Hans Stцtter MD

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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
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• 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

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Pediatric studies by age group
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Pediatric trials by indication
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European Union ? 75 million children (20 of
total population) ? 45000 pediatricians ? 12
clinical pediatric pharmacologists ? Only limited
research unit networks and trial platforms in
Europe
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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
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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
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• 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

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• 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

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• 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

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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  Regula
tion (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 
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• 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

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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

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Incentives
Orphan Indication 102 years
Significant therapeutic benefit 1 additional
year
PUMA 10 years
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• The role of the paediatric committee (PDCO)
• The paediatric investigations plan (PIP)
• Other measures
• Timelines for implementation

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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

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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

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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
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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
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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)

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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

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APPLICANTS 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

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APPLICANTS 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
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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

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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

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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.

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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

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

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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

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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)

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

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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
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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

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Pharmacovigilance

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

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• 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

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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

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Thank you for your kind attention
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All existing paediatric data should be submitted
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