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

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

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

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)

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

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.

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

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.

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

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.

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

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.

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.

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.

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;

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)

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

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.

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)

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.

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

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)

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.

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.

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