Europe

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Europe USAInteractions on Pediatric Clinical
Trials

• Dr. Dianne Murphy
• Director, Office of Pediatric Therapeutics
• Office of the Commissioner,
• Food and Drugs Administration
• April, 2008

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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

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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
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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)

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The European Regulatory Framework

• EMEAs 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

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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.

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Differences between Europe and USA Pediatric
Processes (contd)

• 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

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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.

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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

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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.

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Principles of InteractionsEMEA 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

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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.

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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.
  

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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.

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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

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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)

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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

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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.

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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)

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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.

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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

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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)

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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.

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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 others experience.

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