medicines still covered by patent protection. It will start to apply 18 months after the Regulation enters into force. The Regulation also includes incentives for companies to develop medicines for use in children. This is to stimulate paediatric development for products not bound by the requirements discussed above, as well as to reward the industry for conducting the obligatory investigation programmes. When an agreed paediatric plan has been completed and all the information has been submitted to the regulatory authorities, the medicinal product will be granted an extra 6 months’ patent protection (through an extension of the duration of its SPC), provided that the medicinal product is authorised in all Member States and that relevant information (whether negative or positive) from the paediatric studies has been incorporated into the summary of product characteristics. This extension will be granted whether or not the data support a paediatric indication. The incentive only applies if the product has an active SPC; there is no financial incentive in cases where there is no SPC or where the SPC has expired, and there is no mechanism to extend the duration of the period of the patent itself. For orphan medicinal products, the incentive takes the form of an extra 2 years’ market exclusivity in addition to the 10 years’ market exclusivity that is granted on authorisation of an orphan medicine. The financial incentives do not apply retrospectively. Therefore, they do not apply if the contents of an agreed PIP were completed before entry into force of the Regulation, unless the plan contains ‘significant studies’ that were completed after the Regulation’s entry into force. The requirements and the financial incentives are independent of each other. Thus, a marketing authorisation holder may be required to provide a completed PIP for a product but may be ineligible for the incentive (for example, because the SPC has expired before the PIP has been completed). Conversely, a marketing authorisation holder may not be obliged to submit a completed plan but may do so in order to benefit from the financial incentives. The Regulation also establishes a new type of marketing authorisation, called the paediatric use marketing authorisation (PUMA), intended to stimulate the development of
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off-patent products for use in the paediatric population. Only medicines that are intended solely for use in children will be eligible for a PUMA. The incentives associated with a PUMA are relatively weak. Nevertheless, it is hoped that they will encourage the development of new paediatric formulations for these older products. Applications for PUMAs, which must contain the results from an agreed PIP, can refer to third-party data for the same active substance, are able to use the centralised procedure for authorisation and, if authorised, will benefit from 10 years, market protection.
Paediatric investigation plan The PIP is a research and development programme aimed at ensuring that the necessary data are generated to determine the conditions in which a medicinal product may be authorised for the paediatric population. It is necessary to draw up such a plan whenever there is an intention to apply either for a marketing authorisation for a new medicine, or for a new indication, pharmaceutical form or route of administration of an existing authorised medicine that is covered by patent protection, or when applying for a PUMA. The plan must specify the timing and the measures proposed to assess the quality, safety and efficacy of the medicinal product in all relevant subsets of the paediatric population, as defined in ICH E11.9 In addition, it must describe any measures to adapt the formulation of the medicinal product that make its use more acceptable, easier, safer or more effective for the different subsets of the paediatric population. The PIP must be submitted to the Paediatric Committee no later than upon completion of the pharmacokinetic studies in adults. This time point was chosen to ensure that the paediatric development of the product is considered at a very early stage of the overall product development rather than as an afterthought. It is accepted that the initial submission will in many cases be preliminary as it will be too early in the development process to have a complete and detailed plan. The Regulation, therefore, allows the Committee to request further information or initial modifications to the plan. It also allows for modifications of the plan at a later stage as the product development progresses. The plan must, however, be agreed by the Paediatric Committee, both in order to fulfil the requirements for a valid application for marketing authorisation and to fulfil the criteria to qualify for the financial incentives provided by the Regulation. If the Paediatric Committee refuses to agree a plan, the applicant can request the Committee to re-examine its opinion. If following re-examination the Committee remains negative and the applicant disagrees with the opinion, the applicant has recourse to the European Courts of Justice. The Paediatric Committee also has to agree to any requests for deferral of the timing of the studies in the plan or for waivers from the requirement to
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develop the product for use in all or part of the paediatric population.
Paediatric Committee Membership The Regulation establishes a new scientific committee of the EMEA, the Paediatric Committee, which must be set up within 6 months of entry into force of the Regulation. The Committee membership includes five members of the Committee on Human Medicinal Products (CHMP) plus their alternates. The CHMP is the main scientific committee of the EMEA and is responsible, among other things, for giving opinions on applications for centralised marketing authorisations for medicinal products and on scientific advice on medicines development. These five members will provide an important link between the two committees. Member States that are not represented on the Paediatric Committee by a CHMP member will appoint a member and an alternate. In addition, the European Commission will appoint three members plus alternates to represent health professionals, and three members plus alternates to represent patient associations. The European Commission will appoint these six members and alternates following a public call for expressions of interest and after consulting the European Parliament. The EMEA, the Agency and the Commission are expected to cooperate to ensure that the final composition of the Committee, including members and alternates, covers those scientific areas relevant to paediatric medicines. The members, who are appointed for a renewable period of 3 years, may be accompanied by other relevant experts at the Committee meetings. The members, alternates and experts must not have any financial or other interests in the pharmaceutical industry that could affect their impartiality.
Tasks The Paediatric Committee has a number of important responsibilities, and its effective functioning will be pivotal to the success of the Regulation. Its most important task is to assess the content of PIPs for individual medicinal products and to produce opinions on them. In addition, the Committee gives opinions on applications for deferrals and waivers. In this regard, the Committee may itself impose a waiver if it considers that the product may be unsafe or ineffective in the paediatric population or that the product will not provide any significant therapeutic benefit. The Committee will also, on request, give an opinion on the compliance of an application for marketing authorisation with an agreed PIP or on the safety, quality and efficacy of a medicinal product for paediatric use. Other specific tasks include establishing an inventory of specific needs for paediatric medicinal products and giving scientific input
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in the development of any documents related to achieving the Regulation’s objectives. The Committee also has an advisory role to the EMEA and to the Commission. This includes giving advice on the new symbol that is to appear on the labels of all medicines with an authorised paediatric use, on the establishment of the European paediatric clinical trials network, on communication issues relating to conducting research in the paediatric population and on any question relating to the paediatric use of medicines. The Committee is expected to meet monthly for 3–4 days. Members will also need to devote a significant amount of time to preparation prior to meetings, so the workload involved with membership is not to be underestimated.
Paediatric use symbol All products that have an authorised paediatric indication will be required to display a new designated symbol on the package label to ensure that they are readily identifiable. This applies irrespective of when the indication was granted. The meaning of this symbol, which will be selected by the European Commission on the basis of a recommendation from the Paediatric Committee, will be explained in the patient information leaflet. Companies whose products were authorised for paediatric use before the publication of the symbol will have 2 years following publication to change their package labels.
Paediatric study programme Funding for research into the paediatric use of off-patent medicines or active substances will be provided through the Community research programmes. The exact amount of funding is not specified in the Regulation. This will be established by the European Commission following consultation with the European Parliament and the Member States as well as the scientific community, industry and other stakeholders. To obtain Community funding under the rules governing the Framework Programme, the applicants must bid successfully in response to a call for research proposals. The study must take place in more than one Member State of the EU or with a qualifying associated, candidate or third country. An inventory of therapeutic needs for the paediatric population will be compiled by the Paediatric Committee and will help to identify research priorities. It is anticipated that the first calls for proposals will be issued by the European Commission in late 2006/early 2007.
Research network The Regulation also requires the EMEA to develop a European network for paediatric clinical trials. This network will bring together existing national and European networks
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as well as individual investigators and centres with specific expertise in the conduct of studies in the paediatric population. The objectives of the European network include coordinating studies relating to paediatric medicinal products, building up the necessary scientific and administrative competences at European level, and avoiding the unnecessary duplication of studies and testing in the paediatric population. There is no specific funding provided through the Regulation for this European network, although some funds will be made available from the EMEA budget. Constituent individual networks, centres and investigators will still need to obtain funding for their infrastructure and research activities from other sources, such as national governments, the pharmaceutical industry or the Community Framework Programmes. Some Member States, anticipating the increased amount of research that the Regulation will stimulate, have already taken steps to create national networks for paediatric clinical trials. One such example is the UK, where the Medicines for Children Research Network was formally launched in December 2006.
ACHIEVING THE OBJECTIVES Increasing the development of medicines for use in children The regulatory requirements and financial incentives established by the Regulation should go a long way to increasing the development of medicines for paediatric use. As described above, for all new medicines data must be generated covering all the relevant subsets of the paediatric population and age-appropriate formulations, unless the product has been granted a waiver. This also applies to new indications, new pharmaceutical forms and new routes of administration for medicines still covered by patent protection. Furthermore, unless the product has been granted a deferral, these data must be submitted at the time of the application for marketing authorisation. The creation of the PUMA, which has its own associated incentives, should stimulate the development of off-patent medicines for paediatric use. This will also be helped by the provision of Community funding for studies relating to medicines or active substances not covered by patent protection.
Ensuring that medicines used to treat children are subject to high quality research and appropriately authorised for use in children A number of measures contained within the Regulation are aimed at ensuring that the research conducted in children is of high quality. For example, the EMEA and its scientific committees will provide free advice to applicants on the design and conduct of the studies in a PIP and on the design
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and conduct of paediatric pharmacovigilance and risk management systems. In support of the latter, the EMEA/CHMP has already finalised guidance on the conduct of pharmacovigilance in the paediatric population. Further guidance will be developed on the conduct of paediatric clinical trials in different therapeutic areas and in specific paediatric populations. In addition, the European Commission is developing a document on ethical considerations for clinical trials performed in children, which was released for a 4-month consultation period in October 2006.10 The European network established by the Regulation aims to facilitate the coordination of studies relating to paediatric medicines as well as helping to increase the expertise necessary to conduct high-quality research, for example by providing training and developing guidance on best practice. The application process for marketing authorisations can appear complex, especially for smaller companies that may not have much experience in this area. The EMEA, as well as national authorities, will give free regulatory advice on submitting applications for marketing authorisations in paediatric indications. Such applications are also eligible for the centralised procedure, which, in a single process, enables a company to obtain a marketing authorisation that applies throughout the EU. It is particularly frustrating when authorised paediatric medicines are discontinued from the market. The Regulation contains a provision to discourage this. If a company intends to discontinue a paediatric medicine that has benefited from the financial incentives of the Regulation, the company must either transfer the marketing authorisation to a third party or allow a third party to use the scientific documentation relating to the medicine in order to support an application for marketing authorisation.
publishing an inventory of all national incentives and rewards for paediatric medicine development offered by the Member States; the names of all those infringing the terms and provisions of the Regulation; the names of the companies and products that have benefited from the Regulation; and the names of companies that have failed to comply with any of the obligations of the Regulation. The Commission is also charged with writing a general report on the experience acquired as a result of the application of the Regulation. This will include a detailed inventory of all medicinal products authorised for paediatric use since its entry into force. The Commission must also present an analysis of the economic impact of the rewards and incentives, together with an analysis of the estimated public health impact. There are three principal measures that will increase the information publicly available on the paediatric use of medicines. The Regulation establishes a paediatric clinical trials database that will contain information on all clinical trials conducted according to a PIP, including trials conducted solely in countries outside the EU. This will be based on the clinical trials database that was established by the Clinical Trials Directive.11 Parts of this paediatric database, including the trial results, will be publicly accessible. In addition, companies must submit to the regulatory authorities the data from all paediatric trials completed before the entry into force of the Regulation. The regulatory authorities have the power to update the relevant summaries of product characteristics and patient information leaflets with this information, if appropriate. Finally, when the data from PIPs have been submitted, the relevant summaries of product characteristics and patient information leaflets must reflect the results of the studies, whether these are positive or negative.
Increasing the information available
Avoiding unnecessary trials
The Regulation contains a number of measures that are intended to increase transparency as well as the amount of information publicly available on the paediatric use of medicines. The responsibilities for transparency are divided between the EMEA and the European Commission. The EMEA has the responsibility of publishing the following: the names and qualifications of the members of the Paediatric Committee; the list of waivers; all opinions of the Paediatric Committee, after the deletion of commercially confidential information; a register of all medicines with paediatric indications authorised following completion of a PIP and the deadlines for placing the products on the market; the names of any marketing authorisation holder intending to discontinue a paediatric medicine from the market; and the inventory of paediatric therapeutic needs compiled by the Paediatric Committee. The European Commission is responsible for: selecting and publishing the new symbol that must be placed on the label of every medicine with an authorised paediatric use;
The Regulation contains a number of measures aimed at avoiding unnecessary trials in the paediatric population. This is particularly important in view of the heightened ethical concerns about involving children in clinical trials. The Regulation specifies that, whenever carrying out its tasks, the Paediatric Committee must consider whether or not any proposed studies can be expected to be of significant therapeutic benefit to and/or fulfil a therapeutic need of the paediatric population. A principal provision in this respect is the power of the Paediatric Committee to impose a waiver from the requirement to provide data from a PIP, for example if it considers that the product is likely to be ineffective or unsafe in part or all of the paediatric population or that the product does not represent a significant therapeutic benefit over existing treatments. If such a waiver is imposed, the product cannot benefit from the financial incentives of the Regulation, and it is therefore unlikely that a commercial sponsor would proceed with development of the product for children.
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Perhaps of equal importance is public availability of parts of the paediatric clinical trials database. Access to details of trials in progress and the results of completed trials will help investigators, applicants and others to judge whether the proposed trial will contribute to the evidence base for the product. In addition, the free scientific advice on the content of a PIP provided by the EMEA and national authorities should help to avoid errors in design and methodology that may render the trial uninterpretable.
CONCLUSION The entry into force of the Regulation on paediatric medicines will mark the beginning of a new era in the development of medicines for children. It will entail a heavy workload for all of the interested parties and, in some areas at least, a steep leaning curve. But, finally, we have a comprehensive set of tools to achieve the goal of providing children with appropriately tested, authorised and formulated medicines, and can anticipate tangible public health benefits as a result.
REFERENCES 1. Section 111 of Title I of the Food and Drug Administration Modernization Act of 1997 (the Modernization Act). http://www.fda.gov/ cder/guidance/2891fnl.htm#ATTACHMENT%20A 2. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients (‘‘Pediatric Rule’’), 21 C.F.R. §§ 201, 312, 314, 601, 63 Fed. Reg. 66,632 (December 2, 1998).
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3. Best Pharmaceuticals for Children Act. http://www.fda.gov/opacom/ laws/pharmkids/pharmkids.html. 4. Pediatric Research Equity Act of 2003, http://www.fda.gov/cder/ pediatric/S-650-PREA.pdf. 5. Report on the Experts’ Round Table on the Difficulties Related to the Use of New Medicinal Products in Children Held on 18 December 1997. http://www.emea.eu.int/pdfs/human/regaffair/2716498en.pdf 6. Council Resolution on Paediatric Medicinal Products, 14 December 2000, J.O. C-17, 19/01/2001. http://europa.eu.int/eur-lex/en/archive/ 2001/c_01720010119en.html 7. Proposal for a Regulation of the European Parliament and Council on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/ 2004. http://ec.europa.eu/enterprise/pharmaceuticals/paediatrics/ docs/_2004_09/en.pdf. 8. Regulation (EC) No.141/2000 of the European Parliament and of the Council on Orphan Medicinal Products (Official Journal L 18, 22/1/ 2000, pp. 1–5). http://ec.europa.eu/enterprise/pharmaceuticals/ orphanmp/doc/141_2000/141_2000_en.pdf 9. Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population (CPMP/ICH/2711/99). http://www. emea.eu.int/pdfs/human/ich/271199en.pdf 10. Ethical Considerations for Clinical Trials Performed in Children. Recommendations of the Ad Hoc Group for the Development of Implementing Guidelines for Directive 2001/20/EC Relating to Good Clinical Practice in the Cconduct of Clinical Trials on Medicinal Products for Human Use. http://ec.europa.eu/enterprise/pharmaceuticals/ paediatrics/docs/paeds_ethics_consultation20060929.pdf 11. Directive 2001/20/EC OF the European Parliament and of the Council of 4 April 2001 on the Approximation of the Laws, Regulations and Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use (Official Journal L 121, 1/ 5/2001, pp. 34–44). http://ec.europa.eu/enterprise/pharmaceuticals/ eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf