CELEX: 52004PC0599
Language: en
Date: 2004-09-29
Title: Proposal for a Regulation of the European Parliament and of the Council on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004 {SEC(2004) 1144}

COMMISSION OF THE EUROPEAN COMMUNITIES
                                                     Brussels, 29.9.2004
                                                     COM(2004) 599 final
                                                     2004/0217 (COD)
                                        Proposal for a
     REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
   on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92,
                  Directive 2001/83/EC and Regulation (EC) No 726/2004
                               (presented by the Commission)
                                     {SEC(2004) 1144}
EN                                                                                    EN
 ---pagebreak---                                    EXPLANATORY MEMORANDUM
   1.       INTRODUCTION AND BACKGROUND
   The public health concern and its causes
   The paediatric population is a vulnerable group with developmental, physiological and
   psychological differences from adults, which makes age and development related research of
   medicines particularly important. In contrast to the situation in adults, more than 50% of the
   medicines used to treat the children of Europe have not been tested and are not authorised for
   use in children: the health and therefore quality of life of the children of Europe may suffer
   from a lack of testing and authorisation of medicines for their use.
   Although there may be concerns voiced about conducting trials in the paediatric population,
   this has to be balanced by the ethical issues related to giving medicines to a population in
   which they have not been tested and therefore their effects, positive or negative, are unknown.
   In order to address the concerns about trials in children, the EU Directive on clinical trials1
   lays down specific requirements to protect children who take part in clinical trials in the EU.
   Related initiatives: EU Orphan Regulation and US legislation on medicines for children
   The absence of research into treatments for rare diseases led the Commission to propose the
   Regulation on orphan medicinal products, subsequently adopted in December 1999. This
   Regulation has proved successful in stimulating research leading to the authorisation of
   medicines to treat rare diseases.
   In the US, specific legislation to encourage the performance of clinical trials in children has
   been introduced, containing combined measures of incentives and obligations which have
   proven successful in stimulating the development of medicinal products for paediatric use.
   Council Resolution
   The Council Resolution of 14 December 2000 called on the Commission to make proposals in
   the form of incentives, regulatory measures or other supporting measures in respect of clinical
   research and development to ensure that new medicinal products for children and medicinal
   products already on the market are fully adapted to the specific needs of children.
   2.       JUSTIFICATION
   Objective
   The overall policy objective is to improve the health of the children of Europe by increasing
   the research, development and authorisation of medicines for use in children.
   General objectives are: to increase the development of medicines for use in children; to ensure
   that medicines used to treat children are subject to high quality research; to ensure that
   medicines used to treat children are appropriately authorised for use in children; to improve
   1
           OJ L 121, 1.5.2001, p. 34.
EN                                                2                                                EN
 ---pagebreak---    the information available on the use of medicines in children, and; to achieve these objectives
   without subjecting children to unnecessary clinical trials and in full compliance with the
   EU Clinical Trials Directive.
   Scope, legal basis and procedure
   The proposed system covers medicinal products for human use within the meaning of
   Directive 2001/83/EC.
   The proposal is based on Article 95 of the EC Treaty. Article 95, which prescribes the
   codecision procedure described in Article 251, is the legal basis for achieving the aims set out
   in Article 14 of the Treaty, which includes the free movement of goods (Article 14(2)), in this
   case human medicinal products. While taking account of the fact that any regulations on the
   manufacture and distribution of medicinal products must be fundamentally aimed at
   safeguarding public health, this aim must be achieved by means that do not impede the free
   movement of medicinal products within the Community. Since the Amsterdam Treaty came
   into force, all legislative provisions adopted by the European Parliament and the Council in
   this field have been adopted on the basis of that Article, since the differences between the
   national legislative, regulatory and administrative provisions on medicinal products tend to
   hinder intra-Community trade and therefore directly affect the operation of the internal
   market. Any action to promote the development and authorisation of medicinal products for
   paediatric use is justified at a European level with a view to preventing or eliminating these
   obstacles.
   Subsidiarity and proportionality
   The proposal builds on the experience gained with the existing regulatory framework for
   medicines in Europe and learns from the requirements and incentives for paediatric medicines
   in the US and the EU orphan regulation. On the basis of the available evidence it is concluded
   that it is unlikely that the current public health issue regarding medicines for children will be
   resolved in the EU until a specific legislative system is put in place.
   Community action allows the best possible use of the instruments set up in the pharmaceutical
   sector to complete the internal market. In addition, authorisation of medicines for children is a
   Europe-wide issue. However, Member States will have an important role in the fulfilment of
   the objectives of the proposal.
   Legislative and administrative simplification
   All the key measures in the proposal build on or strengthen the existing framework for the
   regulation of medicinal products. This proposal directly interfaces with five existing
   Community legislative texts: Directive 2001/83/EC of the European Parliament and of the
   Council of 6 November 20012 which sets the framework for the regulation of medicinal
   products; Regulation (EC) No 726/2004 of the European Parliament and of the Council of
   31 March 20043 which establishes the European Medicines Agency (EMEA) and created the
   centralised authorisation procedure for medicinal products; Directive 2001/20/EC of the
   European Parliament and of the Council of 4 April 2001 which provides a framework for the
   regulation and conduct of clinical trials in the Community; Regulation (EC) No 141/2000 of
   2
            OJ L 311, 28.11.2001 p. 67.
   3
            OJ L 136, 30.4.2004 p. 1.
EN                                                   3                                               EN
 ---pagebreak---    the European Parliament and of the Council which establishes a Community system for the
   designation of medicinal products as orphan medicinal products and incentives to stimulate
   their development and authorisation4 and; Council Regulation (EEC) No 1768/92 of
   18 June 19925 which created the Supplementary Protection Certificate.
   This proposal for a regulation establishes a precise legal framework, however, where more
   detailed implementing provisions are required, a Commission regulation is foreseen and it is
   proposed that further provisions be adopted by the Commission as guidelines, in consultation
   with the Member States, the EMEA and the parties concerned.
   Consistency with other Community policies
   Consistency will be sought with activities in the areas of research and development and health
   and consumer protection.
   Outside consultation
   Interested parties have been widely consulted on this proposal. Detail on the consultation
   conducted by the Commission is included in the Extended Impact Assessment that
   accompanies this proposal.
   Evaluation of the proposal: Extended impact assessment
   This proposal has been the subject of a Commission extended impact assessment, attached to
   this proposal, which is based on data collected by an independent contracted study.
   3.        PRESENTATION
   A brief description of the main elements of the proposal is hereby provided. For a more
   detailed description, we refer to the Commission’s explanatory document attached to this
   proposal.
   Key measures included in the proposal
   The Paediatric Committee
   A committee with expertise in all aspects related to medicines for children is central to the
   proposal and its operation. The Paediatric Committee will be responsible primarily for the
   assessment and agreement of paediatric investigation plans and requests for waivers and
   deferrals described below. In addition it may assess compliance with paediatric investigation
   plans and be asked to assess the results of studies. In all its work it will consider the potential
   significant therapeutic benefits of studies in children including the need to avoid unnecessary
   studies, it will follow existing Community requirements and will avoid any delay in the
   authorisation of medicines for other populations as a result of the requirements for studies in
   children.
   4
           OJ L 18, 22.1.2000, p. 1.
   5
           OJ L 182, 2.7.1992, p. 1.
EN                                                 4                                                   EN
 ---pagebreak---    Marketing authorisation requirements
   The paediatric investigation plan will be the document upon which the studies in children are
   based and will have to be agreed by the Paediatric Committee. When assessing such plans the
   Paediatric Committee will have to take into consideration two overarching principles: that
   studies should only be performed if there is a potential therapeutic benefit to children (and
   avoiding duplication of studies) and that the requirements for studies in children should not
   delay the authorisation of medicines for other populations.
   A core measure is a new requirement for the results of all studies performed in accordance
   with a completed, agreed paediatric investigation plan to be presented at the time of
   applications, unless a waiver or a deferral has been granted. This core requirement has been
   included to ensure that medicines are developed for children based on their therapeutic needs.
   The paediatric investigation plan will be the basis upon which compliance with this
   requirement is judged.
   Waivers from the requirements
   Not all medicines being developed for adults will be suitable for children or will be needed to
   treat children and unnecessary studies in children should be avoided. To deal with such
   situations a system of waivers from the requirements described above is proposed. The
   Paediatric Committee will start work as soon as it is set up, on lists of waivers of specific
   medicinal products and classes of medicinal product. For products not included in the
   published lists, a simple procedure is proposed for companies to request waivers.
   Deferrals from the timing of initiation or completion of studies in children
   Sometimes studies in children will be more appropriate when there exists some initial
   experience on use of a product in adults or studies in children might take longer than studies
   in adults. This might apply to the entire paediatric population or just a subset. Therefore, to
   deal with this situation, a system of deferrals is proposed together with a procedure for
   agreeing them with the Paediatric Committee.
   Marketing authorisation procedures
   The procedures set out in existing pharmaceutical legislation are not altered by the proposals.
   The requirements above will require the Competent Authorities to check compliance with the
   agreed paediatric investigation plan at the existing validation step for marketing authorisation
   applications. The assessment of safety, quality and efficacy of medicines for children and the
   granting of marketing authorisations remain the remit of the Competent Authorities. To
   increase the availability of medicines for children across the Community, because the
   requirements in the proposals are linked to Community-wide rewards and to prevent the
   distortion of free trade within the Community, it is proposed that an application for a
   marketing authorisation including at least one paediatric indication based on the results of an
   agreed paediatric investigation plan will have access to the centralised Community procedure.
   The Paediatric Use Marketing Authorisation (PUMA)
   In order to establish a vehicle for providing incentives for off-patent medicines, a new type of
   marketing authorisation, the Paediatric Use Marketing Authorisation (PUMA) is proposed. A
EN                                                 5                                                EN
 ---pagebreak---    PUMA will utilise existing marketing authorisation procedures but is specifically for
   medicinal products developed exclusively for use in children.
   The name of the medicinal product granted a PUMA can utilise the existing brand name of
   the corresponding product authorised for adults but the product names of all medicines
   granted a PUMA will include a superscript of the letter “P” to aid recognition and prescribing.
   Thus, pharmaceutical companies will be able to capitalise on existing brand recognition while
   benefiting from the data protection associated with a new marketing authorisation. The data
   protection period associated with the PUMA may prove more valuable in light of the recent
   case law of the European Court of Justice concerning the interpretation of data protection
   rules6.
   An application for a PUMA will require the submission of data necessary to establish safety,
   quality and efficacy specifically in children, collected in accordance with an agreed paediatric
   investigation plan. However, an application for a PUMA may refer to data contained in the
   dossier of a medicinal product which is or has been authorised in the Community.
   Extension of the duration of the supplementary protection certificate
   For new medicines and for products covered by a patent or a Supplementary Protection
   Certificate (SPC), if all the measures included in the agreed paediatric investigation plan are
   complied with, if the product is authorised in all Member States and if relevant information on
   the results of studies is included in product information, the six-month SPC extension will be
   granted. The mechanism for this will be the inclusion of a statement in the marketing
   authorisation that these measures have been met. Companies will then be able to present the
   marketing authorisation to patent offices that will then award the SPC extension. The need to
   have a marketing authorisation in all Member States is to prevent a Community-wide reward
   without Community-wide benefits to child-health. Because the reward is for conducting
   studies in children and not for demonstrating that a product is safe and effective in children,
   the reward will be granted even when a paediatric indication is not granted. However, relevant
   information on use in paediatric populations will have to be included in authorised product
   information.
   Extended market exclusivity for orphan medicinal products
   Under the EU orphan regulation, medicinal products designated as orphan medicinal products
   gain ten-years of market exclusivity on the granting of a marketing authorisation in the orphan
   indication. As such products are frequently not patent protected the reward of SPC extension
   can not be applied and when they are patent-protected, SPC extension would provide a double
   incentive. Therefore it is proposed to extend the ten-year period of orphan market exclusivity
   to twelve-years if the requirements for data on use in children are fully met.
   Paediatric study programme: Medicines Investigation for the Children of Europe (MICE)
   An additional tool for promoting high quality, ethical research that may lead to the
   development and authorisation of medicines for children should be the provision of funding
   for studies into the paediatric use of medicines not covered by a patent or a supplementary
   protection certificate. The Commission intends to examine the possibility of setting up a
   6
           Case C-106/01, Novartis Pharmaceuticals UK, judgment of 29 April 2004, not yet reviewed.
EN                                                    6                                             EN
 ---pagebreak---    paediatric study programme: Medicines Investigation for the Children of Europe, taking into
   consideration existing Community Programmes.
   Information on the use of medicines for children
   One of the objectives of this proposal is to increase the information available on the use of
   medicines for children. Through increased availability of information, the safe and effective
   use of medicines for children can be increased so promoting public health. In addition,
   availability of this information with help prevent the duplication of studies in children and the
   conduct of unnecessary studies in children.
   The Clinical Trials Directive establishes a Community database of clinical trials (EudraCT). It
   is proposed to build onto this database an information resource of all ongoing and terminated
   paediatric studies conducted both in the Community and in third countries.
   In addition, based on a survey of existing use of medicines in Europe, an inventory of
   therapeutic needs of children will be established by the Paediatric Committee.
   It is also proposed to create a Community network to link together national networks and
   clinical trial centres in order to build up the necessary competences at a European level and to
   facilitate the conduct of studies, to increase co-operation and avoid duplication of studies.
   Pharmaceutical companies have, in some cases, already conducted clinical trials in children.
   However, frequently, the results of these studies have not been submitted to Competent
   Authorities and have not resulted in updates to product information. To deal with this issue, it
   is proposed that any studies completed before this proposed legislation is adopted will not be
   eligible for the rewards and incentives proposed for the EU. They will, however, be taken into
   account for the requirements contained in the proposals and it will be mandatory for
   companies to submit the studies to the competent authorities once this proposed legislation is
   adopted.
   Other measures
   The interface between the Committee for Medicinal Products for Human Use, its Scientific
   Advice Working Group and other Community committees and working groups on medicines
   and the Paediatric Committee will be managed by the EMEA. In addition, free scientific
   advice from the EMEA to sponsors developing medicines for children is proposed.
   The proposals presented will place demands on competent authorities and particularly on the
   EMEA. It is proposed to increase the Community subsidy, to be allocated to the EMEA to
   take account of the new tasks. A financial statement accompanies this proposal.
EN                                                   7                                               EN
 ---pagebreak---                                                            2004/0217 (COD)
                                              Proposal for a
       REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
     on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92,
                      Directive 2001/83/EC and Regulation (EC) No 726/2004
                                       (Text with EEA relevance)
   THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,
   Having regard to the Treaty establishing the European Community, and in particular
   Article 95 thereof,
   Having regard to the proposal from the Commission1,
   Having regard to the Opinion of the European Economic and Social Committee2,
   Having regard to the Opinion of the Committee of the Regions3,
   In accordance with the procedure referred to in Article 251 of the Treaty4,
   Whereas:
   (1)     Before a medicinal product for human use is placed on the market of one or more
           Member States, it generally has to have undergone extensive studies, including
           pre-clinical tests and clinical trials, to ensure that it is safe, of high quality and
           effective for use in the target population.
   (2)     Such studies may not have been done for use in children and many of the medicines
           currently used to treat children have not been studied or authorised for such use.
           Market forces alone have proven insufficient to stimulate adequate research,
           development and authorisation of medicines for children.
   (3)     Problems resulting from the absence of suitably adapted medicines for children
           include inadequate dosing information leading to increased risks of adverse reactions
           including death, ineffective treatment through under-dosing, non-availability to
           children of therapeutic advances, as well as the use of extemporaneous formulations to
           treat children which may be of poor quality.
   1
           OJ C […], […], p. […].
   2
           OJ C […], […], p. […].
   3
           OJ C […], […], p. […].
   4
           OJ C […], […], p. […].
EN                                                  8                                             EN
 ---pagebreak---    (4) The aim of this Regulation is to increase the development of medicines for use in
       children, to ensure that medicines used to treat children are subject to high quality,
       ethical research and are appropriately authorised for use in children, and to improve
       the information available on the use of medicines in the various paediatric populations.
       These objectives should be achieved without subjecting children to unnecessary
       clinical trials and without delaying the authorisation of medicinal products for other
       populations.
   (5) While taking into account the fact that any regulations on medicinal products must be
       fundamentally aimed at safeguarding public health, this aim must be achieved by
       means that do not impede the free movement of medicinal products within the
       Community. The differences between the national legislative, regulatory and
       administrative provisions on medicinal products tend to hinder intra-Community trade
       and therefore directly affect the operation of the internal market. Any action to
       promote the development and authorisation of medicinal products for paediatric use is
       therefore justified with a view to preventing or eliminating these obstacles. Article 95
       of the Treaty is therefore the proper legal basis.
   (6) The establishment of a system of both obligations and rewards and incentives has
       proved necessary to achieve these objectives. The precise nature of the obligations and
       rewards and incentives should take account of the status of the particular medicinal
       product concerned. This Regulation should apply to all the medicines required by
       children and therefore its scope should cover products in development and yet to be
       authorised, authorised products still covered by intellectual property rights and
       authorised products no longer covered by intellectual property rights.
   (7) Any concerns about conducting trials in the paediatric population should be balanced
       by the ethical concerns about giving medicines to a population in which they have not
       been tested. The public health threat from the use of untested medicines in children
       can be safely addressed through the study of medicines for children, which should be
       carefully controlled and monitored through the specific requirements for the protection
       of children who take part in clinical trials in the Community laid down in
       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 use5.
   (8) It is appropriate to create a scientific committee, the Paediatric Committee, within the
       European Medicines Agency, hereinafter ‘the Agency’, with expertise and competence
       in the development and assessment of all aspects of medicinal products to treat
       paediatric populations. The Paediatric Committee should be primarily responsible for
       the assessment and agreement of paediatric investigation plans and for the system of
       waivers and deferrals thereof, and it should also be central to various support measures
       contained in this Regulation. In all its work the Paediatric Committee should consider
       the potential significant therapeutic benefits of studies in children including the need
       to avoid unnecessary studies. It should follow existing Community requirements,
       including Directive 2001/20/EC, as well as International Conference on
       Harmonisation (ICH) guideline E11 on the development of medicines for children, and
   5
       OJ L 121, 1.5.2001, p. 34.
EN                                               9                                              EN
 ---pagebreak---         it should avoid any delay in the authorisation of medicines for other populations as a
        result of the requirements for studies in children.
   (9)  Procedures should be established for the Agency to agree and modify a paediatric
        investigation plan, the document upon which the development and authorisation of
        medicines for children should be based. The paediatric investigation plan should
        include details of the timing and the measures proposed to demonstrate the quality,
        safety and efficacy of the medicinal product in the paediatric population. Because the
        paediatric population is in fact made up of a number of subpopulations, the paediatric
        investigation plan should specify which subpopulations need to be studied, by what
        means and by when.
   (10) The introduction of the paediatric investigation plan in the legal framework concerning
        medicinal products for human use aims at ensuring that development of medicines for
        children becomes an integral part of the development of medicinal products, integrated
        into the development programme for adults. Thus, paediatric investigation plans
        should be submitted early during product development, in time for studies to be
        conducted in children before marketing authorisation applications are submitted.
   (11) It is necessary to introduce a requirement for new medicinal products and for
        authorised medicinal products covered by a patent or a supplementary protection
        certificate to present the results of studies in children in accordance with an agreed
        paediatric investigation plan in order to obtain validation of a marketing authorisation
        application or an application for a new indication, new pharmaceutical form or new
        route of administration. The paediatric investigation plan should be the basis upon
        which compliance with that requirement is judged. However, that requirement should
        not apply to generics or similar biological medicinal products and medicinal products
        authorised through the well-established medicinal use procedure, or to homeopathic
        medicinal products and traditional herbal medicinal products authorised through the
        simplified registration procedures of Directive 2001/83/EC of the European
        Parliament and of the Council of 6 November 2001 on the Community code relating to
        medicinal products for human use6.
   (12) In order to ensure that research in children is only conducted to meet their therapeutic
        needs, there is a need to establish procedures for the Agency to waive that requirement
        for specific products or for classes or part of classes of medicinal products, to be then
        published by the Agency. As knowledge on science and medicine evolves over time,
        provision should be made for the lists of waivers to be amended. However, if a waiver
        is revoked, the requirement should not apply for a given period in order to allow time
        for at least a paediatric investigation plan to be agreed and studies in children to be
        initiated prior to marketing authorisation application.
   (13) In certain cases, the Agency should defer the initiation or completion of some or all of
        the measures contained in a paediatric investigation plan, with a view to ensuring that
        research is done only when it is safe and ethical to do so and that the requirement for
        study data in children does not block or delay the authorisation of medicines for other
        populations.
   6
        OJ L 311, 28.11.2001, p. 67. Directive as last amended by Directive 2004/27/EC (OJ L 136, 30.4.2004,
        p. 34.)
EN                                                    10                                                     EN
 ---pagebreak---    (14) Free scientific advice should be provided by the Agency as an incentive to sponsors
        developing medicines for children. To ensure scientific consistency, the Agency
        should manage the interface between the Paediatric Committee and the Scientific
        Advice Working Group of the Committee for Medicinal Products for Human Use , as
        well as the interaction between the Paediatric Committee and the other Community
        committees and working groups concerning medicinal products.
   (15) The existing procedures for the marketing authorisation of medicinal products for
        human use should not be changed. However, it follows from the requirement for the
        results of studies in children to be presented in accordance with an agreed paediatric
        investigation plan that competent authorities should check compliance with the agreed
        paediatric investigation plan and any waivers and deferrals at the existing validation
        step for marketing authorisation applications. The assessment of safety, quality and
        efficacy of medicines for children and the granting of marketing authorisations should
        remain the remit of the competent authorities. Provision should be made for the
        possibility of asking the Paediatric Committee for an opinion on compliance and for
        an opinion on the safety, quality and efficacy of a medicine in children.
   (16) To provide healthcare professionals and patients with information on the safe and
        effective use of medicines in children and as a transparency measure, information
        regarding the results of studies in children, as well as on the status of the paediatric
        investigation plans, waivers and deferrals, should be included in product information.
        When all the measures in the paediatric investigation plan have been complied with,
        that fact should be recorded in the marketing authorisation, and should then be the
        basis upon which companies can obtain the rewards for compliance.
   (17) To distinguish medicines authorised for use in children following completion of an
        agreed paediatric investigation plan and enable their prescription , provision should be
        made for the name of medicinal products granted an indication for use in children
        following an agreed paediatric investigation plan to include the letter “P” in blue
        lettering surrounded by the outline of a star, also in blue.
   (18) In order to establish incentives for authorised products no longer covered by
        intellectual property rights, it is necessary to establish a new type of marketing
        authorisation, the Paediatric Use Marketing Authorisation. A Paediatric Use
        Marketing Authorisation should be granted through existing marketing authorisation
        procedures but should apply specifically for medicinal products developed exclusively
        for use in children. It should be possible for the name of the medicinal product granted
        a Paediatric Use Marketing Authorisation to utilise the existing brand name of the
        corresponding product authorised for adults, in order to capitalise on existing brand
        recognition while benefiting from the data exclusivity associated with a new
        marketing authorisation.
   (19) An application for a Paediatric Use Marketing Authorisation should include the
        submission of data concerning use of the product in the paediatric population,
        collected in accordance with an agreed paediatric investigation plan. These data may
        be derived from the published literature or from new studies. An application for a
        Paediatric Use Marketing Authorisation should also be able to refer to data contained
        in the dossier of a medicinal product which is or has been authorised in the
        Community. That is intended to provide an additional incentive to attract small and
EN                                              11                                               EN
 ---pagebreak---         medium sized enterprises, including generic companies, to develop off-patent
        medicines for children.
   (20) This Regulation should include measures to maximise access of the Community
        population to new medicinal products tested and adapted for paediatric use, and
        minimise the chance of Community-wide rewards and incentives being granted
        without sections of the Community paediatric population benefiting from the
        availability of a newly authorised medicine. An application for a marketing
        authorisation, including an application for a Paediatric Use Marketing Authorisation,
        which contains the results of studies conducted in compliance with an agreed
        paediatric investigation plan should be eligible for the Community centralised
        procedure set out in Articles 5 to 15 of Regulation (EC) No 726/2004 of the European
        Parliament and of the Council of 31 March 2004 laying down Community procedures
        for the authorisation and supervision of medicinal products for human and veterinary
        use and establishing a European Medicines Agency7.
   (21) When an agreed paediatric investigation plan has led to the authorisation of a
        paediatric indication for a product already marketed for other indications, the
        marketing authorisation holder should be obliged to place the product on the market
        taking into account the paediatric information within two years following the date of
        approval of the indication. That requirement should relate only to products already
        authorised, but not to medicines authorised via a Paediatric Use Marketing
        Authorisation.
   (22) An optional procedure should be established to make it possible to obtain a single
        Community-wide opinion for a nationally authorised medicinal product when data on
        children following an agreed paediatric investigation plan form part of the marketing
        authorisation application. To achieve this, the procedure set out in Articles 32 to 34 of
        Directive 2001/83/EC may be used. This will allow the adoption of a Community
        harmonised Decision on use of the medicinal product in children and its introduction
        in all national product information.
   (23) It is essential to ensure that pharmacovigilance mechanisms are adapted to meet the
        specific challenges of collecting safety data in children, including data on possible
        long-term effects. Efficacy in children may also need additional study following
        authorisation. Therefore, an additional requirement for applying for a marketing
        authorisation that includes the results of studies conducted in compliance with an
        agreed paediatric investigation plan should be an obligation for the applicant to
        indicate how he proposes to ensure the long-term follow-up of possible adverse
        reactions to the use of the medicinal product and efficacy in the paediatric population.
        Additionally, where there is a particular cause for concern, provision is made for the
        possibility of requiring the applicant to submit and implement a risk management
        system and/or perform specific post-marketing studies as a condition of the marketing
        authorisation.
   (24) For products falling within the scope of the requirement to submit paediatric data, if
        all the measures included in the agreed paediatric investigation plan are complied with,
        if the product is authorised in all Member States and if relevant information on the
   7
        OJ L 136, 30.4.2004, p. 1.
EN                                             12                                                 EN
 ---pagebreak---         results of studies is included in product information, a reward should be granted in the
        form of a 6-month extension of the Supplementary Protection Certificate created by
        Council Regulation (EEC) No 1768/928.
   (25) Because the reward is for conducting studies in children and not for demonstrating that
        a product is safe and effective in children, the reward should be granted even when a
        paediatric indication is not authorised. However, to improve the information available
        on the use of medicines in the paediatric population, relevant information on use in
        paediatric populations should be included in authorised product information.
   (26) Under Regulation (EC) No 141/2000 of the European Parliament and of the Council of
        16 December 1999 on orphan medicinal products9, medicinal products designated as
        orphan medicinal products gain ten years of market exclusivity on the granting of a
        marketing authorisation for the orphan indication. As such products are frequently not
        patent-protected, the reward of Supplementary Protection Certificate extension cannot
        be applied and when they are patent-protected, such an extension would provide a
        double incentive. Therefore, for orphan medicinal products, instead of extension of the
        Supplementary Protection Certificate, the ten-year period of orphan market exclusivity
        should be extended to twelve years if the requirement for data on use in children is
        fully met.
   (27) The measures provided for in this Regulation should not preclude the operation of
        other incentives or rewards. To ensure transparency on the different measures
        available at Community and Member State levels, the Commission should draw up a
        detailed list of all the incentives available, on the basis of information provided by the
        Member States. The measures set out in this Regulation, including the agreement of
        paediatric investigation plans, should not be grounds for obtaining any other
        Community incentives to support research, such as the funding of research projects
        under the multi-annual Community Framework Programmes for Research,
        Technological Development and Demonstration Activities.
   (28) In order to increase the availability of information on the use of medicines in children,
        and to avoid the repetition of studies in children which do not add to the collective
        knowledge, the European database provided for in Article 11 of Directive 2001/20/EC
        should include an information resource of all ongoing, prematurely terminated, and
        completed paediatric studies conducted both in the Community and in third countries.
   (29) An inventory of therapeutic needs of children should be adopted by the Paediatric
        Committee after consultation with the Commission, the Member States and interested
        parties, and regularly updated. The inventory should identify the existing medicines
        used by children and highlight the therapeutic needs of children and the priorities for
        research and development. In this way, companies should be able to identify easily
        opportunities for business development; the Paediatric Committee should be able to
        better judge the need for medicines and studies when assessing draft paediatric
        investigation plans, waivers and deferrals; and healthcare professionals and patients
        should have an information source available to support their decisions as to which
        medicines to choose.
   8
        OJ L 182, 2.7.1992, p. 1. Regulation as last amended by the Act of Accession 2003.
   9
        OJ L 18, 22.1.2000, p. 1.
EN                                                     13                                          EN
 ---pagebreak---    (30)   Clinical trials in the paediatric population may require specific expertise, specific
          methodology and, in some cases, specific facilities and should be carried out by
          appropriately trained investigators. A network linking together existing national and
          European initiatives and study centres in order to build up the necessary competences
          at a European level, would help facilitating co-operation and avoiding duplication of
          studies. This network should contribute to the work of strengthening the foundations
          of the European Research Area in the context of Community Framework Programmes
          for Research, Technological Development and Demonstration Activities, benefit the
          paediatric population and provide a source of information and expertise for industry.
   (31)   For certain authorised products, pharmaceutical companies may already hold data on
          safety or efficacy in children. To improve the information available on the use of
          medicines in the paediatric populations, companies holding such data should be
          required to submit them to all competent authorities where the product is authorised.
          In this way the data can be assessed and, if appropriate, information should be
          included in the authorised product information aimed at healthcare professionals and
          patients.
   (32)   Community funding should be envisaged to cover all aspects of the work of the
          Paediatric Committee and of the Agency resulting from the implementation of this
          Regulation, such as the assessment of paediatric investigation plans, fee waivers for
          scientific advice, and information and transparency measures, including the database
          of paediatric studies and the network.
   (33)   The measures necessary for the implementation of this Regulation should be adopted
          in accordance with Council Decision 1999/468/EC of 28 June 1999 laying down the
          procedures for the exercise of implementing powers conferred on the Commission10.
   (34)   Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC)
          No 726/2004 should therefore be amended accordingly,
   HAVE ADOPTED THIS REGULATION:
                                             TITLE I
                                      Introductory provisions
                                             CHAPTER 1
                                SUBJECT-MATTER AND DEFINITIONS
                                              Article 1
   This Regulation lays down rules concerning the development of medicinal products for
   human use in order to meet the specific therapeutic needs of the paediatric population, without
   subjecting children to unnecessary clinical trials and in compliance with
   Directive 2001/20/EC.
   10
           OJ L 184, 17.7.1999, p. 23.
EN                                               14                                                EN
 ---pagebreak---                                                 Article 2
   In addition to the definitions laid down in Article 1 of Directive 2001/83/EC, the following
   definitions shall apply for the purposes of this Regulation:
   (1)      paediatric population means that part of the population aged between birth and
            18 years;
   (2)      paediatric investigation plan means a research and development programme aimed
            at ensuring that the necessary data are generated determining the conditions in which
            a medicinal product may be authorised to treat the paediatric population.
   (3)      medicinal product authorised for a paediatric indication means a medicinal product
            which is authorised for use in part or all of the paediatric population and in respect of
            which the details of the authorised indication are specified in the summary of the
            product characteristics drawn up in accordance with Article 11 of
            Directive 2001/83/EC.
                                              CHAPTER 2
                                     PAEDIATRIC COMMITTEE
                                                Article 3
   1.       A Paediatric Committee is established within the European Medicines Agency set up
            under Regulation (EC) No 726/2004, hereinafter “the Agency”.
            The Agency shall act as the secretariat of the Paediatric Committee and shall provide
            it with technical and scientific support.
   2.       Save where otherwise provided in this Regulation, Regulation (EC) No 726/2004
            shall apply to the Paediatric Committee.
   3.       The Executive Director of the Agency shall ensure appropriate co-ordination
            between the Paediatric Committee and the Committee for Medicinal Products for
            Human Use, the Committee for Orphan Medicinal Products, their working parties
            and any other scientific advisory groups.
            The Agency shall draw up specific procedures for possible consultations between
            them.
                                                Article 4
   1.       The Paediatric Committee shall be composed of the following members:
            (a)    five members of the Committee for Medicinal Products for Human Use,
                   appointed by the latter;
EN                                                 15                                                 EN
 ---pagebreak---              (b)   one person appointed by each Member State whose national competent
                   authority is not represented through the members appointed by the Committee
                   for Medicinal Products for Human Use;
             (c)   six persons appointed by the Commission, on the basis of a public call for
                   expressions of interest, in order to represent paediatricians and the interests of
                   patient associations.
             For the purposes of point (b), the Member States shall cooperate, under the
             coordination of the Executive Director of the Agency, in order to ensure that the final
             composition of the Paediatric Committee covers the scientific areas relevant to
             paediatric medicinal products, and including at least: pharmaceutical development,
             paediatric medicine, paediatric pharmacy, paediatric pharmacology, paediatric
             research, pharmacovigilance and ethics.
   2.        The members of the Paediatric Committee shall be appointed for a renewable period
             of three years. At meetings of the Paediatric Committee, they may be accompanied
             by experts.
   3.        The Paediatric Committee shall elect its Chairman from among its members for a
             term of three years renewable once.
   4.        The names and scientific qualifications of the members shall be published by the
             Agency.
                                                 Article 5
   1.        When preparing its opinions, the Paediatric Committee shall use its best endeavours
             to reach a scientific consensus. If such a consensus cannot be reached, the opinion
             shall consist of the position of the majority of members and divergent positions, with
             the grounds on which they are based.
   2.        The Paediatric Committee shall draw up its own rules of procedure for the
             implementation of its tasks. The rules of procedure shall enter into force after
             receiving a favourable opinion from the Management Board of the Agency and,
             subsequently, from the Commission.
   3.        All meetings of the Paediatric Committee may be attended by representatives of the
             Commission, the Executive Director of the Agency or his representatives.
                                                 Article 6
   Members of the Paediatric Committee and its experts shall undertake to act in the public
   interest and in an independent manner. They shall not have financial or other interests in the
   pharmaceutical industry that could affect their impartiality.
   All indirect interests that could relate to the pharmaceutical industry shall be entered in a
   register held by the Agency which the public may consult. The register shall be updated
   annually.
EN                                                  16                                                EN
 ---pagebreak---    Members of the Paediatric Committee and its experts shall declare at each meeting any
   specific interests which could be considered to be prejudicial to their independence with
   respect to the points on the agenda.
   Members of the Paediatric Committee and its experts shall be required, even after their duties
   have ceased, not to disclose any information of the kind covered by the obligation of
   professional secrecy.
                                                Article 7
   1.       The tasks of the Paediatric Committee shall include the following:
            (a)    to assess the content of any paediatric investigation plan for a medicinal
                   product submitted to it in accordance with this Regulation and formulate an
                   opinion thereon;
            (b)    to assess waivers and deferrals and formulate an opinion thereon;
            (c)    at the request of the Committee for Medicinal Products for Human Use, a
                   competent authority or the applicant, to assess compliance of the application
                   for a Marketing Authorisation with the concerned agreed paediatric
                   investigation plan and formulate an opinion thereon;
            (d)    at the request of the Committee for Medicinal Products for Human Use or a
                   competent authority, to assess any data generated in accordance with an agreed
                   paediatric investigation plan and formulate an opinion on the quality, safety or
                   efficacy of the medicinal product for use in the paediatric population;
            (e)    to advise on the content and format of data to be collected for the survey
                   referred to in Article 41 and to adopt an inventory of therapeutic needs as
                   referred to in Article 42;
            (f)    to support and advise the Agency on establishing the European network
                   referred to in Article 43;
            (g)    to assist scientifically in the elaboration of any documents related to the
                   fulfilment of the objectives of this Regulation;
            (h)    to provide advice on any question related to medicinal products for paediatric
                   use, at the request of the Executive Director of the Agency or the Commission.
   2.       When carrying out its tasks, the Paediatric Committee shall consider whether or not
            any proposed studies can be expected to be of significant therapeutic benefit to the
            paediatric population.
EN                                                  17                                              EN
 ---pagebreak---                                               TITLE II
                        Marketing authorisation requirements
                                              CHAPTER 1
                          GENERAL AUTHORISATION REQUIREMENTS
                                                 Article 8
   1.        An application for marketing authorisation under Article 6 of Directive 2001/83/EC
             in respect of a medicinal product for human use which is not authorised in the
             Community at the time of entry into force of this Regulation shall be regarded as
             valid only if it includes, in addition to the particulars and documents referred to in
             Article 8(3) of Directive 2001/83/EC, one of the following:
             (a)   the results of all studies performed and details of all information collected in
                   compliance with an agreed paediatric investigation plan;
             (b)   a decision of the Agency granting a product-specific waiver;
             (c)   a decision of the Agency granting a class waiver;
             (d)   a decision of the Agency granting a deferral.
             For the purposes of point (a), the decision of the Agency agreeing the paediatric
             investigation plan concerned shall also be included in the application.
   2.        The documents submitted pursuant to paragraph 1 shall, cumulatively, cover all
             subsets of the paediatric population.
                                                 Article 9
   In the case of authorised medicinal products which are protected either by a supplementary
   protection certificate under Regulation (EEC) No 1768/92, or by a patent which qualifies for
   the granting of the supplementary protection certificate, Article 8 of this Regulation shall
   apply to applications for authorisation of new indications, including paediatric indications,
   new pharmaceutical forms and new routes of administration.
                                                Article 10
   Articles 8 and 9 shall not apply to products authorised under Articles 10, 10a, 13 to 16 or 16a
   to 16i of Directive 2001/83/EC.
EN                                                  18                                              EN
 ---pagebreak---                                                 Article 11
   In consultation with the Member States, the Agency and other interested parties, the
   Commission shall draw up the modalities concerning the format and content which
   applications for agreement or modification of a paediatric investigation plan and requests for
   waivers or deferrals must follow in order to be considered valid.
                                              CHAPTER 2
                                               WAIVERS
                                                Article 12
   1.       Production of the information referred to in point (a) of Article 8(1) shall be waived
            for specific medicinal products or for classes of medicinal products, if there is
            evidence showing any of the following:
            (a)    that the specific medicinal product or class of medicinal products is likely to be
                   ineffective or unsafe in part or all of the paediatric population;
            (b)    that the disease or condition for which the specific medicinal product or class is
                   intended occurs only in adult populations;
            (c)    that the specific medicinal product does not represent a significant therapeutic
                   benefit over existing treatments for paediatric patients.
   2.       The waiver provided for in paragraph 1 may be issued with reference only to one or
            more specified subsets of the paediatric population, with reference only to one or
            more specified therapeutic indications, or with reference to a combination of both.
                                                Article 13
   The Paediatric Committee may of its own motion adopt an opinion, on the grounds set out in
   Article 12(1), to the effect that a class or a product-specific waiver, as referred to in
   Article 12(1), should be granted.
   As soon as the Paediatric Committee adopts an opinion, the procedure laid down in Chapter 4
   shall apply. In the case of a class waiver, only Article 26(4) shall apply.
                                                Article 14
   1.       The applicant may, on the grounds set out in Article 12(1), apply to the Agency for a
            product-specific waiver.
   2.       Within 60 days of receipt of the application, the Paediatric Committee shall adopt an
            opinion as to whether or not a product-specific waiver should be granted.
EN                                                  19                                                EN
 ---pagebreak---       Either the applicant or the Paediatric Committee may request a meeting during that
      60-day period.
      Whenever appropriate, the Paediatric Committee may request the applicant to
      supplement the particulars and documents submitted. Where the Paediatric
      Committee avails itself of this option, the 60-day time-limit shall be suspended until
      such time as the supplementary information requested has been provided.
   3. As soon as the Paediatric Committee adopts an opinion, the procedure laid down in
      Chapter 4 shall apply. The Agency shall inform the applicant accordingly without
      delay. The applicant shall be informed of the reasons for the conclusion reached.
                                         Article 15
   1. The Agency shall maintain a list of all waivers.
   2. The Paediatric Committee may, at any time, adopt an opinion advocating the review
      of a granted waiver.
      In the case of a change affecting a product-specific waiver, the procedure laid down
      in Chapter 4 shall apply.
      In the case of a change affecting a class waiver, Article 26(5) shall apply.
   3. If a particular product-specific or class waiver is revoked, the requirement set out in
      Articles 8 and 9 shall not apply for 36 months from the date of its removal from the
      list of waivers.
                                       CHAPTER 3
                         PAEDIATRIC INVESTIGATION PLAN
                                        SECTION 1
                             REQUESTS FOR AGREEMENT
                                         Article 16
   1. Where the intention is to apply in accordance with points (a) or (d) of Article 8(1), a
      paediatric investigation plan shall be drawn up and submitted to the Agency with a
      request for agreement.
   2. The paediatric investigation plan shall specify the timing and the measures proposed
      to assess the quality, safety and efficacy of the medicinal product in all subsets of the
      paediatric population that may be concerned. In addition, it shall describe any
      measures to adapt the formulation of the medicinal product so as to make its use
      more acceptable, easier, safer or more effective for different subsets of the paediatric
      population.
EN                                           20                                                 EN
 ---pagebreak---                                               Article 17
   1.       In the case of applications as referred to in Articles 8 and 9, the paediatric
            investigation plan shall be submitted with a request for agreement, unless otherwise
            justified, not later than upon completion of the human pharmaco-kinetic studies in
            adults specified in Section 5.2.3 of Part I of Annex I to Directive 2001/83/EC, so as
            to ensure that an opinion on use in the paediatric population of the medicinal product
            concerned can be given at the time of the assessment of the marketing authorisation
            or other application concerned.
   2.       Within 30 days of receiving the request referred to in paragraph 1, the Agency shall
            verify the validity of the request and shall prepare a summary report for the
            Paediatric Committee.
   3.       Whenever appropriate, the Agency may ask the applicant to submit additional
            particulars and documents, in which case the time-limit of 30 days shall be
            suspended until such time as the supplementary information requested has been
            provided.
                                              Article 18
   1.       Within 60 days of receiving a proposed paediatric investigation plan which is valid,
            the Paediatric Committee shall adopt an opinion as to whether or not the proposed
            studies will ensure the generation of the necessary data determining the conditions in
            which the medicinal product may be used to treat the paediatric population or subsets
            thereof, and as to whether or not the expected therapeutic benefits justify the studies
            proposed.
            Within the same period, either the applicant or the Paediatric Committee may request
            a meeting.
   2.       Within the 60-day period referred to in paragraph 1, the Paediatric Committee may
            request the applicant to propose modifications to the plan, in which case the
            time-limit referred to in paragraph 1 for the adoption of the final opinion shall be
            extended for a maximum of 60 days. In such cases, the applicant or the Paediatric
            Committee may request an additional meeting during this period. The time-limit
            shall be suspended until such time as the supplementary information requested has
            been provided.
                                              Article 19
   As soon as the Paediatric Committee adopts an opinion, whether positive or negative, the
   procedure laid down in Chapter 4 shall apply.
                                              Article 20
   If, having considered a paediatric investigation plan, the Paediatric Committee concludes that
   Article 12(1)(a), (b) or (c) applies to the medicinal product concerned, it shall adopt a
   negative opinion under Article 18(1).
EN                                                21                                                EN
 ---pagebreak---    In such cases, the Paediatric Committee shall adopt an opinion in favour of a waiver under
   Article 13, whereupon the procedure laid down in Chapter 4 shall apply.
                                               SECTION 2
                                              DEFERRALS
                                                Article 21
   1.        At the same time as the paediatric investigation plan is submitted under
             Article 17(1), a request may be made for deferral of the initiation or completion of
             some or all of the measures set out in that plan. Such deferral shall be justified on
             scientific and technical grounds or on grounds related to public health.
             In any case, a deferral shall be granted when it is appropriate to conduct studies in
             adults prior to initiating studies in the paediatric population or when studies in the
             paediatric population will take longer to conduct than studies in adults.
   2.        On the basis of the experience acquired as a result of the operation of this Article, the
             Commission may adopt provisions in accordance with the procedure referred to in
             Article 51(2) to define further the grounds for granting a deferral.
                                                Article 22
   1.        At the same time as the Paediatric Committee adopts a positive opinion under
             Article 18(1), it shall, of its own motion or following a request submitted by the
             applicant under Article 21, adopt an opinion, if the conditions specified in Article 21
             are met, in favour of deferring the initiation or completion of some or all of the
             measures in the paediatric investigation plan.
             An opinion in favour of a deferral shall specify the time-limits for initiating or
             completing the measures concerned.
   2.        As soon as the Paediatric Committee adopts an opinion in favour of deferral, as
             referred to in paragraph 1, the procedure laid down in Chapter 4 shall apply.
                                               SECTION 3
                   MODIFICATION OF A PAEDIATRIC INVESTIGATION PLAN
                                                Article 23
   If, after the decision agreeing the paediatric investigation plan, the applicant encounters
   difficulties with its implementation such as to render the plan unworkable or no longer
   appropriate, the applicant may propose changes or request a deferral or a waiver, based on
   detailed grounds, to the Paediatric Committee. The Paediatric Committee shall review these
   changes and adopt an opinion proposing their refusal or acceptance. As soon as the Paediatric
   Committee adopts an opinion, whether positive or negative, the procedure laid down in
   Chapter 4 shall apply.
EN                                                  22                                                 EN
 ---pagebreak---                                               SECTION 4
                COMPLIANCE WITH THE PAEDIATRIC INVESTIGATION PLAN
                                                Article 24
   The Paediatric Committee may, in the following cases, be requested to give its opinion as to
   whether studies conducted by the applicant are in compliance with the agreed paediatric
   investigation plan:
   (a)      by the applicant, prior to submitting an application for marketing authorisation or
            variation as referred to in Articles 8 and 9, respectively;
   (b)      by the Agency, or the competent authority, when validating an application, as
            referred to in point (a), which does not include an opinion concerning compliance
            adopted following a request under point (a);
   (c)      by the Committee for Medicinal Products for Human Use, or the competent
            authority, when assessing an application, as referred to in point (a), where there is
            doubt concerning compliance and an opinion has not been given already following a
            request under points (a) or (b).
   Member States shall take account of such an opinion.
   If the Paediatric Committee is asked to give an opinion under the first paragraph, it must do so
   within 60 days of receiving the request.
                                                Article 25
   If, when conducting the scientific assessment of a valid application, the competent authority
   concludes that the studies are not compliant with the agreed paediatric investigation plan, the
   product shall not be eligible for the rewards provided for in Articles 36 and 37.
                                              CHAPTER 4
                                             PROCEDURE
                                                Article 26
   1.       Within 30 days of receiving the opinion of the Paediatric Committee, the applicant
            may submit to the Agency a written request, on detailed grounds, for a
            re-examination of the opinion.
   2.       Within 30 days of receiving a request for re-examination pursuant to paragraph 1, the
            Paediatric Committee, having appointed a new rapporteur, shall issue a new opinion
            confirming or revising its previous opinion. The opinion shall be duly reasoned and a
            statement of reasons for the conclusion reached shall be annexed to the new opinion,
            which shall become definitive.
EN                                                  23                                              EN
 ---pagebreak---    3.       If, within the 30-day period referred to in paragraph 1, the applicant does not request
            re-examination, the opinion of the Paediatric Committee shall become definitive.
   4.       The Agency shall adopt a decision without delay. This decision shall be
            communicated to the applicant.
   5.       In the case of a class waiver as referred to in Article 13, the Agency shall adopt a
            decision, which shall be published.
                                             CHAPTER 5
                                  MISCELLANEOUS PROVISIONS
                                               Article 27
   The sponsor of a medicinal product intended for paediatric use may, prior to the submission
   of a paediatric investigation plan and during its implementation, request advice from the
   Agency on the design and conduct of the various tests and studies necessary to demonstrate
   the quality, safety and efficacy of the medicinal product in the paediatric population in
   accordance with Article 57(1)(n) of Regulation (EC) No 726/2004.
   In addition, the sponsor may request advice on the design and conduct of pharmacovigilance
   and risk management systems as referred to in Article 35.
   The Agency shall provide advice under this Article free of charge.
                                            TITLE III
                         Marketing authorisation procedures
                                               Article 28
   Save where otherwise provided in this Title, marketing authorisation procedures for the
   marketing authorisations covered by this Title shall be governed by the provisions laid down
   in Regulation (EC) No 726/2004 or in Directive 2001/83/EC.
                                             CHAPTER 1
       MARKETING AUTHORISATION PROCEDURES FOR APPLICATIONS FALLING
                           WITHIN THE SCOPE OF ARTICLES 8 AND 9
                                               Article 29
   1.       Applications may be submitted in accordance with the procedure laid down in
            Articles 5 to 15 of Regulation (EC) No 726/2004 for a marketing authorisation as
            referred to in Article 8(1) of this Regulation which includes one or more paediatric
EN                                                 24                                               EN
 ---pagebreak---             indications selected on the basis of studies conducted in compliance with an agreed
            paediatric investigation plan.
            Where authorisation is granted, the results of those studies shall be included in the
            summary of product characteristics and, if appropriate, in the package leaflet of the
            medicinal product, whether or not all the paediatric indications concerned were
            approved.
   2.       Where a marketing authorisation is granted or varied, any waiver or deferral which
            has been granted pursuant to this Regulation shall be recorded in the summary of
            product characteristics and if appropriate, the package leaflet of the medicinal
            product concerned.
   3.       If the application complies with all the measures contained in the agreed completed
            paediatric investigation plan and if the summary of product characteristics reflects
            the results of studies conducted in compliance with that agreed paediatric
            investigation plan, the competent authority shall include within the marketing
            authorisation a statement indicating compliance of the application with the agreed
            completed paediatric investigation plan.
                                               Article 30
   In the case of medicinal products authorised under Directive 2001/83/EC, an application as
   referred to in Article 9 of this Regulation may be submitted, in accordance with the procedure
   laid down in Articles 32, 33 and 34 of Directive 2001/83/EC, for authorisation of a new
   indication, including the extension of an authorisation for use in the paediatric population, a
   new pharmaceutical form or a new route of administration.
   That application shall comply with the requirement laid down in point (a) of Article 8(1).
   The procedure shall be limited to the assessment of the specific sections of the summary of
   product characteristics to be varied.
                                             CHAPTER 2
                        PAEDIATRIC USE MARKETING AUTHORISATION
                                               Article 31
   1.       For the purposes of this Regulation, a paediatric use marketing authorisation shall
            mean a marketing authorisation granted in respect of a medicinal product for human
            use which is not protected by a supplementary protection certificate under
            Regulation (EEC) No 1768/92 or by a patent which qualifies for the granting of the
            supplementary protection certificate, covering exclusively therapeutic indications
            which are relevant for use in the paediatric population, or subsets thereof, including
            the appropriate strength, pharmaceutical form or route of administration for that
            product.
EN                                                 25                                              EN
 ---pagebreak---    2.       Submission of an application for a paediatric use marketing authorisation shall in no
            way preclude the right to apply for a marketing authorisation for other indications.
   3.       An application for a paediatric use marketing authorisation shall be accompanied by
            the particulars and documents necessary to establish safety, quality and efficacy in
            children, including any specific data needed to support an appropriate strength,
            pharmaceutical form or route of administration of the product, in accordance with an
            agreed paediatric investigation plan.
            The application shall also include the decision of the Agency agreeing the paediatric
            investigation plan concerned.
   4.       Where a medicinal product is or has been authorised in a Member State or in the
            Community, data contained in the dossier on that product may, where appropriate, be
            referred to, in accordance with Article 14(11) of Regulation (EC) No 726/2004 or
            Article 10 of Directive 2001/83/EC, in an application for a paediatric use marketing
            authorisation.
   5.       The medicinal product in respect of which a paediatric use marketing authorisation is
            granted may retain the name of any medicinal product which contains the same
            active substance and in respect of which the same holder has been granted
            authorisation for use in adults.
                                                Article 32
   Without prejudice to Article 3(2) of Regulation (EC) No 726/2004, an application for a
   paediatric use marketing authorisation may be made in accordance with the procedure laid
   down in Articles 5 to 15 of Regulation (EC) No 726/2004.
                                             CHAPTER 3
                                         IDENTIFICATION
                                                Article 33
   Where a medicinal product is granted a marketing authorisation for a paediatric indication
   based on the results of studies conducted in compliance with an agreed paediatric
   investigation plan, the label shall display the name of the medicinal product followed by a
   superscript of the letter “P” in blue lettering surrounded by the outline of a star, also in blue,
   for any paediatric presentation.
   The first paragraph shall apply whether the name of the medicinal product is an invented
   name or a common name as referred to in Article 1(20) and (21), respectively, of
   Directive 2001/83/EC.
EN                                                  26                                                EN
 ---pagebreak---                                             TITLE IV
                            Post-authorisation requirements
                                               Article 34
   Where medicinal products are authorised for a paediatric indication following completion of
   an agreed paediatric investigation plan and those products have already been marketed with
   other indications, the marketing authorisation holder shall, within two years of the date on
   which the paediatric indication is authorised, place the product on the market taking into
   account the paediatric indication.
                                               Article 35
   1.       In the following cases, the applicant shall detail, in addition to the normal
            requirements for post-marketing monitoring, the measures to ensure the follow-up of
            efficacy and of possible adverse reactions to the paediatric use of the medicinal
            product:
            (a)   applications for a marketing authorisation that includes a paediatric indication;
            (b)   applications to include a paediatric indication in an existing marketing
                  authorisation;
            (c)   applications for a paediatric use marketing authorisation.
   2.       Where there is particular cause for concern, the competent authority may require, as
            a condition for granting marketing authorisation, that a risk management system be
            set up or that specific post-marketing studies be performed and submitted for review.
            The risk management system shall comprise a set of activities and interventions
            designed to prevent or minimise risks relating to medicinal products, including the
            assessment of the effectiveness of those interventions.
            Assessment of the effectiveness of any risk management system and the results of
            any studies performed shall be included in the periodic safety update reports referred
            to in Article 104(6) of Directive 2001/83/EC and Article 24(3) of Regulation (EC)
            No 726/2004.
            In addition, the competent authority may request submission of additional reports
            assessing the effectiveness of any risk minimisation system and the results of any
            such studies performed.
   3.       In the case of a deferral, the marketing authorisation holder shall submit an annual
            report to the Agency providing an update on progress with paediatric studies in
            accordance with the decision of Agency agreeing the paediatric investigation plan
            and granting a deferral.
EN                                                 27                                               EN
 ---pagebreak---              The Agency shall inform the competent authority if it is found that the marketing
             authorisation holder has failed to comply with the decision of Agency agreeing the
             paediatric investigation plan and granting a deferral.
   4.        The Agency shall draw up detailed guidelines relating to the application of this
             Article.
                                              TITLE V
                                    Rewards and incentives
                                                Article 36
   1.        Where an application under Articles 8 or 9 includes the results of all studies
             conducted in compliance with an agreed paediatric investigation plan, the holder of
             the patent or supplementary protection certificate shall be entitled to a six-month
             extension of the period referred to in Articles 13(1) and 13(2) of Regulation (EEC)
             No 1768/92.
             The first subparagraph shall also apply where completion of the agreed paediatric
             investigation plan fails to lead to the authorisation of a paediatric indication, but the
             results of the studies conducted are reflected in the summary of product
             characteristics, and if appropriate, in the package leaflet of the medicinal product
             concerned.
   2.        The inclusion in a marketing authorisation of the statement referred to in
             Article 29(3) shall be used for the purposes of applying paragraph 1 of this Article.
   3.        Where the procedures laid down in Directive 2001/83/EC have been used, the
             six-month extension of the period referred to in paragraph 1 shall be granted only if
             the product is authorised in all Member States.
   4.        Paragraphs 1, 2 and 3 shall apply to products that are protected by a supplementary
             protection certificate under Regulation (EEC) No 1768/92, or under a patent which
             qualifies for the granting of the supplementary protection certificate.They shall not
             apply to medicinal products designated as orphan medicinal products pursuant to
             Regulation (EC) No 141/2000.
                                                Article 37
   Where an application for a marketing authorisation is submitted in respect of a medicinal
   product designated as an orphan medicinal product pursuant to Regulation (EC) No 141/2000
   and that application includes the results of all studies conducted in compliance with an agreed
   paediatric investigation plan, and the statement referred to in Article 29(3) of this Regulation
   is subsequently included in the marketing authorisation granted, the ten-year period referred
   to in Article 8(1) of Regulation (EC) No 141/2000 shall be extended to twelve years.
EN                                                  28                                                 EN
 ---pagebreak---    The first paragraph shall also apply where completion of the agreed paediatric investigation
   plan fails to lead to the authorisation of a paediatric indication, but the results of the studies
   conducted are reflected in the summary of product characteristics, and if appropriate, in the
   package leaflet of the medicinal product concerned.
                                               Article 38
   1.       Where a paediatric use marketing authorisation is granted in accordance with
            Articles 5 to 15 of Regulation (EC) No 726/2004, the data and marketing protection
            periods referred to in Article 14(11) of that Regulation shall apply.
   2.       Where a paediatric use marketing authorisation is granted in accordance with the
            procedures laid down in Directive 2001/83/EC, the data and marketing protection
            periods referred to in Article 10(1) of that Directive shall apply.
                                               Article 39
   1.       In addition to the rewards and incentives provided for in Articles 36, 37 and 38,
            medicinal products for paediatric use may be eligible for incentives provided by the
            Community or by the Member States to support research into, and the development
            and availability of, medicinal products for paediatric use.
   2.       Within one year of the entry into force of this Regulation, the Member States shall
            communicate to the Commission detailed information concerning any measures they
            have enacted to support research into, and the development and availability of,
            medicinal products for paediatric use. This information shall be updated regularly at
            the request of the Commission.
   3.       Within 18 months of the entry into force of this Regulation, the Commission shall
            publish a detailed inventory of all incentives provided by the Community and
            Member States to support research into, and the development and availability of,
            medicinal products for paediatric use. This inventory shall be updated regularly.
                                            TITLE VI
                           Communication and coordination
                                               Article 40
   1.       Appropriate details of trials that are contained within agreed paediatric investigation
            plans, including those that are carried out in third countries, shall be entered into the
            European database created by Article 11 of Directive 2001/20/EC.
EN                                                 29                                                 EN
 ---pagebreak---    2.       The Commission shall, on a proposal by the Agency and in consultation with
            Member States and interested parties, draw up guidance on the nature of the
            information referred to in paragraph 1 to be entered in the European database created
            by Article 11 of Directive 2001/20/EC.
                                              Article 41
   Member States shall collect available data on all existing uses of medicinal products in the
   paediatric population and, within 2 years of the entry into force of this Regulation, shall
   communicate these data to the Agency.
   The Paediatric Committee shall provide guidance on the content and the format of the data to
   be collected.
                                              Article 42
   1.       The Agency shall assess the data referred to in Article 41, in particular with a view to
            identifying research priorities.
   2.       On the basis of the assessment under paragraph 1 and other information available,
            and following consultation with the Commission, the Member States and interested
            parties, the Paediatric Committee shall establish an inventory of therapeutic needs.
            The Agency shall publish the inventory within 3 years of the entry into force of this
            Regulation, and shall update it on a regular basis.
   3.       In establishing the inventory of therapeutic needs, account shall be taken of the
            prevalence of the conditions in the paediatric population, the seriousness of the
            conditions to be treated, the availability and suitability of alternative treatments for
            the conditions in the paediatric population, including the efficacy and the adverse
            reaction profile of those treatments, including any unique paediatric safety issues.
                                              Article 43
   1.       The Agency shall, with the scientific support of the Paediatric Committee, develop a
            European network of existing national and European networks, investigators and
            centres with specific expertise in the performance of studies in the paediatric
            population.
   2.       The objectives of the European network shall be, inter alia, to coordinate studies
            relating to paediatric medicinal products, to build up the necessary scientific and
            administrative competences at European level, and to avoid duplication of studies
            and testing in children.
   3.       Within one year of the entry into force of this Regulation, the Management Board of
            the Agency shall, on a proposal from the Executive Director and following
            consultation with the Commission, the Member States and interested parties, adopt
            an implementing strategy for the launching and operation of the European network.
            This network must, where appropriate, be compatible with the work of strengthening
EN                                                 30                                                EN
 ---pagebreak---             the foundations of the European Research Area in the context of the Community
            Framework Programmes for Research, Technological Development and
            Demonstration Activities.
                                              Article 44
   1.       Within one year of the entry into force of this Regulation, any paediatric studies
            already completed, by the date of entry into force, in respect of products authorised
            in the Community shall be submitted for assessment to the competent authority.
            The competent authority shall, as appropriate, update the summary of product
            characteristics and package leaflet, and shall vary the marketing authorisation
            accordingly. Competent authorities shall exchange information regarding the studies
            submitted and their implications for any marketing authorisations concerned.
            The Agency shall coordinate the exchange of information.
   2.       All existing paediatric studies, as referred to in paragraph 1, shall be taken into
            consideration by the Paediatric Committee when assessing applications for paediatric
            investigation plans, waivers and deferrals and by competent authorities when
            assessing applications submitted pursuant to Articles 8, 9 or 31.
   3.       No paediatric studies, as referred to in paragraph 1, which have at the date of entry
            into force of this Regulation already been submitted for assessment in a third
            country, shall be taken into consideration for the rewards and incentives provided for
            in Articles 36, 37 and 38.
                                              Article 45
   Any other marketing authorisation holder sponsored studies which involve the use in the
   paediatric population of a medicinal product covered by a marketing authorisation, whether or
   not they are conducted in compliance with an agreed paediatric investigation plan, shall be
   submitted to the competent authority within six months of the completion of the studies
   concerned.
   The first paragraph shall apply whether or not the marketing authorisation holder intends to
   apply for a paediatric indication.
   The competent authority shall, as appropriate, update the summary of product characteristics
   and package leaflet, and shall vary the marketing authorisation accordingly.
   Competent authorities shall exchange information regarding the studies submitted and their
   implications for any marketing authorisations concerned.
   The Agency shall coordinate the exchange of information.
EN                                                31                                               EN
 ---pagebreak---                                              TITLE VII
                                  General and final provisions
                                              CHAPTER 1
                                               GENERAL
                                              SECTION 1
                   FEES, COMMUNITY FUNDING, PENALTIES AND REPORTS
                                               Article 46
   1.       Where an application for a paediatric use marketing authorisation is submitted in
            accordance with the procedure laid down in Regulation (EC) No 726/2004, the
            amount of the reduced fees for the examination of the application and the
            maintenance of the marketing authorisation shall be fixed in accordance with
            Article 70 of Regulation (EC) No 726/2004.
   2.       Council Regulation (EC) No 297/9511 shall apply.
   3.       Assessments of the following by the Paediatric Committee shall be free of charge:
            (a)    applications for waiver;
            (b)    applications for deferral;
            (c)    paediatric investigation plans;
            (d)    compliance with the agreed paediatric investigation plan.
                                               Article 47
   The Community contribution provided for in Article 67 of Regulation (EC) No 726/2004 shall
   cover all aspects of the work of the Paediatric Committee, including scientific support
   provided by experts, and of the Agency, including the assessment of paediatric investigation
   plans, scientific advice and any fee waivers provided for in this Regulation, and shall support
   the Agency’s activities under Articles 40 and 43 of this Regulation.
                                               Article 48
   1.       Without prejudice to the Protocol on the Privileges and Immunities of the European
            Communities, each Member State shall determine the penalties to be applied for
   11
           OJ L 35, 15.2.1995, p. 1.
EN                                                 32                                              EN
 ---pagebreak---            infringement of the provisions of this Regulation or the implementing measures
           adopted pursuant to it in relation to medicinal products authorised through the
           procedures laid down in Directive 2001/83/EC and shall take all measures necessary
           for their implementation. The penalties shall be effective, proportionate and
           dissuasive.
           Member States shall inform the Commission of these provisions no later than […].
           They shall notify any subsequent alterations as soon as possible.
   2.      Member States shall inform the Commission immediately of any litigation instituted
           for infringement of this Regulation.
   3.      At the Agency's request, the Commission may impose financial penalties for
           infringement of the provisions of this Regulation or the implementing measures
           adopted pursuant to it in relation to medicinal products authorised through the
           procedure laid down in Regulation (EC) No 726/2004. The maximum amounts as
           well as the conditions and methods for collection of these penalties shall be laid
           down in accordance with the procedure referred to in Article 51(2) of this
           Regulation.
   4.      The Commission shall publish the names of the marketing authorisation holders
           involved and the amounts of and reasons for the financial penalties imposed.
                                             Article 49
   1.      On the basis of a report from the Agency and at least on an annual basis, the
           Commission shall publish a list of the companies that have benefited from any of the
           rewards and incentives in this Regulation and the companies that have failed to
           comply with any of the obligations in this Regulation. The Member States shall
           provide this information to the Agency.
   2.      Within six years of entry into force of this Regulation, the Commission shall publish
           a general report on experience acquired as a result of its application, including in
           particular a detailed inventory of all medicinal products authorised for paediatric use
           since its entry into force.
                                            SECTION 2
                                           COMMITTEE
                                             Article 50
   The Commission shall, after consulting the Agency, adopt appropriate provisions for the
   performance of the tasks of the Paediatric Committee referred to in Article 7 in the form of a
   Regulation in accordance with the procedure referred to in Article 51(2).
EN                                                33                                               EN
 ---pagebreak---                                                 Article 51
   1.      The Commission shall be assisted by the Standing Committee on Medicinal Products
           for Human Use set up by Article 121 of Directive 2001/83/EC.
   2.      Where reference is made to this paragraph, Articles 5 and 7 of
           Decision 1999/468/EC shall apply, having regard to the provisions of Article 8
           thereof.
           The period laid down in Article 5(6) of Decision 1999/468/EC shall be set at three
           months.
                                              CHAPTER 2
                                             AMENDMENTS
                                                Article 52
   Regulation (EEC) No 1768/92 is amended as follows:
   (1)     In Article 7, the following paragraph 3 is added:
           “3.   The application for an extension of the duration of a certificate already granted
                 in application of Article 13(3) of this Regulation and of Article 36 of
                 Regulation (EC) No […/… of the European Parliament and of the Council
                 (Paediatric Regulation)*] shall be lodged not later than two years before the
                 expiry of the certificate.
                 _____________________
                 *        OJ L […], […], p. […].”
   (2)     Article 8 shall be amended as follows:
           (a)   in paragraph 1, the following point (d) is added:
                 “(d) where the application for a certificate includes a request for an extended
                       duration in application of Article 13(3) of this Regulation and Article 36
                       of Regulation (EC) No […/…(Paediatric Regulation)]:
                       (i)    a copy of the statement indicating compliance with an agreed
                              completed paediatric investigation plan as referred to in
                              Article 36(3)       of    Regulation  (EC)      No […/…(Paediatric
                              Regulation)];
                       (ii)   where necessary, in addition to the copy of the authorisations to
                              place the product on the market as referred to in point (b), copies of
                              the authorisations to place the product on the market of all other
                              Member States, as referred to in Article 36(4) of Regulation (EC)
                              No […/… (Paediatric Regulation)] .”
EN                                                   34                                              EN
 ---pagebreak---        (b)   the following paragraph 1a is inserted:
             “1a. The application for an extension of the duration of a certificate already
                    granted shall contain:
                    (a)    a copy of the certificate already granted;
                    (b)    a copy of the statement indicating compliance with an agreed
                           completed paediatric investigation plan as referred to in
                           Article 36(3) of Regulation (EC) No […/… (Paediatric
                           Regulation)];
                    (c)    copies of the authorisations to place the product on the market of
                           all Member States.”
       (c)   paragraph 2 is replaced by the following:
             “2.    Member States may provide that a fee is to be payable upon application
                    for a certificate and upon application for the extension of the duration of
                    a certificate.”
   (3) Article 9 is amended as follows:
       (a)   in paragraph 1, the following subparagraph is added:
             “The application for an extension of the duration of a certificate already
             granted shall be lodged with the competent industrial property office of the
             Member State which granted the certificate.”
       (b)   the following paragraph 3 is added:
             “3.    Paragraph 2 shall apply to the notification of the application for an
                    extension of the duration a certificate already granted. The notification
                    shall additionally contain the request for an extended duration of the
                    certificate in application of Article 36 of Regulation (EC)
                    No […/… (Paediatric Regulation)].”
   (4) In Article 11, the following paragraph 3 is added:
       “3.   Paragraphs 1 and 2 shall apply to the notification of the fact that an extension
             of the duration of a certificate already granted has been granted or rejected.”
   (5) In Article 13, the following paragraph 3 is added:
       “3.   The periods laid down in paragraphs 1 and 2 shall be extended by six months
             in the case of application of Article 36 of Regulation (EC)
             No […/… (Paediatric Regulation)]. In that case, the duration of the period laid
             down in paragraph 1 of this Article may be extended only once.”
EN                                              35                                              EN
 ---pagebreak---                                                  Article 53
   In Article 6 of Directive 2001/83/EC, the first subparagraph of paragraph 1 is replaced by the
   following:
   “No medicinal product may be placed on the market of a Member State unless a marketing
   authorisation has been issued by the competent authorities of that Member State in accordance
   with this Directive or an authorisation has been granted in accordance with Regulation (EC)
   No. 726/2004, read in conjunction with Regulation (EC) No […/of the European Parliament
   and of the Council (Paediatric Regulation)*].
   ___________________
   *        OJ L […], […], p. […].”
                                                 Article 54
   Regulation (EC) No.726/2004 is amended as follows:
   (1)      Article 56(1) is replaced by the following: :
            “1.    The Agency shall comprise:
                   (a)    the Committee for Medicinal Products for Human Use, which shall be
                          responsible for preparing the opinion of the Agency on any question
                          relating to the evaluation of medicinal products for human use;
                   (b)    the Committee for Medicinal Products for Veterinary Use, which shall be
                          responsible for preparing the opinion of the Agency on any question
                          relating to the evaluation of medicinal products for veterinary use;
                   (c)    the Committee on Orphan Medicinal Products;
                   (d)    the Committee on Herbal Medicinal Products;
                   (e)    the Paediatric Committee;
                   (f)    a Secretariat, which shall provide technical, scientific and administrative
                          support for the committees and ensure appropriate coordination between
                          them;
                   (g)    an Executive Director, who shall exercise the responsibilities set out in
                          Article 64;
                   (h)    a Management Board, which shall exercise the responsibilities set out in
                          Articles 65, 66 and 67.”
EN                                                   36                                               EN
 ---pagebreak---    (2)      The following Article 73a is inserted:
                                              “Article 73a
            Decisions taken by the Agency under Regulation (EC) No […/… of the European
            Parliament and of the Council (Paediatric Regulation)*] may form the subject of an
            action before the Court of Justice of the European Communities under the conditions
            laid down in Article 230 of the Treaty.
            ___________________
            *      OJ L […], […], p. […].”
                                              CHAPTER 3
                                           FINAL PROVISIONS
                                               Article 55
   The requirement laid down in Article 8(1) shall not apply to valid applications pending at the
   time of entry into force of this Regulation.
                                               Article 56
   1.       This Regulation shall enter into force on the thirtieth day following that of its
            publication in the Official Journal of the European Union.
   2.       Article 8 shall apply from … [18 months following the entry into force].
            Article 9 shall apply from … [24 months following the entry into force].
            Articles 31 and 32 shall apply from … [6 months following the entry into force].
   This Regulation shall be binding in its entirety and directly applicable in all Member States.
   Done at Brussels, […]
   For the European Parliament                   For the Council
   The President                                 The President
   […]                                           […]
EN                                                 37                                             EN
 ---pagebreak---                             LEGISLATIVE FINANCIAL STATEMENT
   Policy area(s): Internal market
        Activities: The activities of the European Medicines Agency are included in the following policies:
        -  Support for the development of paediatric medicines ;
        -  Improvement in the protection of public health and for consumers across the Community
        -  Maintaining a reliable and independent source of scientific advice and information, and
        -  Support and achievement of the internal market for the pharmaceutical sector.
   TITLE   OF ACTION: REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL ON
   MEDICINAL PRODUCTS FOR PAEDIATRIC USE AND AMENDING REGULATION (EEC) NO 1768/92,
   DIRECTIVE 2001/83/EC AND REGULATION (EC) NO 726/2004
   1.        BUDGET LINE(S) + HEADING(S)
   02.040201 – European Agency for the Evaluation of Medicinal Products — Subsidy under
   Titles 1 and 2
   02.040202 – European Agency for the Evaluation of Medicinal Products — Subsidy under
   Title 3
   2.        OVERALL FIGURES
   2.1.      Total allocation for action (Part B): € million for commitment
   EUR 21 282 million
   2.2.      Period of application:
   2007 to 2012
   2.3.      Overall multiannual estimate of expenditure:
   (a)       Schedule of commitment appropriations/payment                   appropriations     (financial
             intervention) (see point 6.1.1)
                                                        EUR million (to three decimal places)
                                                                                     2012
                                                                                      and
                                  Year       2008     2009      2010       2011      subs.     Total
                                  2007                                               Years
           Commitments          1,000      3,039     3,377     3,598      5,053     5,215     21,282
             Payments           1,000      3,039     3,377     3,598      5,053     5,215     21,282
EN                                                  38                                                     EN
 ---pagebreak---    (b)      Technical and administrative assistance and support expenditure(see point 6.1.2)
          Commitments
            Payments
           Subtotal a+b
       Commitments                1,000       3,039       3,377     3,598  5,053    5,215  21,282
       Payments                   1,000       3,039       3,377     3,598  5,053    5,215  21,282
   (c)      Overall financial impact of human resources and other administrative expenditure
            (see points 7.2 and 7.3)
          Commitments/
            payments
         TOTAL a+b+c
       Commitments                1,000       3,039       3,377     3,598  5,053    5,215  21,282
       Payments                   1,000       3,039       3,377     3,598  5,053    5,215  21,282
   2.4.     Compatibility with financial programming and financial perspective
            [X] Proposal will entail reprogramming of the relevant heading in the financial
                    perspective. The proposal is compatible with the new financial framework
                    (2007-2013) proposed by the Commission (Communication from the
                    Commission to the Council and the European Parliament COM(2004) 101).
   2.5.     Financial impact on revenue1:
            [X] Proposal has no financial implications (involves technical aspects regarding
                    implementation of a measure)
   3.       BUDGET CHARACTERISTICS
            Type of expenditure             Budget        New       EFTA   Contributions Heading in
                                              line                 contrib      from       financial
                                                                    ution     applicant   perspective
                                                                              countries
            Non-comp Non-diff             02.040201        NO        YES         NO           1a
            Non-comp Non-diff             02.040202        NO        YES         NO           1a
   1
           For further information, see separate explanatory note.
EN                                                       39                                           EN
 ---pagebreak---    4.        LEGAL BASIS
   – Treaty establishing the European Community and notably article 235.
   – Draft Regulation of the European Parliament and of the Council on medicinal products for
      paediatric use (to support the Agency’s work required for the operation of the draft
      Regulation including all work of the Paediatric Committee, scientific advice and any fee
      waivers provided for by virtue of the draft Regulation).
   – Regulation (EC) No 726/2004 of the European parliament and of the Council of 30 May
      2004, establishing the community procedures for the authorisation and follow up of
      medicines for human and veterinary use, and establishing the European Agency for the
      Evaluation of Medicinal Products (OJ L 136, 30.4.2004, p. 1).
   – Council Regulation (EC) No 297/95 of 10 February 1995 modified by Council
      Regulation (EC) No 2743/98 of 14 December 1998 concerning fees payable to the
      European Agency for the Evaluation of Medicinal Products (OJ L 345, 19.12.1998, p. 3).
   5.        DESCRIPTION AND GROUNDS
   5.1.      Need for Community intervention
   5.1.1.    Objectives pursued
   It is estimated that between 50 and 90% of medicinal products used in the paediatric
   population have never been specifically studied or authorised (licensed) for use in that age
   group. This leaves no alternative to the prescriber than to use products “off-label” (i.e. use of
   product authorised for adults - products that have not been tested or authorised for paediatric
   use) or use of completely unauthorised products with the associated risks of inefficacy and/or
   adverse reactions (side effects).
   The overall policy objective is to improve the health of the children of Europe by increasing
   the research, development and authorisation of medicines for use in children.
   General objectives are to:
   • increase the development of medicines for use in children;
   • ensure that medicines used to treat children are subject to high quality research;
   • ensure that medicines used to treat children are appropriately authorised for use in
      children;
   • improve the information available on the use of medicines in children;
   • achieve these objectives without subjecting children to unnecessary clinical trials and in
      full compliance with the EU Clinical Trials Directive.
EN                                                40                                                 EN
 ---pagebreak---    5.1.2.    Measures taken in connection with ex ante evaluation
   The draft Regulation of the European Parliament and of the Council on medicinal products for
   paediatric use was the subject of a Commission Extended Impact Assessment (EIA). The EIA
   accompanies this Financial Statement. The Commission’s EIA is based on an independent,
   externally contracted study, specifically designed to estimate the economic, social and
   environmental impacts of the proposal. The EIA also draws on experience with the existing
   EU pharmaceutical market and regulatory framework, experience with legislation on
   paediatric medicines in the US, experience with orphan medicines in the EU, extensive
   consultation with stakeholders, and the published literature.
   5.1.3.    Measures taken following ex post evaluation
   The draft Regulation of the European Parliament and of the Council on medicinal products for
   paediatric use is a new legislative proposal and no interim or ex post evaluation has been
   conducted.
   5.2.      Action envisaged and budget intervention arrangements
   The key measures included in the draft paediatric regulation are:
   • the establishment of an expert committee, the Paediatric Committee within the EMEA;
   • a requirement at the time of marketing authorisation applications for new medicines and
      line-extensions for existing patent-protected medicines for data on the use of the medicine
      in children resulting from an agreed paediatric investigation plan;
   • a system of waivers from the requirement for medicines unlikely to benefit children;
   • a system of deferrals of the requirement to ensure medicines are tested in children only
      when it is safe to do so and to prevent the requirements delaying the authorisation of
      medicines for adults;
   • excluding orphan medicines, a mixed reward and incentive for compliance with the
      requirement in the form of a six-month extension to the supplementary protection
      certificate (in effect, a six-month patent extension on the active moiety);
   • for orphan medicines, a mixed reward and incentive for compliance with the requirement
      in the form of an additional two-years of market exclusivity added to the existing ten years
      awarded under the EU orphan regulation;
   • a new type of marketing authorisation, the PUMA, which allows ten years of data
      protection for innovation (new studies) on off-patent products;
   • amended data requirements for PUMA applications to attract SMEs including generics
      companies;
   • a reference in the explanatory memorandum to the establishment, via separate legislation
      of an EU paediatric study programme to fund research leading to the development and
      authorisation of off-patent medicine for children;
EN                                                  41                                             EN
 ---pagebreak---    • access to an optional centralised procedure via the community referral procedure for
      existing nationally authorised medicines to gain an EU-wide Commission Decision on use
      in children;
   • measures to increase the robustness of pharmacovigilance for medicines for children;
   • a requirement for industry to submit to the authorities study reports they already hold on
      use of their medicine in children, to maximise the utility of existing data and knowledge;
   • an EU inventory of the therapeutic needs of children to focus research, development and
      authorisation of medicines;
   • an EU network of investigators and trial centres to conduct the research and development
      required;
   • a system of free scientific advice for the industry, provided by the EMEA;
   • a database of paediatric studies (based on the existing database set up by the EU Directive
      on clinical trials (OJ L 121, 1.5.2001, p. 34).
   Populations affected by the activity:
   • more than 100 million children in the newly enlarged EU stand to benefit from better
      medicines for children. Children will also be enrolled into clinical trials;
   • healthcare professionals will benefit through the supply of medicines specifically
      developed for children and may take part in clinical research on medicines for children;
   • all pharmaceutical companies seeking to access the EU market will be affected by the draft
      Regulation;
   • the EMEA and all National competent authorities will have to change their working
      practices as a result of the draft Regulation;
   Expense type
   Article 47 of the draft Regulation on medicinal products for paediatric use foresees a
   contribution from the Community to cover the work resulting from the draft Regulation on
   medicinal products for paediatric use, incorporated into the contribution provided for in
   Article 67 of Regulation (EC) No 726/2004 and in Article 7 of Regulation (EC) No 141/2000
   to be allocated to the European Medicines Agency. This contribution should cover all aspects
   of the work of the European Medicines Agency to implement and operate the draft
   Regulation, in particular: the operation of the Paediatric Committee including assessment of
   paediatric investigation plans, requests for waivers and deferrals, assessment of compliance
   with paediatric investigation plans and assessment of the safety, quality and efficacy of
   medicinal products for paediatric use; an EU inventory of the therapeutic needs of children;
   an EU network of investigators and trial centres to conduct the research; free scientific advice
   for the industry; a database of paediatric studies.
   The explanatory memorandum of the draft paediatric regulation makes a reference to the
   possible creation of a paediatric study programme: Medicines Investigation for the Children
EN                                                 42                                               EN
 ---pagebreak---    of Europe (MICE)2. The creation of the funding and its operation would be included in a
   separate Commission initiative. A detailed assessment of the impacts of the programme will
   accompany that separate initiative. However, given the interface between legislation on a
   paediatric study programme and the draft paediatric Regulation assessed here, some
   consideration is required. An EU paediatric study programme, focussed on funding or part
   funding studies on off-patent medicines will be important if research and authorisation for
   children of off-patent products are to occur for the majority of products needed by children. It
   is envisaged that the paediatric study programme may be funded, at least in part, from the
   Community budget. The paediatric study programme would also need to take account of other
   relevant Community funding, including the 6th and 7th Framework Programmes operated by
   the Commission Directorate General Research. Community funding for studies into off-patent
   medicines for children (which may lead to the authorisation of an off-patent medicine for
   children) may only be partial, e.g. 50% funding: the remainder of the funding may need to
   come from industry, Member State governments or medical charities.
   An EU paediatric study programme has the potential to stimulate research and development of
   off-patent medicines for children and could have a major beneficial impact on EU
   pharmaceutical companies, including SMEs, and a major impact on clinical trials conducted
   in the EU including strengthening pharmaceutical R&D in Europe.
   Estimated resources and costs of the paediatric Regulation, based on the draft proposal
   released for consultation by the European Commission on 8 March 2004
   The increased contribution will cover: increased administration costs of the European
   Medicines Agency relating to all tasks of the Paediatric Committee; the costs of free scientific
   advice and fee reductions for paediatric use marketing authorisations.
   Justifications of the resources implications based on its coming into force in 2007
   As of 2006, the EMEA would have to set up a task force to prepare for the work of the
   Paediatric Committee and the procedures as laid out in the Regulation. It is estimated that the
   task force would require 1 A grade full time and 1 C grade half time. This will be covered by
   an internal redeployment.
   In 2007
   Activities planned for the first year. All activities are based on the EMEA’s experience of
   Committee activities, and in particular the experience gained in the last 3 years of activities on
   orphan medicinal products and the Committee for orphan medicinal products. Activities will
   start in full as soon as the Regulation is implemented due to the legal obligations created by it.
   2
            The impact of the referenced paediatric study programme will critically depend on its funding, size and
            awarding rules. A fund, set up under the United States Best Pharmaceuticals for Children Act 2002, is
            of $ 200 000 000 for fiscal year 2000 and such sums as are necessary for each of the succeeding five
            years for the study of the use in the paediatric population of medicinal products for which there is no
            patent protection or market exclusivity. The CHMP Paediatric Expert Group has produced a
            preliminary list of sixty-five off-patent active substances considered to be priorities for research and
            development for children in the EU.
EN                                                         43                                                        EN
 ---pagebreak---    A.      Paediatric Committee
   Functioning of the Paediatric Committee
   • Meeting costs
   A monthly meeting of 2-3 days is necessary. Eleven meetings a year with 31 members are
   envisaged, representing 682-1023 expert days. In addition, it is anticipated that additional
   experts will be needed on an ad-hoc basis by the Paediatric Committee.
   • Meeting Management and Conference services
   Eleven meetings a year of 31 members plus additional experts will have heavy implications
   on the Meeting Management & Conferences Sector of the EMEA which will have to organise
   travel and accommodation and meetings, as well as on the meeting room occupation.
   • Secretariat costs
   The secretariat of the Paediatric Committee represents a full time position all year round,
   therefore taking into consideration the need for a back-up, this represents 1.5 A grade and
   1.5 C grade positions.
   • Expert costs
   Estimated at 5-10 experts per Paediatric Committee meeting, in addition to members of the
   Paediatric Committee (i.e. 55-110 experts per year).
   Activities of the Paediatric Committee
   – Paediatric Investigation Plans
   – Deferrals
   – Waiver of Paediatric Investigation Plans
   – Paediatric needs
   – Paediatric priorities
   – Compliance
   – Expert work
   In the draft paediatric Regulation, there is an obligation to submit the results of studies
   performed according to an agreed Paediatric Investigation Plan for applications for marketing
   authorisations of new products (Marketing Authorisation Applications) and variations for
   patented products. The best estimate of the number of Paediatric Investigation Plans to be
   submitted per year to the Agency in the first years is about 235-285.
   The activities related to the submission of Paediatric Investigation Plans are rather similar to
   the work done for orphan drug designation. However the level of scientific involvement to
EN                                                44                                                EN
 ---pagebreak---    judge the submitted plan is considered higher, more complex, and the number of procedures is
   2.5 times more than the current number of orphan applications.
             –     Agreed Paediatric Investigation Plans revisions
                               –      Procedures
   It is not expected that applications for the revision of Paediatric Investigation Plans would
   occur in the first year. Only procedures would have to be established.
   B.       Other activities created by the Regulation
   –         Paediatric scientific advice
   There will be an increase in scientific advice for paediatric development. It is expected that up
   to 60% of companies may seek advice (the current situation is about 30% for products
   submitted for Marketing Authorisation). This represents about three times the current number
   of Scientific Advice requests (currently 100 per year). See section 6.2 for details of the
   financial implications of fee waivers for paediatric scientific advice.
   –         Information publication and management
   This has implications on the current development of the databases at the EMEA and on other
   forms of EMEA communication.
   –         Survey of paediatric use and inventory of research priorities
   These activities will be performed by the staff in charge of other paediatric activities but will
   represent a significant part of the workload.
   –         Establishment of a paediatric research network
   This is a new type of activity for the EMEA, which will require at least a full time position for
   an A and a C grade.
   C.       Impact on the Agency
   In addition to involving specific staff all activities have direct implications on other sectors
   such as Meeting Management and Conference, IT and administration.
   The activities will generate the need for regular training, workshops and will involve missions
   outside the Agency (for example for the establishment of a network of paediatric clinical
   research).
   D.       Need for Experts in Secondment
   To strengthen the collaboration between EMEA and Member States in particular in relation to
   paediatric activities on national products, authorisations and pharmacovigilance, the EMEA
   will invite Experts in Secondment to join the Agency to facilitate the work. This will be done
   also at the stage of the preparatory work.
EN                                                 45                                                EN
 ---pagebreak---    A typical stabilised year
   It has been considered that year 2009 would represent a typical year, when the number of
   applications per year would be stable, and all activities provided for by the Regulation would
   be developed.
   A.      Paediatric Committee
   Functioning of the Paediatric Committee
   – Meeting costs
   No major changes in activities are anticipated.
   – Meeting Management and Conference services
   No major changes in activities are anticipated.
   – Secretariat costs
   No major changes in activities are anticipated.
   – Experts costs
   Changes in activities may be needed. Estimates are however given for the same numbers.
   Activities of the Paediatric Committee
   Figures for new products (on patent) should remain stable. Variations capturing products that
   never included a Paediatric Investigation Plan should slightly decrease, as some products
   would have been captured at the stage of marketing authorisation applications. This would
   however not be the case of variation applications in a new indication (new therapeutic area)
   for which a new Paediatric Investigation Plan may have to be submitted.
   There should not be any more products undergoing purely national procedures in respect of
   the obligation to submit a Paediatric Investigation Plan.
   The ‘stable’ number of Paediatric Use Marketing Authorisation procedures cannot be
   estimated. It is judged that the initial figure of 15 per year should be kept.
   Overall the level of activities should remain around 235-285 procedures per year.
   The additional (fully developed) tasks will include in particular the Annual Reports on
   deferrals, and the revision of agreed Paediatric Investigation Plans. Once a Paediatric
   Investigation Plan is agreed, the draft Regulation offers the possibility to amend it as often as
   needed on request from the sponsor. It is estimated that 30% of the Paediatric Investigation
   Plans may need revision at some point in time. This may represent a minimum of 80
   additional applications a year.
EN                                                   46                                              EN
 ---pagebreak---    B.     Activities created by the Regulation
   – Scientific Advice
   Paediatric Scientific Advice and follow up procedures would increase progressively over
   time.
   – Pharmacovigilance and risk management
   This activity will be fully developed.
   – Information publication and management
   Modifications or developments of the current structures will take place over several years.
   – Inventory of research priorities
   Regular updates are forecasted for in the Regulation.
   – Establishment of a paediatric research network
   The implementation and running of the network should be in place.
   C.     Impact on the Agency
   In addition to involving specific staff all activities and their related increases have direct
   implications on other sectors.
   5.3.     Methods of implementation
   The draft Regulation will be implemented and operated primarily by the existing European
   Medicines Agency. Certain aspects will also be operated by the National Competent
   Authorities. The Commission will be responsible for an implementing regulation and a
   number of supporting guidelines.
EN                                               47                                               EN
 ---pagebreak---    6.         FINANCIAL IMPACT
   6.1.       Total financial impact on Part B - (over the entire programming period)
   (The method of calculating the total amounts set out in the table below must be explained by
   the breakdown in Table 6.2. )
   6.1.1.     Financial intervention
                                          Commitments (in EUR million to three decimal places)
            Breakdown            2007     2008       2009      2010      2011     2012       Total
                                                                                   and
                                                                                  subs.
                                                                                  Years
   02.040201 – European
   Agency for the Evaluation of
   Medicinal Products —           0,800    2,397      2,688     2,881     4,280    4,409    17,455
   Subsidy under Titles 1 and 2
   02.040202 – European
                                  0,200    0,642      0,689     0,717     0,773    0,806      3,827
   Agency for the Evaluation of
   Medicinal Products —
   Subsidy under Title 3
   Action 2
   etc.
                       TOTAL      1,000    3,039      3,377     3,598     5,053    5,215    21,282
EN                                                48                                              EN
 ---pagebreak---     6.1.2.    Technical and administrative assistance, support expenditure and IT expenditure
              (commitment appropriations)
                                  2007    2008      2009     2010       2011     2012      Total
                                                                                  and
                                                                                 subs.
                                                                                Years
   1) Technical and              N.A.
   administrative assistance
   a) Technical assistance
   offices
   b) Other technical and
   administrative assistance:
   - intra muros:
   - extra muros:
   of which for construction
   and maintenance of
   computerised management
   systems
                      Subtotal 1
   2) Support expenditure
   a) Studies
   b) Meetings of experts
   c) Information and
   publications
                      Subtotal 2
                        TOTAL
EN                                               49                                             EN
 ---pagebreak---    6.2.       Calculation of costs by measure envisaged in Part B (over the entire
              programming period)3
   (Where there is more than one action, give sufficient detail of the specific measures to be
   taken for each one to allow the volume and costs of the outputs to be estimated.)
                                                   Commitments (in EUR million to three decimal places)
               Breakdown                         Type              Number of      Average unit    Total cost
                                              of outputs             outputs         cost
                                           (projects, files )                                  (total for years
                                                                 (total for years                2007-2012)
                                                                   2007-2012)
                                                   1                     2             3          4=(2X3)
   Paediatric medicines management
   - Measure 1                            Paediatric
                                          activities costs
                                          for the EMEA
                                          general subsidy
                                          Staff
                                          Expenditure
                                          other.                                                   17,455
                                                                                                    3,827
              TOTAL COST                                                                           21,282
   These costs are mainly due to: 1. the supplementary staff needed to perform the tasks induced
   by the new regulation on medicinal products for paediatric use, 2. scientific advice being
   given without a fee, and, 3. fee reductions for marketing authorisation applications.
   Staff will be required to: provide the secretariat of the new expert committee the Paediatric
   Committee, administer requests for opinions from the Paediatric Committee, create and
   maintain an inventory of the therapeutic needs of the children of Europe, create and maintain
   an EU network of clinical trial centres to conduct tests of medicines for children, and,
   collation and publication of information about medicines for children. Projections for 2011
   foresee that 24 people (14,5 A and 9,5 C) will be necessary to support the EMEA work related
   to the paediatric regulation. Support staff will bring the overall figure to 26.
   Regarding scientific advice, currently, requests for such advice command a fee from the
   EMEA. This fee is used mainly to pay experts from the National agencies who conduct the
   scientific evaluation of the requests (with their accompanying dossiers). The draft paediatric
   regulation will lead to such scientific advice being given without the payment of fees.
   Therefore the EMEA will have to pay money to the National agencies and this will have to be
   3
            For further information, see separate explanatory note.
EN                                                            50                                                EN
 ---pagebreak---     covered. Furthermore, the total number of requests for scientific advice is predicted to
    increase dramatically as a result of the paediatric regulation. The current average fee for
    scientific advice is about 40 000 € and it is predicted that, For the period of six years starting
    in 2007, about 330 free pieces of scientific advice will be given.
    Regarding fee reductions for marketing authorisation applications, the current fee is
    approximately 200 000 €. This pays mainly for the scientific evaluation conducted by experts
    from the National agencies. The fee reduction foreseen in the paediatric regulation is 50% and
    this will apply to a small proportion of all paediatric marketing authorisations (the so called
    Paediatric Use Marketing Authorisations – PUMAs). For the period of six-years starting in
    2007 it is estimated that about 30 paediatric use marketing authorisation applications will be
    made that will attract the 50% fee reduction. Hence the EMEA will have to pay the National
    agencies but this will not be covered by adequate fees.
   Staff requirement             2007      2008        2009       2010       2011       2012
                                                                                         and
                                                                                        subs.
                                                                                        Years
   Secretariat Paediatric             1           3          3          3         3           3
   Committee Paediatric
   Investigation Plan
   applications                       1         10         10          10        14         14
                                                  1          1          1         3           3
   Paediatric Research Network
                                                             1          2         2           2
   Funding of studies
                                      1           2          2          2         4           4
   Support staff
                        TOTAL         3         16         17          18        26         26
    Expenditure costs will mostly cover the reimbursement of the experts in relation with the new
    committee ‘Paediatric Committee’, as well as other missions and trainings. Some IT
    developments will also be necessary in order to include this new category of medicinal
    products in the several existing databases.
EN                                                  51                                                 EN
 ---pagebreak---    Expenditure Other               2007         2008         2009     2010     2011         2012
                                                                                             and
                                                                                           subs.
                                                                                           Years
   Meetings Paediatric
   Committee
   31 members and 5 experts          0,050        0,413       0,452    0,474    0,498        0,523
   11 x 2-day meetings
   Workshops, trainings and
   missions                          0,100        0,119       0,127    0,133    0,165        0,173
   IT development and web
   publication                       0,050        0,110       0,110    0,110    0,110        0,110
                       TOTAL         0,200        0,642       0,689    0,717    0,773        0,806
    7          IMPACT ON STAFF AND ADMINISTRATIVE EXPENDITURE
    7.1.       Impact on human resources
                            Staff to be assigned to management of the        Description of tasks deriving from the
                                  action using existing resources                             action
         Types of post                                                 Total
                                Number of               Number of
                             permanent posts          temporary posts
                       A    N.A.
    Officials or
                       B                                                     If necessary, a fuller description of the
    temporary staff
                                                                                     tasks may be annexed.
                       C
    Other human resources
    Total
EN                                                        52                                                   EN
 ---pagebreak---    7.2.       Overall financial impact of human resources
                  Type of human resources                      Amount (€) Method of calculation *
   Officials                                                N.A.
   Temporary staff
   Other human resources
                                      (specify budget line)
                                                     Total
   The amounts are total expenditure for twelve months.
   7.3.       Other administrative expenditure deriving from the action
   Budget line
                                                                 Amount €  Method of calculation
   (number and heading)
   Overall allocation (Title A7)
   ex A0701 – Missions                                      N.A.
   ex A07030 – Meetings
   ex A07031 – Compulsory committees 1
   Paediatric Committee
   A07032 – Non-compulsory committees 1
   A07040 – Conferences
   ex A0705 – Studies and consultations
   Other expenditure (specify)
   Training
   Information systems (A-5001/A-4300)
   Other expenditure - Part A (specify)
   IT developments
                                                     Total
   The amounts are total expenditure for twelve months.
   1
     Specify the type of committee and the group to which it belongs.
EN                                                       53                                       EN
 ---pagebreak---    I.       Annual total (7.2 + 7.3) in 2011
   II.      Duration of action
   III.     Total cost of action (2007 to 2012)
   The needs for human and administrative resources shall be covered within the allocation
   granted to the managing DG in the framework of the annual allocation procedure
   8.         FOLLOW-UP AND EVALUATION
   8.1.       Follow-up arrangements
   Many of the effects of the draft paediatric legislation lend themselves to measurement. Others,
   including the overall objective of improved child health will be more difficult to measure due
   to a lack of robust EU-wide data. Collection of the following data is possible.
   • The dates on which the Paediatric Committee and EU network of clinical trialists are
        established and guidelines and first inventory of therapeutic needs are adopted.
   • The date on which the database of paediatric studies becomes operational.
   • The number of clinical trials in children initiated and completed (broken down by country
        and type of trial).
   • The number of children enrolled into clinical trials.
   • The number of draft paediatric investigation plans submitted for assessment and the
        number of paediatric investigation plans agreed by the Paediatric Committee.
   • The number of requests for waivers and the number of waivers granted by the Paediatric
        Committee.
   • The number of requests for deferrals and the number of deferrals granted by the Paediatric
        Committee.
   • The number of requests for scientific advice.
   • The numbers of marketing authorisation applications made and granted for adults and
        children.
   • The number of PUMA applications made and PUMAs (with their associated data
        protection) granted.
   • The number of requests for post-marketing studies, pharmacovigilance plans and risk
        management systems and the delivery against those plans.
   • The number of existing studies in children submitted and the number of marketing
        authorisations updated as a result.
EN                                                  54                                             EN
 ---pagebreak---    • The number of times marketing authorisations record that a paediatric investigation plan
      has been complied with. This provides a measure of the number of supplementary
      protection certificates that can be extended.
   • Impact on the budget of the EMEA.
   These data would provide a robust measure of the impact of the draft paediatric regulation in
   terms of stimulating research, development and authorisation of medicines for children and
   any collateral effect on the authorisation of medicines for other populations. They would also
   provide a measure of the financial impacts on the EMEA.
   Prospective measurement of the costs to industry and on the price of medicines is not
   proposed as such measurement lends itself better to a post-hoc study.
   Section 4 of the extended impact assessment points out that the impact, both financial and
   social, of improved health of the children of Europe is very difficult to measure. Unless there
   is major investment in the central collection of indices of EU child health, this difficulty will
   remain when attempting to measure, in the future, the impact of the draft paediatric
   Regulation.
   8.2.      Arrangements and schedule for the planned evaluation
   The draft paediatric regulation includes proposals for: a database of paediatric studies; annual
   reports from the Member States to the Commission on problems encountered with the
   implementation of the draft paediatric regulation; annual publication of lists of companies that
   have benefits from the rewards / incentives or companies that have failed to comply with the
   obligations, and; within six years of entry into force, a general report on experienced acquired
   as a result of the application of the draft paediatric Regulation, including in particular a
   detailed inventory of all medicinal products authorised for paediatric use since it came into
   force.
   Through these measures, specifically proposed in the draft paediatric Regulation, ex post
   evaluation is already planned. The general report will likely be based on the indices listed in
   section 8.1. Furthermore, the need for a designated independent study to support the general
   report should be considered. Such an independent study could include within its scope the
   financial and social impacts for which prospective data collection is problematic.
   9.        ANTI-FRAUD MEASURES
   The European Medicines Agency has specific budgetary control mechanisms and procedures.
   The Management Board, which comprises representatives of the Member States, the
   Commission and the European Parliament, adopts the draft budget (Article 57.5) as well as
   the final budget (Article 57.6). The European Court of Auditors examines the execution of the
   budget each year (Article 57.9) and the Management Board gives a discharge to the Director
   regarding the budget (Article 57.10). In addition the Agency adopted on 1 June 1999 a
   decision concerning co-operation with the European Anti-Fraud Office (EMEA/D/15007/99).
   The Quality Management System applied by the Agency supports a continuous review with
   the intention of ensuring that the correct procedures are followed and that these procedures
   and policies are pertinent and efficient. Several internal audits are undertaken each year as
   part of this process.
EN                                                 55                                                EN