New regulation for paediatric medicinal products – issues and opportunities-

1. New regulation for paediatric medicinal products – issues and opportunities- Hans Stötter MD Internal Medicine + Oncology/Haematology Clinical Reviewer Division Prescription Drugs ATC II Head of paediatric working group Swissmedic Swissmedic Swiss Agency for Therapeutic Products Berne, Switzerland New paediatric regulation 6/2007

2. Background and history of the regulatory initiative • Incentives • The role of the paediatric committee (PDCO), the paediatric investigations plan (PIP), deferrals and waivers • Other measures • Ethics

3. Pediatric studies by age group

4. Pediatric trials by indication

9. European Union:  75 million children (=20% of total population)  45‘000 pediatricians  12 clinical pediatric pharmacologists  Only limited research unit networks and trial platforms in Europe

10. Some time ago...... ICH International conference on harmonization E11 Clinical Investigations of medicinal products in the pediatric population Step 4 on 19 July 2000 At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA Timing of studies Type of studies Age definitions

11. “Data on the appropriate use of medicinal products in the pediatric population should be generated unless the use of a specific medicinal product in pediatric patients is clearly inappropriate” “Pediatric study results should be part of the marketing application database.” “Lack of data should be justified in detail” ICH-E11

13. 1979 Labelling changes • 1994 Pediatric rule (adult extrapolated to pediatric) • 1997 FDA Modernization Act (FDAMA) • 1998 Pediatric rule (pediatric assessment required) • 1999 The Pediatric Exclusivity Provision • 2001 Status Report to Congress • 2002 Best Pharmaceuticals for Children Act (BPCA) • 2003 Pediatric Research Equity Act (PREA) • Both have a Sunset Clause 2007

14. 1997 Expert round table discussion organized by European Council • Dec 2000 Council of (Health) Minister adopted a Resolution asking the European Commission to draw up a legislative proposal • Nov 2001 Brainstorming / discussion with interested parties • February 2002 Public Consultation, November 2002 Reflection paper • December 2002 Requirement for extended impact assessment (EIA) • 2003 meetings with stakeholders and MSs (via Pharmaceutical Committee). EIA starts • March 2004, the EU Commission consulted on a draft Regulation

15. 29 September 2004, the EU Commission released the first proposal together with an explanatory memorandum, the Extended Impact Assessment and questions and answers document • 7 September 2005 following the plenary vote of the European Parliament on the Commission's proposal the Commission has responded to the parliamentary amendments in the form of a modified proposal • 9 December 2005 The Council of Health Ministers reached political agreement. The proposal went into a second reading in the European Parliament. • 1st June 2006 The Regulation was agreed on by the European Parliament

16. Official Journal of the European Union 27 December 2006 Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004  Regulation (EC) No 1902/2006 of the European Parliament and of the Council of 20 December 2006 amending Regulation 1901/2006 on medicinal products for paediatric use 

17. Since 2002 Update of the label in the SPC • Nov 2002 Extension of data protection for 5 years on request • Nov 2002 Fee reduction on request • 2004 Request for Submission of paediatric data • 2006 Updated version of the „NAS Guidance“ with request for submission of PIP and paediatric data • 2006 A request for updating the legislation is submitted

18. A • Regulatory authorities have a new responsibility • Development of medicinal products for paediatric populations is now obligatory • Together with every application for marketing authorisation (also line extension) a paediatric development plan has to be submitted. • Otherwise a marketing authorisation request is not valid

19. NAS 10y SPC + Paediatric Indication Additional 6 months PIP Transitional measure: Significant study Incentives Significant therapeutic benefit 1 additional year Orphan Indication 10+2 years PUMA 10 years

20. The role of the paediatric committee (PDCO) • The paediatric investigations plan (PIP) • Other measures • Timelines for implementation

21. PAEDIATRIC COMMITTEE • PDCO assesses the content of any PIP, waivers and deferrals (significant benefit, waiver, deferral). • Opinion within 60 days • If within a 30 day period the applicant does not request re-examination the opinion of the PDCO will become definitive • PDCO assesses compliance with the PIP • Non-compliance will be blamed

22. Paediatric investigation plan (PIP) • Research and development programme to ensure availability of data in the paediatric population • Describes any measures to adapt formulation for different subsets of the paediatric population • PIP content can be discussed with scientific advice • PIP is a dynamic process • To be agreed and/or amended by the Paediatric Committee • Without a PIP a marketing authorisation application is not valid • Approved PIP is binding

23. Content of PIP • Basis for the development and authorisation of a medicinal product for the paediatric population subsets • Include details of the timing and the measures proposed to demonstrate PK/PD, efficacy and safety • Marketing Authorisation criteria • Describes any measures to adapt formulation for different subsets of the paediatric population • Quality - Paediatric formulation • Preclinical studies - Juvenile animals • Clinical studies - PK/PD, Efficacy, Safety Details: i.e. Study design, study size, endpoints, timelines

24. PIP FORMAT AND CONTENT • Information (administrative, product) • Overall development of the product including information on the target disease(s)/condition(s) • Overall strategy for development in children • Full information expected for products primarily intended in the paediatric populations • Details of individual studies • Waiver request • Proposed timelines (and request for deferral) • References Template to be developed

25. PIP AND PAEDIATRIC SUBSETS • PIP should cover all relevant subsets of paediatric population • Combination of waivers and PIP possible according to condition, product, and significant therapeutic benefit/paediatric needs • ‘Full’ waiver would cover all subsets • NB: full waiver= no reward • Partial waiver (some subsets)

26. WHAT ARE SIGNIFICANT STUDIES? • Presence is basis for reward • Significant studies need to be completed after entry into force of Regulation If studies are already completed, they are not eligible for reward, but data are taken in account for PIP

27. APPLICANT’S REQUEST FOR PIP • Timing of submission: • for a new product: end of pharmacokinetic studies in adults (~ end of Phase I) • for variation or PUMA no legal deadline • Available information may not be complete • Possible modification of an agreed PIP • Early dialogue engaged with Scientific advice / PDCO

28. APPLICANT’S REQUEST FOR PIP PIP  deferral  Partial waiver YES PIP  deferral PIP  deferral PDCO PDCO  Partial waiver new  Partial waiver NO agreement REFUSAL Full WAIVER NB: full waiver= no reward

29. WAIVER REQUEST Based on: • Grounds based on efficacy and safety • Grounds based on disease or condition occurring only in adults population • Grounds based on lack of significant therapeutic benefit + the disease or condition, product or product class, is on the list of waivers published by EMEA

30. Neonates • Due to different body water and fat content the volume of distribution of medicinal products may vary • High body-surface-area to weight ratio • Blood-brain barrier not fully mature • Oral absorption less predictable • hepatic and renal clearance mechanisms are immature and rapidly changing

31. Requirement for Incentives - Extension of supplementary protection certificate (SPC) • MA application contains results of all measures in the agreed PIP (compliance mentioned in MA) • Significant studies completed after the entry into force of the regulation • Relevant information included in Summary of Product Characteristics • Medicinal product is authorised in all MSs • SPC extension request filed at least 2 years before expiry (transitional period of 5 years request within 6 months) • SPC has not yet been extended in the EU • Note, if data fails to lead to authorisation of paediatric indication but relevant information included in Summary of Product Characteristics – still get 6 months extension.

32. Requirement for Incentives - off patent medicines • MA application contains results of all measures in the agreed PIP (compliance mentioned in PUMA) • Medical need and significant studies completed after the entry into force of the regulation • Relevant information included in Summary of Product Characteristics • Successful clinical trials

33. Other measures • Database (EudraCT, EudraPharm) • Guidelines • Study Networks • Ethics • Pharmacovigilance

34. Efficacy Guidance EMEA • CHMP/EWP/83561/05 Guideline on Clinical Trials in Small Populations (Released for consultation March 2005) • CPMP/EWP/147013/04 Guideline on the Role of Pharmacokinetics in the Development of Medicinal Products in the Paediatric Population (Released for consultation 2/2005) • Guideline on the evaluation of the pharmacokinetics of medicinal products in the paediatric population (CPMP/EWP/968/02). Release for consultation expected 1/2Q 2006 • CPMP/EWP/422/04 Guideline on Clinical Investigation of Medicinal Products for the Treatment of Juvenile Idiopathic Arthritis (Released for consultation June 2005) • CPMP/EWP/569/02 Addendum on Paediatric Oncology (CPMP adopted July 2003) • CPMP/EWP/463/97 Note for guidance on Clinical Evaluation of  New Vaccines

35. How to avoid duplication of clinical trials More clinical trials in children expected • Publication of results also when negative (Declaration of Helsinki) • Publication of clinical trials in EUDRACT, open for everyone with respect to pediatric studies (EU Regulation) • Crosstalk between study networks (Medichildren is set up by EMEA)

37. Basic ethic principles Golombek SG Int J Pharm Med 2007; 21 (2): 121-9

38. Paediatric Study Networks • National paediatric pharmacology networks • National disease specific networks • To facilitate recruitment worldwide • Improve training and data monitoring • Infrastructure • Paediatric clinical pharmacology platform • Methodology research platform • Paediatric pharmaceutical research

39. MEDICHILDREN (EU) MCRN UK National Dutch Paediatric Pharmacotherapy Expertise Network PAED-NET Germany RIPPS France Paediatric Network Finland Paediatric Network Austria Paediatric Network Belgium Disease related Neonatology network Children Epilepsy network Renal Diseases network Oncology PRINTO Rheumatology PENTA HIV UK - CCSG CH - SPOG EU - SIOP

40. OBJECTIVES OF MEDICHILDREN • Foster paediatric research • on innovative methodology • to reduce invasiveness, number of patients • (methodological approaches, tools, biomarkers) • on formulations adapted to children • on developmental pharmacology • influence of maturation PK, PD, PK/PD • interference with pharmacogenetics

41. Pharmacovigilance • Increase Reporting of ADR by paediatricians • Capture ADR by age group • Get data on long term safety

42. Timelines for implementation of EC1901/2006 • Submission of available clinical data 26.1.2007 • Off-patent medicines 26.7.2007 • New medicines 26.7.2008 • On-patent medicines 26.7.2009

43. EU Regulation and Paediatric Drug Market Europe • A product authorized for use in children has to be marketed within 2 years after marketing authorisation has been granted • If a company wishes to withdraw a product, which has been authorised, the authority has to be notified 6 months earlier and the company has to find a new marketing holder

44. Thank you for your kind attention

45. All existing paediatric data should be submitted