1. The State of Pediatric Clinical Trials in Europe A Regulatory Overview by Virinder Nohria, MD, PhD Presented at ASENT Annual Meeting Dinner Symposium Washington DC March 9, 2007 Contact Information: vnohria@aol.com; 1-828-349-0247vnohria@aol.com

2. March 09, 2007 Virinder Nohria/ASENT_Dinner 2 History of Pediatric Clinical Trials 605-562 BC - Daniel 1: 8-18 King Nebuchadnezzar II carried out the first clinical trial when he ordered that a strict diet of meat and wine be followed for three years. However, four children of royal blood convinced Nebuchadnezzar to allow them to exchange bread and water for the required meal. After only ten days, those who had switched to bread and water appeared more resplendent and well nourished than those who had stuck to wine and meat.

3. March 09, 2007 Virinder Nohria/ASENT_Dinner 3 The European Union

4. March 09, 2007 Virinder Nohria/ASENT_Dinner 4 The Paediatric Regulation  Regulation (EC) No. 1901/2006 was passed on December 12, 2006 with minor amendments on December 20, 2006  Published in the official journal of the European Union on December 27, 2006  Entered in to force on January 26, 2007

5. March 09, 2007 Virinder Nohria/ASENT_Dinner 5 Objectives of Paediatric Regulation  The regulation aims to –Stimulate the research and development of medicines for paediatric population(s) –Ensure that these products are appropriately tested and authorized –Improve the availability of information on the use of medicines in children  The above objectives should be achieved without –Any un-necessary clinical trials in children –Any delay in product authorization in other populations –Any impediment to intra-community trade

6. March 09, 2007 Virinder Nohria/ASENT_Dinner 6 Features of Paediatric Regulation  Establishment of Paediatric Committee (PDCO) with in the EMEA  Regulation will apply to –Products under development on Jan 26, 2007 –Approved products covered by IP –Products not covered by patents  Rewards and Incentives for the industry  Provision for Waivers and Deferrals

7. March 09, 2007 Virinder Nohria/ASENT_Dinner 7 The Paediatric Committee (PDCO)  Established by July 26, 2007  Will be composed of 33 members –5 members appointed by CHMP –1 member appointed by the 27 member states unless represented by the 5 above –3 members representing health professionals appointed by EC –3 members representing patient’s associations appointed by EC –Additional experts may be invited

8. March 09, 2007 Virinder Nohria/ASENT_Dinner 8 The Paediatric Committee (PDCO)  Members of the PDCO –Appointed for renewable period of 3 years –Names and qualifications will be public –Will not have any financial interests in the pharmaceutical industry –Should undertake to act in the public interest and in an independent manner –Should make an annual declaration of their financial interest

9. March 09, 2007 Virinder Nohria/ASENT_Dinner 9 PDCO – Responsibilities and Tasks  Provide scientific advice - internal and external  Assess & approve the contents of Paediatric Investigation Plan (PIP)  Assess waivers and deferrals  Assess compliance with PIP  Assess the data generated under the PIP  Approve language for inclusion in the SPC  Establish an inventory of paediatric medicinal product needs by Jan 26, 2010

10. March 09, 2007 Virinder Nohria/ASENT_Dinner 10 Paediatric Investigation Plan (PIP)  PIP should include –Measures to assess quality, safety and efficacy –Timing of investigations –Subpopulations of children –Formulation development –For approved products data from the literature may be included; or reference may be made to existing data in the dossier

11. March 09, 2007 Virinder Nohria/ASENT_Dinner 11 Obligations for the Industry  For products in development –Include results of the studies as per PIP or a waiver or deferral in the submission as of July 26, 2008 –PIP should be submitted by the end of phase I in adults unless the product is already beyond  For approved patented products –For any line extensions or new indications, new formulation or new route of administration as of Jan 26, 2009  For approved patent expired products –No obligation but Paediatric label may be sought after July 26, 2007

12. March 09, 2007 Virinder Nohria/ASENT_Dinner 12 Waivers  If products or class is likely to be in- effective or unsafe in children  Disease or condition only occurs in adults  Product does not present a significant benefit over existing products  Can be issued for one or more paediatric populations or for one or more indications

13. March 09, 2007 Virinder Nohria/ASENT_Dinner 13 Deferrals  When it is appropriate to conduct studies in adults before initiating studies in children because of safety concerns  When studies in children may take longer than in adults  May be requested at the same time as the PIP is submitted  May be requested for specific paediatric populations on technical grounds – formulation development

14. March 09, 2007 Virinder Nohria/ASENT_Dinner 14 Incentives for Industry  Free scientific advice on PIPs and other paediatric issues  Products approved for children will be identified with a special symbol  Paediatric Use Marketing Authorization (PUMA) – for products no longer patent protected

15. March 09, 2007 Virinder Nohria/ASENT_Dinner 15 Rewards for Industry  Products in Development or approved and patent protected products when PIP is followed and submission is made for approval in all member states –6-month extension of exclusivity/patent Even if the product fails to gain approval in children as long as the results of PIP studies are included in the label –Extension may be one-year if the paediatric indication brings a significant clinical benefit compared with existing therapies

16. March 09, 2007 Virinder Nohria/ASENT_Dinner 16 Rewards for Industry  Orphan designated products –Exclusivity extended from 10 to 12 years, even if the results fail to attain approval  For off-patent products – Paediatric Utilization Marketing Authorization (PUMA) –10 year data exclusivity –Continued use of the “Brand” name with “Paediatric Symbol” –May use published literature and may refer to data even if the product is only approved in one or more member state and not in the whole community

17. March 09, 2007 Virinder Nohria/ASENT_Dinner 17 Other Provisions in The Regulation  A product approved for a new paediatric indication will have to be marketed within two years of approval  Industry will be required to submit existing paediatric data to authorities  Funded EU paediatric study program “Medicines Investigation for the Children of Europe (MICE)” for off-patent medicines  Establish a EU database of paediatric studies  Establish an EU network of trial centers  Establish a robust pharmacovigilance program for long-term use of medicines in children

18. March 09, 2007 Virinder Nohria/ASENT_Dinner 18 Other Provisions in The Regulation  List of companies and products benefiting from this regulation and list of companies not compliant with obligations will be made public annually  There is provision for financial penalties for infringement of provisions of this regulation  By Jan 26, 2013 commission will present a progress report on products approved in children to the European Parliament  By Jan 26, 2017 commission will present a report to the European Parliament on the economic impact and impact on public health of this regulation

19. We are guilty of many errors and many faults, but our worst crime is abandoning the children, neglecting the fountain of life. Many of the things we need can wait. The child can not. Right now is the time his bones are being formed, his blood is being made, and his senses are being developed. To him we can not answer ‘Tomorrow’, his name is today. By Gabriela Mistral March 09, 2007 Virinder Nohria-ASENT-Dinner19