1. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Challenges in Paediatric Drug and Device Development – EU Perspectives Karl Broich Federal Institute for Drugs and Medical Devices Kurt-Georg-Kiesinger-Allee 38, D-53175 Bonn Germany

2. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Agenda Paediatric Regulation  Pharmaceutical Legislation  Paediatric Committee  Paediatric Investigation Plan  Examples Medical Devices in Paediatrics

3. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Intention of Paediatric Regulation (REGULATION (EC) No 1901/2006) 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 Community legislation on clinical trials Better medicines for children!!!

4. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC PIP opinion from PDCO for line extension (product with patent according Art. 8) Implementation of Regulation (EC) No 1901/2006 Every line extension with PIP or Waiver 26.January 2009 PIP application for products with planned EU MAA January 2007 PIP opinion from PDCO every MAA (product according Art. 7) July 2007July 2008 Every MAA with PIP or Waiver PDCO established EU Regulation 1906/2006 in force

5. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Assessment and formulation of opinions on Paediatric Investigation Plans, waivers and deferrals Consideration of whether proposed studies can be expected to be of significant therapeutic benefit and/or fulfil a therapeutic need of the paediatric population Advice on surveys regarding existing paediatric use Support of the EMA regarding the network of paediatric experts Providing advice (on request) – no fee Establishment of an inventory of paediatric needs Mandate of the Paediatric Committee (PDCO) (Regulation (EC) No 1901/2006, Art. 6)

6. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Treatment of schizophrenia 6* Treatment of bipolar I disorders Treatment of major depression: 2 Treatment of ADHD: 3 Epilepsie (all) 7 * 1 product specific waiver Paediatric Investigation Plans finalised and opinion published

7. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/pip_search.jsp&murl=menus/medicines/medicines.jsp&mid= WC0b01ac058001d129

8. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC PIPs: Treatment of schizophrenia/bipolar disorders Summary Key Principles: Waiver: below 12 years of age PK data requested Efficacy & Safety data requested with Placebo-control and active control Long-term studies (up to 2 years)

9. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Waiver: children from birth to less than 12 years of age; Study 1: Randomised, 6 weeks double blind multicentre, placebo controlled study, efficacy and safety study of paliperidone extended release tablets for the treatment of schizophrenia in adolescents. Study 2: 26 week, randomised, double blind multicentre, active controlled study, efficacy and safety study of paliperidone extended release tablets for the treatment of schizophrenia in adolescent patients. Study 3: Open label long term safety study of paliperidone in adolescents from 12 to less than 18 years of age. Treatment of schizophrenia / bipolar disorders Paliperidone/paliperidone palmitate

10. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC 2 PIPs Treatment of epilepsy with partial onset seizure Summary Key Principles: No waiver (exemptions birth to 1 months waiver) Staggered approach a)Age Birth – 2 years 2- 18 years b) therapeutic design Adjunct therapy naive patients Long term study

11. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Waiver: All subsets of the paediatric population from birth to less than 1 month years of age. Study 1 Open-label, multiple-dose study to evaluate pharmacokinetics, safety and tolerability of eslicarbazepine acetate (ESL) for partial-onset epilepsy in paediatric patients from 2 years to less than 18 years. Study 2 Double blind parallel-group, randomised placebo-controlled, multicentre, 2 part study in paediatric patients with partial-onset seizures aged from 6 years to less than 16 years to evaluate efficacy and safety, including effect on cognitive function of eslicarbazepine acetate (ESL) as adjunctive therapy with an open-label extension (48 weeks). Study 3 Double-blind, randomised, placebo-controlled, parallel-group, multi-centre trial to evaluate efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in children aged 2 years to less than 18 years with a one year open-label extension phase. Study 4 Open-label, 2 dose level trial to evaluate pharmacokinetics, safety and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in infants with refractory epilepsy with partial-onset seizures aged from 1 month to less than 2 years. Study 5 Double-blind, randomised, placebo-controlled, parallel-group, multicentre clinical trial to evaluate efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in children aged from 7 months to less than 24 months with a one year open- label extension phase. Study 6 Double-blind, randomised, placebo-controlled, parallel-group, multicentre clinical trial to evaluate safety and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in children aged from 1 month to less than 7 months with a one year open- label extension phase. Study 7 Double-blind, randomised, parallel-group, multicenter study to evaluate efficacy and safety of eslicarbazepine acetate (ESL) as monotherapy for children aged from 4 years to less than 18 years with newly diagnosed partial-onset seizures. Study 8 Open-label, multicentre study to evaluate tolerability and safety of eslicarbazepine acetate (ESL) as monotherapy for young children 1 month to 4 years with newly diagnosed partial-onset seizures. Study 9 Double blind study in paediatric epileptic subjects aged from 5 years to less than 8 years to compare the subject preference for eslicarbazepine acetate (ESL) oral suspension formulation with alternative flavours. Treatment of epilepsy with partial onset seizure Eslicarbazepine (acetate)

12. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) Enpr-EMA aims to foster high-quality ethical research on quality, safety and efficacy of medicines to be used in children. It does this through networking and stakeholder collaboration with members from within and outside the European Union (EU). Enpr-EMA's main objectives are to: –foster high-quality, ethical research on medicines for use in children; –enable collaboration between networks and and stakeholders; –co-ordinate studies relating to paediatric medicines and avoid unnecessary testing in children; –build up scientific and administrative competence at a European level; –help with the recruitment of patients for clinical trials; –promote European Commission framework programme applications. –Enpr-EMA does not perform clinical trials or fund studies or research or decide on areas for paediatric research, as this is the responsibility of Member States, the European Commission or each individual network. The European Medicines Agency is responsible for ensuring collaboration within the network.

13. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC International Cooperation The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have agreed on principles for interaction and exchange of information on paediatric matters, to foster the global development of medicines for children. Collaboration with other regulators outside the EU and with the World Health Organization (WHO) are also ongoing.

14. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Clinical Trials of Medical Devices in Children – Legal Requirements in Germany Medical Devices Act, Section 20: General prerequisites for clinical investigations Subsection 4 (excerpt): 1.The medical device must be intended for the detection or prevention of diseases in minors. 2.The use of the medical device must be indicated in accordance with scientific medical knowledge for the purpose of detecting disease in the minor or protecting the minor from disease. 3.Clinical investigations performed on adults cannot be expected to produce satisfactory test results according to scientific medical knowledge. 4.Consent is granted by the minor's legal representative or person having the care of the minor. (…)

15. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Clinical trials of medical devices in children - Legal requirements in Germany Medical Devices Act, Section 22: Procedure regarding the ethics committee Assessement of the clinical trial especially from an ethical and legal perspective Subsection 1 (excerpt): The ethics committee (…) must invite experts or solicit expert opinions in the case of a clinical investigation on minors if it does not possess its own specialist knowledge in the area of paediatrics, including the ethical and psychological questions of paediatrics.

16. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Clinical Trials of Medical Devices in Children in Germany Authorization procedure introduced by the 4th amendment of the Medical Devices Act (came into force on March, 21st 2010) Applications for authorization of a medical device clinical trial (Status: January, 1st 2012): –455 totally –266 requests for authorization –191 requests for waiving the authorization –by 214 sponsors (69 % located or represented in Germany) 6 involved children (minor subjects) –4 requests for authorization authorization –2 request for waiving the authorization

17. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC

18. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Regulation (EC) 1901/2006 Regulation (EC) 726/2004 Directive 2001/83 Clinical trials in minor & database Public database MA requirements & Information Guideline: Ethical Consideration SmPC Guideline Guidance: Public information Directive 2001/20 Commission Regulation (EC) No !41/2000 Scientific Advice (SAWP) Protocol assisstent Scientific Advice = free off charge Compliance Check Regulatory framework for Paediatrics in EU

19. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Clock stop Re- start Day 30 first Discussion at PDCO Day 60 second Discussion at PDCO Rapporteur => Day 20 Peer Reviewer => Day 28 Opinion or Liste with open issues 60 Days Day 90 third Discussion at PDCO 60 Days OE = Oral Explanation TC = Telephon Conference Day 120 Discussion and Opinion by PDCO (OE) EMEA Decision send to applicant 30 Days Day -30 PIP validated by EMA Day 61 PIP update validated by EMA Discussion at Request for Modification TC app. 90 Days PIP assessment procedure

20. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC Day 30 first Discussion at PDCO Day 60 second Discussion at PDCO Rapporteur => Day 20 Peer Reviewer => Day 28 Opinion EMA Decision send to applicant 30 Days 60 Days30 Days Day -30 PIP validated by EMA Modification of agreed PIP The PIP can/has to be modified according to e.g. new scientific data

21. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC PIP and Consequences Clinical trials appliction: Ethics Committees & national competent authority Validation of MA application – COMPLIANCE CHECK MA with SmPC & PL MA & Summary of Product Characteristics & Package leaflet Marketing authorisation (MA) application/ Validation/ compliance check EMEA/NCA *Ethics Committee & **national competent authority Evaluation of MA***-Dossier (210days) CHMP/ NCA Clinical Trials Application PDCO/PIP (60/120 days) Opinion of PDCO on PIP EMEA Decision to applicant EU-Commission oder NCA Decision on MA EC* & NCA** PDCO

22. Bundesinstitut für Arzneimittel und Medizinprodukte Joint ISCTM/ASENT Meeting, Feb. 2012, Washington, DC EMA Website on Paediatrics for further information: http://www.ema.europa.eu/ema/index.jsp?curl=pages /regulation/general/general_content_000023.jsp&mid =WC0b01ac05800240cd