Europe & USA: Interactions on Pediatric Clinical Trials

1. Europe & USA:Interactions on Pediatric Clinical Trials Dr. Dianne Murphy Director, Office of Pediatric Therapeutics Office of the Commissioner, Food and Drugs Administration April, 2008

2. Overview • Differences: US legislation and EU law • Principles of Interactions between FDA and EMEA • Process and Scope of Work to Date • Scientific information exchanged and types of issues discussed • Summary

3. The European context: regulatory framework • 27 Member States:(Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxemburg, The Netherlands, Portugal, Spain, Sweden, United Kingdom, Estonia, Latvia, Lithuania, Czech Republic, Slovak Republic, Poland, Hungary, Slovenia, Malta, Cyprus, Bulgaria & Romania) • EEA countries:Norway, Iceland, Liechtenstein • Observers:Croatia, Turkey, Macedonia • EFTA Switzerland excluded • 23 languages! EMEA European Commission

5. The European context: regulatory framework • EMEA is not an FDA for Europe! • Member States have pooled their sovereignty for authorisation of medicines • EMEA coordinates the existing scientific resources of Member States • An interface with all partners • All parties linked by an IT network (EudraNet)

6. The European Regulatory Framework • EMEA’s centralized process coordinates the assessment by representatives from the member states • Approval recommendation is from an EMEA committee (CHMP) comprised of member states. (Pediatric Committee has members from the CHMP) • Approval authorization is from European Commission • Company can opt for individual country assessment & approval in certain cases

7. Differences between Europe and USA Pediatric Processes • US: Can ask for indication that does not exist in adults or not approved for marketing in adults • EU: Significant Therapeutic Benefit or Fulfilled Therapeutic need vs US Meaningful Therapeutic Benefit or Substantial number of pediatric patients.

8. Differences between Europe and USA Pediatric Processes (cont’d) • US has 2 separate triggering processes (incentive and requirement) that are only partially coordinated by a pediatric committee while Europe has 1 pediatric law. • Europe has a “centralized” procedure. All appropriate applications are submitted for review by a Pediatric Committee which addresses the studies needed for the Pediatric Investigational Plan (PIP), waivers and deferrals. • The incentive is also linked to the PIP. • In the US only those studies in response to a Written Request are eligible for the incentive

9. Differences between Europe and USA Pediatric Processes • European filing of a product for an adult indication can be denied if it does not have the required pediatric plan, waiver or deferral; not possible in US • European process is asking for more definitive information early in development process • US: Has required pediatric focused PM safety reviews with public presentation.

10. PEDIATRIC DIFFERENCES: Post-Marketing SAFETY • USA: Mandated pediatric focused review of post marketing adverse events and a public review of the data, even if the product does not have a pediatric indication (not approved but labeled) • EUROPE: If the product is not marketed for pediatrics the safety review is not obligatory

11. Principles of Interactions: EU/EMEA and FDA • Based on ICH E-11 • Pediatric patients should be given medicines that have been appropriately evaluated for their use in those populations. • Development of product information in pediatric patients should be timely. • Well-being of pediatric patients participating in clinical trials should not be compromised. • This responsibility is shared among companies, regulatory authorities, health professionals and society as a whole.

12. Principles of Interactions:EMEA and FDA • Objectives Regular exchange of scientific and ethical information on pediatric development programs in Europe and the U.S. • To avoid exposing children to unnecessary trials. • To optimize global pediatric development

13. FDA and EMEA: Process of Information Exchange • Monthly t-con to discuss product-specific pediatric development: Pediatric Investigational Plans (PIPs), Written Requests (WRs), waivers and deferrals, other development and safety activities. • Documents are exchanged through a secure link, Eudralink because the majority of the information exchanged is confidential.

14. FDA and EMEA: Scope of Information Exchanged • From August ‘07 through February ‘08: • 119 PIPs with preliminary information received • 112 PIPs for which FDA provided scientific information • 57 PIPs discussed of which 17 were in-depth or expanded scientific discussions.

15. Elements of Standard Information Exchanged: EMEA • Monthly, EMEA sends FDA an excel spreadsheet that includes the product name, active substance, formulation, approved conditions, proposed PIP indication or proposal to waive or defer pediatric studies. • Summary Reports are sent for some products that require expanded scientific discussion.

16. Elements of Standard Information: USA • Monthly, FDA sends EMEA an excel spreadsheet that includes: • the product name; • active substance; • information from the WR and, if applicable, the PREA application (including indication, types of studies, age studied, date studies are due); • approved indications;

17. Elements of Standard Information: USA (continued) • Excel spreadsheet • regulatory status (e.g. end-of-Phase 2 meeting, pre-NDA meeting, pediatric studies completed and ongoing, waivers and deferrals); • issues (e.g. clinical hold and other safety concerns)

18. Scientific Information Exchanged • Status of ongoing pediatric studies • Results of studies conducted in pediatric patients, including negative studies • Safety concerns, including clinical holds. • Plans for long-term safety monitoring. • Differences in endpoints • Differences in trial design • Differences in dosing regimen

19. Scientific Information Exchanged • Pending Written Requests • Waivers (rationale) • Deferrals (e.g. need for additional safety data in adults before initiating studies in pediatric patients) • Collaboration on conduct of pediatric studies with international sites.

20. Expanded Scientific Discussions • Type of study (e.g. placebo control vs. active control for antihypertensive agents and for treatment of multiple sclerosis) • Choice of comparator for active-controlled trials (active control may be standard of care and that may be different)

21. Expanded Scientific Discussions • Age group(s) to study (e.g. should neonates be included in the study; lower age limit for antihypertensive, cholesterol-lowering trials and topical anti-viral agents). Example: Anti-convulsant requested studies in US down to 1 month of age while EMEA proposal includes neonates. Discussion of accuracy in diagnosis of and distinguishing between types of seizures in neonates.

22. Expanded Scientific Discussions • Indications for study Example: Anti-fungal product • Differences in indication being sought by the EMEA and the FDA concerning prophylaxis vs. treatment of fungal infections. FDA had data from treatment trial studies. • FDA has flexibility in determining indication; it is not limited to indication approved in adults

23. Expanded Scientific Discussions • Choice of efficacy endpoints Examples: -For antihypertensive studies: choice of systolic blood pressure (BP), diastolic BP or mean BP as the primary endpoint for antihypertensive studies. -For oncology studies of rare tumors: choice of a single primary endpoint (complete response) or co-primary endpoints (complete response and survival)

24. Expanded Scientific Discussion • Reasons for “failed” studies Example: Treatment of migraine in adolescents- discussion of the timing of the endpoint assessment and the impact of a high placebo response rate on the ability to demonstrate a treatment effect.

25. Summary • Principles of interactions between FDA and EMEA are those of ICH E-11. • Interactions between FDA and EMEA occur monthly and the process is evolving. • The overwhelming majority of the information exchanged is confidential with documents exchanged through a secure link, Eudralink. • The goal is for global pediatric development to avoid exposing children to unnecessary trials and to benefit from each other’s experience.

26. The Future= This Special PopulationStill remains largely unstudied: many of the products go “off-patent” before we are ready to study this population