PAEDIATRIC REGULATION Good morning everyone and welcome to my presentation. Today I will speak about the pediatric regulation especially about the regulation 1901/2006 PaEDIATRIC REGULATION EC 1901/2006 WINTERGERST Delphine November the 14th

Summary Introduction The European Paediatric Regulation Paediatric Committee Paediatric Investigation Plan Marketing authorisation Rewards, incentives and penalties Conclusion First of all I will tell a short introduction. Then we will see together the provisions taked in this regulation, in particular the Paediatric Committe, the PIP, the procedures of marketing autorisation and the rewards and penalites. I will finish with a conclusion.

20% of the European population are children ⇒ 100 millions of people Introduction Paediatric population : “part of the population aged between birth and 18 years” Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006. Title 1, Chapter 1, Article 2. 20% of the European population are children ⇒ 100 millions of people Many of the medicinal products currently used to treat the paediatric population have not been studied or authorised for such use Increased risks of adverse reactions including death, ineffective treatment through under-dosage, non-availability to the paediatric population Creation of Regulation (EC) in order to develop the medicinal product for paediatric use The Paediatric population is the part of the population aged between birth and 18 years as it is described in the Article 2 of the regulation. This definition represent 20% of the European population so 100 million of people. Before 2006 many products were currently used to treat the paediatric pouplation without have been studied for such use. What’s more the off label use increased the risk of adverse reactions, inclusding deah, ineffective treatment through under-dosage or others risks. That’s why it was crucial to create a regulation in order to develop the medicinal product for paediatric use. Source: Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006. European Commission. Progress report on the paediatric regulation EC n°1901/2006. 2013.

The European Paediatric Regulation Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006 Regulation (EC) no 1901/2006 facilitate the development and accessibility of medicinal products for use in the paediatric population ensure that medicinal products used to treat the paediatric population are subject to ethical research of high quality improve the information available on the use of medicinal products in the various paediatric populations achieved objectives without subjecting the paediatric population to unnecessary clinical trials and without delaying the authorisation of medicinal products for other age populations So the regulatoin 1901/2006 was created by the European parliament and the council and published the 12 December 2006 It is Adressed to: The pharmaceutical industry The Member States The Community as funds for research into medicinal products for pediatric population The goal of this Regulation is to facilate the development and accessibility of medicinal products for paediatric use, to ensure that medicina products used to treat pediatric population are subject to ethical research of High Quality, to improve the information available on the use of this producs and then, last but not least to achieved this obejectives without delaying the other age populations. Source: Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006.

Structure of regulation (EC) no 1901/2006 Title I: Introductory provisions Title II: Marketing authorisation requirements Title III: Marketing authorisation procedures Title IV: Post-authorisation requirements Title V: Rewards and incentives Title VI: Communication and coordination Title VII: General and final provisions Now we will speak more specifically about this regulation. Forst of all, I will explain you how it is structured. In a first part we find the introduction and the definitions. Then we find the marketing autorisation requirements and procedure. Title IV we can read the article about the post-marketing requirement. In Fifth, ther is the rewards and incentives and to finish there is the communication and coordination in title VI and the general final provisions in seventh. I have tried durind this explanation to identify in all this title the most important change appeared with this regulation Source: Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006.

➡ Assessment and advice about medicinal products for paediatric use Paediatric Committee By 26 July 2007 ⇒ Creation of a Paediatric Committee within the European Medicines Agency ➡ Assessment and advice about medicinal products for paediatric use Composition of the Paediatric Committee: Article 4 Organisation of the Paediatric Committee: Article 5 Tasks of the Paediatric Committee: Article 6 Creation of a symbol (Article 6 & 32) Collect available data on all existing uses of medicinal products in the paediatric population (Article 6 & 42) Establish the inventory of therapeutic needs (Article 6 & 43) 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 (Article 6 & 44) This regulation created a new Committee by 26 july 2007 named the Paediatric Committee. It has been created in order to assess and give advice about the medicinal products for paediatric use. All the organisation and composition is described in the regulation at the article 4 and 5. The tasks of the Committed are pointed at the article 6. I noted some of interessant tasks. Creation of a symbol (Article 6 & 32) By the 26 January 2008 Collect available data on all existing uses of medicinal products in the paediatric population (Article 6 & 42) By the 26 january 2009 Establish the inventory of therapeutic needs (Article 6 & 43) By 26 January 2010 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 (Article 6 & 44) By the 26 January 2008 Source: Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006.

Paediatric Investigation Plan (PIP) « 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 » Article 2 Products which don’t need any PIP: Ineffective or unsafe drugs Drugs occurs only in adult population Not a significant therapeutic benefit over existing treatment. Article 11 ➡ Justification needed Specification of the timing and the measures proposed to assess the quality, safety and efficacy of the medicinal product in paediatric population for : Products which apply for a marketing authorisation. Article 7 Products which apply for a supplementary protection certificate. Article 8 Paediatric Products which apply for a marketing authorisation. Article 30 In the regulation we can read something really interessant : the creation of PIP. What is really a PIP ? It is a 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 as it is defined in the second article of the regulation. According to the regulation different kind of products have to submit a PIP to the Paediatric Committee: Products which apply for a marketing authorisation. Article 7 Products which apply for a supplementary protection certificate. Article 8 Paediatric Products which apply for a marketing authorisation. Article 30 The exceptions, that’s mean products which have not to create a PIP, are described in the article 11 of the regulation. Ineffective or unsafe drugs Drugs occurs only in adult population Not a significant therapeutic benefit over existing treatment. ➡ Justification needed In the schema we can see the number of PIP agreed between 2007 and 2012. They made a difference between the products submitted under article 7 or 8. Source : European Commission. Progress report on the paediatric regulation EC n°1901/2006. 2013 Source: Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006.

Time table for PIP Final decision by the Agency 10 days the Agency verify the validity of the request and prepare a summary report for the Paediatric Committee Article 16 60 days the Paediatric Committee appoint a rapporteur and adopt an opinion as to whether or not the proposed studies Article 17 Paediatric Committee negative opinion The company request for re-examination Article 25 The Paediatric Committee shall appoint a rapporteur and shall adopt a new opinion Article 25 Paediatric Committee positive opinion Final decision by the Agency 10 days In the regulation it is described the procedure of the PIP submission. I have tried to explain it on a schema. First of all, the Agency has 30 days to verify the request and prepare a summary for the paediatric Committee as it is written on the 16th article. Then the Paediatric Committee has 60 days to appoint a rapporteur and adopt an opinion on the PIP. You can find the time table of this decision in the 17th article. After this step there is two possibilitie. The first one is a positive opinion from the Paediatric Committee. The second one is a negative opinion. If we consider this last possibility, the Company has 30 days to request for a reexamination as we can read it on the 25th article. So the Paediatric Committee appoint a new rapporteur and adopt a new position in 30 days. Then in any possibility there is the final decision with is given in 10 days by the Agency. Source: Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006.

Marketing authorisation Regulation CE 26/2004, Article 5 to 15 Article 28 Products described in article 7 Directive 2001/83/CE, Article 32,33 and 34 Article 29 Products described in article 8 Article 30 Products described in article 30 After the positive opinion of a PIP, the Company could ask for a marketing autorisation or a supplementary protection certificate. The procedure that the Company could use is described in the article 28 until 30 of the regulation. Then the products described in article 7 and 30 could apply for a marketing authorisation as it is descried in the regulation CE 26/2004 in the Article 5 to 15. For the products described in article 8, the company could apply for a marketing authorisation as it is described in the directive 2001/83/Ce in the Article 32,33 and 34 After the marketing autorisation we can see different issue from the PIP: The company could apply for a marketing authorisation that includes a paediatric indication or to include a paediatric indication in an existing marketing authorisation or could apply for a paediatric use marketing authorisation. After the marketing authorisation and thanks to the PIP: Applications for a marketing authorisation that includes a paediatric indication Applications to include a paediatric indication in an existing marketing authorisation Applications for a paediatric use marketing authorisation Article 34 Source: Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006.

Rewards, incentives and penalties Six-month extension on the supplementary protection certificate granted only if the product is authorised in all Member States OR One-year extension of the period of marketing protection for the medicinal product concerned Article 36 Concerning the orphan medicinal products, the ten-year period of protection granted in the marketing authorisation is extended to twelve years. Article 37 Funds for research into medicinal products for the paediatric population is provided for in the Committee budget Article 40 Before the conclusion I just want to address the reward and penalties described and the article. As it is written on the 36th article, If the Compagny write a performant PIP, the supplementary protection certificate could be extented of six month if the product is authorised in all member states or the marketing authorisation protection could be extended of 1 year. Concerning the orphan medicinal products, the article 37th alllow an extension of the period of protection from ten to twelve years. Then the article 40th described the creation of funds for research into medicinal products for the paediatric population. In some case, some penalties could be applicate by the member state. As it is written in the article 48th, this penalties should be effective, proportionate and dissuassive. Penalties Each Member State determine the penalties to be applied for infringement of the provisions of this Regulation ➡ Penalties effective, proportionate and dissuasive. Article 48 Source: Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006.

Facilitate medicinal products for paediatric population development To Conclude Creation of a regulation for medicinal products for paediatric population ➡ Regulation (EC) no 1901/2006 Improve research and number of medicinal products for paediatric population Facilitate medicinal products for paediatric population development Ensure Safety, Efficacy and Quality of products for paediatric population To conclude we can say that the creation of a regulation for medicinal products for paediatric population was needed in Europe and that’s why they created the Regulation (EC) no 1901/2006. This regulation has allowed to improve the research and the number of medicinal products for paediatric population, to facilitate the development of the product and ensure the efficacy safety and quality of the products. To finish I would like to show you this two graphs. The first one explain the number of people working in paediatric area from 2006 until 2012. On the second one we can observe the budget contribution to the paediatric regulation. It is easy to notice that in th EU budget, the paediatric area is permently increase. Source : European Commission. Progress report on the paediatric regulation EC n°1901/2006. 2013

Thank you Any question ?